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• Kamberov 2013 Cell  + (An adaptive variant of the human Ectodyspl … An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candidates of recent positive selection from genome-wide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in central China approximately 30,000 years ago. Although EDAR370A has been associated with increased scalp hair thickness and changed tooth morphology in humans, its direct biological significance and potential adaptive role remain unclear. We generated a knockin mouse model and find that, as in humans, hair thickness is increased in EDAR370A mice. We identify new biological targets affected by the mutation, including mammary and eccrine glands. Building on these results, we find that EDAR370A is associated with an increased number of active eccrine glands in the Han Chinese. This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans.of adaptive variation among modern humans.)
• Devaux 2015 Abstract MiP2015  + (An adequate oxygen supply is crucial for v … An adequate oxygen supply is crucial for vertebrate survival because ATP is almost exclusively produced by mitochondria though oxidative phosphorlyaltion (OXPHOS). Anoxia leads to ATP depletion and altered metabolic pathways including succinate accumulation which during re-oxygenation triggers a reverse of electron flow to CI accompanied by an enhanced deleterious reactive oxygen species (ROS) production [1]. A few species are able to survive prolonged periods of hypoxia and anoxia at tropical temperatures [2,3]. Two closely related elasmobranchs have very different adative responses to anoxia [2] while both can survive prolonged periods of anoxia the epaulette shark enters a phase of metabolic depression in response to hypoxia or anoxia while the grey carpet shark maintains its metabolic rate but releases additional red blood cells to prolong survival. Mitochondria in heart fibers from the anoxia tolerant epaulette shark maintained mitochondrial efficiency with a low ROS release in response to oxygen limitation, including anoxia [4]. The extent of mitochondrial plasticity in response to diminished oxygen (hypoxia or anoxia) and the triggers involved in this adative process are currently being investigated in our laboratories.</br></br>Our aim was to determine the response of mitochondrial complexes to elevated succinate after a bout of diminished oxygen in two closely related anoxia tolerant species. Sharks were acclimated in aerated sea-water (100L tanks) held at 22°C and were not fed 24 hours prior to sampling. Sharks were euthanised, the cerebellum isolated and homogenised in cold MiR05. Mitochondrial respiration was measured using high resolution respirometry (Oroboros Oxygraph-2k) with a SUIT protocol. Respiration flux (pmol O2 s^-1 mg^-1) was determined using DatLab 6.0 and statistical analysis were performed using SPSS™. Calculations were made to determine CI capacity, CII activation and coupling efficiency with and without a 20 min episode of anoxia followed by reoxygenation and stepwise succinate titrations (using a TIP2K microPump).ation and stepwise succinate titrations (using a TIP2K microPump).)
• Varela-Lopez 2016 J Gerontol A Biol Sci Med Sci  + (An age-dependent model of the periodontium … An age-dependent model of the periodontium was reproduced to evaluate the effect of life-long feeding on a low coenzyme Q10 dosage in n-6, n-3 polyunsaturated fatty acid or monounsaturated fatty acid-based diets on periodontal tissues of young and old rats. Results shown that exacerbated age-related alveolar bone loss previously associated to n-6 polyunsaturated fatty acid diet was attenuated by coenzyme Q10 Gene expression analysis suggests that involved mechanisms might be related to a restored capacity of mitochondria to adapt to aging in gingival cells from rats fed on n-6 polyunsaturated fatty acid. In particular, this could be due to an age-related increase of the rate of mitochondrial biogenesis and a better oxidative and respiratory balance in these animals. From the nutritional and clinical point of view, it is noteworthy that supplementation with coenzyme Q10 could counteract the negative effects of n-6 polyunsaturated fatty acid on alveolar bone loss (a major feature of periodontitis) associated to age.</br></br>© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. of The Gerontological Society of America.)
• Ye 2013 Anal Biochem  + (An approach has been developed to quantita … An approach has been developed to quantitate oxidative phosphorylation in harvested human skin fibroblasts that have been permeabilized with digitonin. In protocol 1, state 3 rates are measured with Complex I and II substrates, followed by uncoupled maximal oxidative capacity measured in the presence of these combined substrates, as well as through Complex IV. In protocol 2, state 3 rates are measured using palmitoylcarnitine to monitor fatty acid oxidation, and duroquinol to assess the flux through Complex III; uncoupled duroquinol oxidation measures maximal oxidative capacity through Complex III. The activity of citrate synthase is determined in every experiment as a marker of the amount of mitochondria per chamber. Data are expressed on the basis of cell count (per million fibroblasts), of protein, or of citrate synthase activity. Cell growth conditions are optimized and it is necessary to keep cultured cells from reaching confluency. Cultures in passages 3 to 10 show reproducible oxidative phosphorylation data. Based on the data from the 15 normal human skin fibroblast lines, we are evaluating the use of this approach to diagnose systemic mitochondrial disease and avoid issues associated with open skeletal muscle biopsy.sociated with open skeletal muscle biopsy.)
• Schrauwen-Hinderling 2015 Antioxid Redox Signal  + (An early hallmark in the development of ty … An early hallmark in the development of type 2 diabetes is the resistance to the effect of insulin in skeletal muscle and in the heart. Since mitochondrial function was found to be diminished in patients with type 2 diabetes, it was suggested that this defect might be involved in the etiology of insulin resistance. Although several hypotheses were suggested, yet unclear is the mechanistic link between these two phenomena. </br></br>Herein, we review the evidence for disturbances in mitochondrial function in skeletal muscle and the heart in the diabetic state. Also the mechanisms involved in improving mitochondrial function are considered and, whenever possible, human data is cited. Reported evidence shows that interventions that improve skeletal muscle mitochondrial function also improve insulin sensitivity in humans. In the heart, available data from animal studies suggests that enhancement of mitochondrial function can reverse aging-induced changes in heart function, and can be protective against cardiomyopathy and heart failure.</br></br>Mitochondria and their functions can be targeted with the aim of improving skeletal muscle insulin sensitivity and cardiac function. However, human clinical intervention studies are needed to fully substantiate the potential of mitochondria as a target to prevent cardiometabolic disease.target to prevent cardiometabolic disease.)
• Fuhr 2018 EBioMedicine  + (An endogenous molecular clockwork drives v … An endogenous molecular clockwork drives various cellular pathways including metabolism and the cell cycle. Its dysregulation is able to prompt pathological phenotypes including cancer. Besides dramatic metabolic alterations, cancer cells display severe changes in the clock phenotype with likely consequences in tumor progression and treatment response. In this study, we use a comprehensive systems-driven approach to investigate the effect of clock disruption on metabolic pathways and its impact on drug response in a cellular model of colon cancer progression. We identified distinctive time-related transcriptomic and metabolic features of a primary tumor and its metastatic counterpart. A mapping of the expression data to a comprehensive genome-scale reconstruction of human metabolism allowed for the in-depth functional characterization of 24 h-oscillating transcripts and pointed to a clock-driven metabolic reprogramming in tumorigenesis. In particular, we identified a set of five clock-regulated glycolysis genes, ''ALDH3A2'', ''ALDOC'', ''HKDC1'', ''PCK2'', and ''PDHB'' with differential temporal expression patterns. These findings were validated in organoids and in primary fibroblasts isolated from normal colon and colon adenocarcinoma from the same patient. We further identified a reciprocal connection of HKDC1 to the clock in the primary tumor, which is lost in the metastatic cells. Interestingly, a disruption of the core-clock gene ''BMAL1'' impacts on HKDC1 and leads to a time-dependent rewiring of metabolism, namely an increase in glycolytic activity, as well as changes in treatment response. This work provides novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and identifies new connections between both systems with pivotal roles in cancer progression and response to therapy.ancer progression and response to therapy.)
• Kang 2018 Exp Mol Med  + (An excess of reactive oxygen species (ROS) … An excess of reactive oxygen species (ROS) relative to the antioxidant capacity causes oxidative stress, which plays a role in the development of Parkinson's disease (PD). Because mitochondria are both sites of ROS generation and targets of ROS damage, the delivery of antioxidants to mitochondria might prevent or alleviate PD. To transduce the antioxidant protein human metallothionein 1A (hMT1A) into mitochondria, we computationally designed a cell-penetrating artificial mitochondria-targeting peptide (CAMP). The recombinant CAMP-conjugated hMT1A fusion protein (CAMP-hMT1A) successfully localized to the mitochondria. Treating a cell culture model of PD with CAMP-hMT1A restored tyrosine hydroxylase expression and mitochondrial activity and reduced ROS production. Furthermore, injection of CAMP-hMT1A into the brain of a mouse model of PD rescued movement impairment and dopaminergic neuronal degeneration. CAMP-hMT1A delivery into mitochondria might be therapeutic against PD by alleviating mitochondrial damage, and we predict that CAMP could be used to deliver other cargo proteins to the mitochondria. other cargo proteins to the mitochondria.)
• Greco 2003 FASEB J  + (An extensive analysis has been carried out … An extensive analysis has been carried out of mitochondrial biochemical and bioenergetic properties of fibroblasts, mostly skin-derived, from a large group of subjects ranging in age between 20 wk fetal and 103 yr. A striking age-related change observed in a fundamental process underlying mitochondrial biogenesis and function was the very significant decrease in rate of mitochondrial protein synthesis in individuals above 40 yr. The analysis of endogenous respiration rate revealed a significant decrease in the age range from 40 to 90 yr and a tendency to uncoupling in the samples from subjects above 60 yr. A surprising finding was the occurrence of a subgroup of individuals >or=90 yr old whose skin fibroblasts exhibited an exceptionally high respiration rate. This high rate was not due to respiration uncoupling, rather pointing to a compensatory phenomenon, not involving an increase in mtDNA content, in the corresponding skin fibroblast populations, or, possibly, to a selection of a different cell type secondary to more extensive dermal atrophy. The most important aging-related phenotypic effects observed were those that affected the cell oxidative phosphorylation (OX-PHOS) capacity. These were, in particular, the very significant reduction in the ratio of uncoupled to oligomycin-inhibited endogenous respiration observed in intact fibroblasts, which pointed to a decrease with donor's age in the control of respiration by the mitochondrial membrane potential, the very significant decrease in efficiency of OX-PHOS, as determined by novel in situ measurements of P:O ratios, and, consistent with these results, the very significant reduction in the respiratory control ratios. These findings clearly pointed to a dramatic mitochondrial dysfunction, which would lead to a decrease in ATP synthesis rate, with the observed decline in mitochondrial protein synthesis rate being a likely contributing factor. These observations have important implications for understanding the biology of aging, as well as the pathogenesis of aging-related degenerative diseases.nesis of aging-related degenerative diseases.)
• Sies 1997 Exp Physiol  + (An imbalance between oxidants and antioxid … An imbalance between oxidants and antioxidants in favour of the oxidants, potentially leading to damage, is termed 'oxidative stress'. Oxidants are formed as a normal product of aerobic metabolism but can be produced at elevated rates under pathophysiological conditions. Antioxidant defense involves several strategies, both enzymatic and non-enzymatic. In the lipid phase, tocopherols and carotenes as well as oxy-carotenoids are of interest, as are vitamin A and ubiquinols. In the aqueous phase, there are ascorbate, glutathione and other compounds. In addition to the cytosol, the nuclear and mitochondrial matrices and extracellular fluids are protected. Overall, these low molecular mass antioxidant molecules add significantly to the defense provided by the enzymes superoxide dismutase, catalase and glutathione peroxidases.ase, catalase and glutathione peroxidases.)
• Salin 2021 Mar Environ Res  + (An important, but underappreciated, conseq … An important, but underappreciated, consequence of climate change is the reduction in crucial nutrient production at the base of the marine food chain: the long-chain omega-3 highly unsaturated fatty acids (n-3 HUFA). This can have dramatic consequences on consumers, such as fish as they have limited capacity to synthesise n-3 HUFA ''de novo''. The n-3 HUFA, such as docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3), are critical for the structure and function of all biological membranes. There is increasing evidence that fish will be badly affected by reductions in n-3 HUFA dietary availability, however the underlying mechanisms remain obscure. Hypotheses for how mitochondrial function should change with dietary n-3 HUFA availability have generally ignored ATP production, despite its importance to a cell's total energetics capacity, and in turn, whole-animal performance. Here we (i) quantified individual variation in mitochondrial efficiency (ATP/O ratio) of muscle and (ii) examined its relationship with content in EPA and DHA in muscle membrane of a primary consumer fish, the golden grey mullet ''Chelon auratus'', receiving either a high or low n-3 HUFA diet. Mitochondria of fish fed on the low n-3 HUFA diet had higher ATP/O ratio than those of fish maintained on the high n-3 HUFA diet. Yet, mitochondrial efficiency varied up about 2-fold among individuals on the same dietary treatment, resulting in some fish consuming half the oxygen and energy substrate to produce the similar amount of ATP than conspecific on similar diet. This variation in mitochondrial efficiency among individuals from the same diet treatment was related to individual differences in fatty acid composition of the membranes: a high ATP/O ratio was associated with a high content in EPA and DHA in biological membranes. Our results highlight the existence of interindividual differences in mitochondrial efficiency and its potential importance in explaining intraspecific variation in response to food chain changes.riation in response to food chain changes.)
• Gnaiger 2015 Abstract MiP2015  + (An increasing number of metabolic and othe … An increasing number of metabolic and other diseases is recognized as being linked to mitochondrial physiology and dysfunction of oxidative phosphorylation ([[OXPHOS]]), which can be analyzed effectively and quantitatively by [[high-resolution respirometry]] (HRR). Instrumental quality control is a fundamental component of HRR applied in many laboratories [1]. Beyond the instrumental level, a standardized mt-laboratory quality management system (QMSmtf [2]) is required for establishing a global data base on mitochondrial function (mtf) in human cells and tissues, taking into account the variables of evolution, age, gender, life style and environment ([[MitoEAGLE]]). A QMSmtf requires the availability of a mt-reference sample which is functionally stable over time and across geographical space, as a basis of standard proficiency tests within and between reference laboratories. Mammalian mt-preparations (isolated mitochondria, tissue preparations) appear to be neither suitable for prolonged storage nor large scale production. Therefore, we focused on cryopreserved human cells [3]. Using the widely applied cell line HEK 293T we optimized cryopreservation to maintain cell viability and stabilize respiratory characteristics of intact and permeabilized cells over variable periods of time.</br> </br>HEK 293T cells were cultured under standard conditions with DMEM, were cryopreserved by cooling cells suspended in a freezing medium with fetal calf serum (FCS) and 10% dimethyl sulfoxide (DMSO), and stored at -80 °C for variable periods of time. Cells were thawed by addion of and careful mixing in pre-warmed PBS or MiR05. Cell counts and viability were assessed by determination of Trypan blue exclusion using an automated Countess cell counter. Respiration was measured in the Oroboros Oxygraph-2k applying standard substrate-uncoupler-inhibitor-titration ([[SUIT]]) protocols for permeabilized cells in [[MiR05]]. For HRR with intact cells, cyropreserved cells were suspended in pre-warmed DMEM. Results were compared with tests on cells cryopreserved with addition of the powerful antioxidant [[melatonin]] at 10 nM or 25 µM.[melatonin]] at 10 nM or 25 µM.)
• Doerrier 2015 Abstract MiP2015  + (An increasing number of studies point to m … An increasing number of studies point to mitochondria as key regulators of many physiological and pathological conditions, related to life style (including physical exercise and nutrition), neurodegenerative diseases, metabolic disorders, inflammatory diseases, cancer, heart failure, and aging. Moreover, mitochondria are an important source of reactive oxygen species (ROS), which are needed for cell signaling. However, an increase in ROS production generates an oxidative stress which is implicated in the pathogenesis of many diseases. In particular, the NADH redox state is related to ROS production. Succinate is a substrate of succinate dehydrogenase (CII). For analysis of mitochondrial function with CII-linked substrates, rotenone (inhibitor of CI) is added to prevent accumulation of oxaloacetate (Oa), which is a strong competitive inhibitor of CII [1]. Ischaemic accumulation of succinate has been related to mitochondrial ROS production during reperfusion by reverse electron transfer [2]. In the present study, we used succinate with and without rotenone as a model for pathophysiological mitochondrial ROS-production.</br></br>We investigated the effect of succinate (10 mM) alone, S, or succinate (10 mM) with rotenone (0.5 μM), S(Rot), on mitochondrial respiration, hydrogen peroxide (H₂O₂) production and NADH redox state in cardiac isolated mitochondria from C57BL/6 mice. Respiration media (37 °C) were optimized for the specific protocols. High-resolution respirometry (HRR) was applied with the O2k-Fluorometer (Oroboros , Innsbruck, Austria). H₂O₂ production was measured simultaneously using Amplex Ultrared [3]. NAD(P)H autofluorescence was monitored in a prototype NextGen-O2k, which combines HRR with O2k-Spectrofluorometry. Step changes of the fluorescence signal were calibrated with NADH and corrected for changes observed in chemical background tests. These methods allow analyzing simultaneously relevant bioenergetic parameters to assess mitochondrial function.</br></br>Oxygen consumption levels were similar for S and S(Rot) in the LEAK state (without adenylates). However, H₂O₂ production was substantially higher with S in LEAK state. Adding ADP (2 mM) to S(Rot) to induce OXPHOS capacity, mitochondrial respiration increased by 70%. In contrast ADP titration to S induced a decline in respiration by 30% with respect to the LEAK state, which is the so-called “succinate paradox” [4].ed a decline in respiration by 30% with respect to the LEAK state, which is the so-called “succinate paradox” [4].)
• Cagnone 2016 Sci Rep  + (An increasing number of women fail to achi … An increasing number of women fail to achieve pregnancy due to either failed fertilization or embryo arrest during preimplantation development. This often results from decreased oocyte quality. Indeed, reduced mitochondrial DNA copy number (mitochondrial DNA deficiency) may disrupt oocyte quality in some women. To overcome mitochondrial DNA deficiency, whilst maintaining genetic identity, we supplemented pig oocytes selected for mitochondrial DNA deficiency, reduced cytoplasmic maturation and lower developmental competence, with autologous populations of mitochondrial isolate at fertilization. Supplementation increased development to blastocyst, the final stage of preimplantation development, and promoted mitochondrial DNA replication prior to embryonic genome activation in mitochondrial DNA deficient oocytes but not in oocytes with normal levels of mitochondrial DNA. Blastocysts exhibited transcriptome profiles more closely resembling those of blastocysts from developmentally competent oocytes. Furthermore, mitochondrial supplementation reduced gene expression patterns associated with metabolic disorders that were identified in blastocysts from mitochondrial DNA deficient oocytes. These results demonstrate the importance of the oocyte's mitochondrial DNA investment in fertilization outcome and subsequent embryo development to mitochondrial DNA deficient oocytes.nt to mitochondrial DNA deficient oocytes.)
• Friederich 2017 Hum Mol Genet  + (An infant presented with fatal infantile l … An infant presented with fatal infantile lactic acidosis and cardiomyopathy, and was found to have profoundly decreased activity of respiratory chain complex I in muscle, heart and liver. Exome sequencing revealed compound heterozygous mutations in NDUFB10, which encodes an accessory subunit located within the PD part of complex I. One mutation resulted in a premature stop codon and absent protein, while the second mutation replaced the highly conserved cysteine 107 with a serine residue. Protein expression of NDUFB10 was decreased in muscle and heart, and less so in the liver and fibroblasts, resulting in the perturbed assembly of the holoenzyme at the 830 kDa stage. NDUFB10 was identified together with three other complex I subunits as a substrate of the intermembrane space oxidoreductase CHCHD4 (also known as Mia40). We found that during its mitochondrial import and maturation NDUFB10 transiently interacts with CHCHD4 and acquires disulfide bonds. The mutation of cysteine residue 107 in NDUFB10 impaired oxidation and efficient mitochondrial accumulation of the protein and resulted in degradation of non-imported precursors. Our findings indicate that mutations in NDUFB10 are a novel cause of complex I deficiency associated with a late stage assembly defect and emphasize the role of intermembrane space proteins for the efficient assembly of complex I.s for the efficient assembly of complex I.)
• SiouNing 2023 Molecules  + (An infectious disease is the most apprehen … An infectious disease is the most apprehensive problem in aquaculture as it can lead to high mortality in aquatic organisms and massive economic loss. Even though significant progress has been accomplished in therapeutic, prevention, and diagnostic using several potential technologies, more robust inventions and breakthroughs should be achieved to control the spread of infectious diseases. MicroRNA (miRNA) is an endogenous small non-coding RNA that post-transcriptionally regulates the protein-coding genes. It involves various biological regulatory mechanisms in organisms such as cell differentiation, proliferation, immune responses, development, apoptosis, and others. Furthermore, an miRNA also acts as a mediator to either regulate host responses or enhance the replication of diseases during infection. Therefore, the emergence of miRNAs could be potential candidates for the establishment of diagnostic tools for numerous infectious diseases. Interestingly, studies have revealed that miRNAs can be used as biomarkers and biosensors to detect diseases, and can also be used to design vaccines to attenuate pathogens. This review provides an overview of miRNA biogenesis and specifically focuses on its regulation during infection in aquatic organisms, especially on the host immune responses and how miRNAs enhance the replication of pathogens in the organism. In addition to that, we explored the potential applications, including diagnostic methods and treatments, that can be employed in the aquaculture industry.n be employed in the aquaculture industry.)
• Salvadego 2016 J Appl Physiol (1985)  + (An integrative evaluation of oxidative met … An integrative evaluation of oxidative metabolism was carried out in 9 healthy young men (age, 24.1 ± 1.7 yr mean ± SD) before (CTRL) and after a 10-day horizontal bed rest carried out in normoxia (N-BR) or hypoxia (H-BR, FiO₂ = 0.147). H-BR was designed to simulate planetary habitats. Pulmonary O₂ uptake (''V''_O2) and vastus lateralis fractional O₂ extraction (changes in deoxygenated hemoglobin+myoglobin concentration, Δ[deoxy(Hb+Mb)] evaluated using near-infrared spectroscopy) were evaluated in normoxia and during an incremental cycle ergometer (CE) and one-leg knee extension (KE) exercise (aimed at reducing cardiovascular constraints to oxidative function). Mitochondrial respiration was evaluated ''ex vivo'' by high-resolution respirometry in permeabilized vastus lateralis fibers. During CE ''V''_O2peak and Δ[deoxy(Hb+Mb)]peak were lower (''P'' < 0.05) after both N-BR and H-BR than during CTRL; during KE the variables were lower after N-BR but not after H-BR. During CE the overshoot of Δ[deoxy(Hb+Mb)] during constant work rate exercise was greater in N-BR and H-BR than CTRL, whereas during KE a significant difference vs. CTRL was observed only after N-BR. Maximal mitochondrial respiration determined ''ex vivo'' was not affected by either intervention. In N-BR, a significant impairment of oxidative metabolism occurred downstream of central cardiovascular O₂ delivery and upstream of mitochondrial function, possibly at the level of the intramuscular matching between O₂ supply and utilization and peripheral O₂ diffusion. Superposition of hypoxia on bed rest did not aggravate, and partially reversed, the impairment of muscle oxidative function ''in vivo'' induced by bed rest. The effects of longer exposures will have to be determined.</br></br>Copyright © 2016 the American Physiological Society.vivo'' induced by bed rest. The effects of longer exposures will have to be determined. Copyright © 2016 the American Physiological Society.)
• CTCM 2019 Ankara TR  + (An international symposium on cellular therapy in cardiovascular medicine (CTCM): stem cell opportunity, Ankara, Turkey, 2019)
• Boardman 2020 Am J Physiol Heart Circ Physiol  + (An ischemic insult is accompanied by an ac … An ischemic insult is accompanied by an acute increase in circulating fatty acid (FA), which can induce adverse changes related to cardiac metabolism/energetics. Although chronic hyperlipidemia contributes to the pathogenesis of obesity/diabetes-related cardiomyopathy, it unclear how these hearts are affected by an acute high FA-load. We hypothesize that adaptation to chronic FA exposure enhances the obese hearts' ability to handle an acute high FA-load. Diet-induced obese (DIO) and age-matched control (CON) mouse hearts were perfused in the presence of low or high FA-load (0.4 and 1.8 mM). Left ventricular (LV) function, FA oxidation rate, myocardial oxygen consumption and mechanical efficiency were assessed, followed by analysis of myocardial oxidative stress, mitochondrial respiration, protein acetylation as well as gene expression. Finally, ischemic tolerance was determined by examining LV functional recovery and infarct size. Under low FA conditions, DIO hearts showed mild LV dysfunction, oxygen wasting, mechanical inefficiency, and reduced mitochondrial OxPhos. High FA-load increased FA oxidation rates in both groups, but this did not alter any of the above parameters in DIO hearts. In contrast, CON hearts showed FA-induced mechanical inefficiency, oxidative stress and reduced OxPhos, as well as enhanced acetylation and activation of PPARα-dependent gene expression. While high FA-load did not alter functional recovery and infarct size in CON hearts, it increased ischemic tolerance in DIO hearts. Thus, this study demonstrates that acute FA-load affects normal and obese hearts differently, and that chronically elevated circulating FA levels render the DIO heart less vulnerable to the disadvantageous effects of an acute FA-load.sadvantageous effects of an acute FA-load.)
• Haack 2010 Nat Genet  + (An isolated defect of respiratory Complex … An isolated defect of respiratory Complex I activity is a frequent biochemical abnormality in mitochondrial disorders. Despite intensive investigation in recent years, in most instances, the molecular basis underpinning Complex I defects remains unknown. We report whole-exome sequencing of a single individual with severe, isolated Complex I deficiency. This analysis, followed by filtering with a prioritization of mitochondrial proteins, led us to identify compound heterozygous mutations in ACAD9, which encodes a poorly understood member of the mitochondrial acyl-CoA dehydrogenase protein family. We demonstrated the pathogenic role of the ACAD9 variants by the correction of the Complex I defect on expression of the wildtype ACAD9 protein in fibroblasts derived from affected individuals. ACAD9 screening of 120 additional Complex I-defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles. a total of five pathogenic ACAD9 alleles.)
• Wardle 2023 Issues Sci Technol  + (An obsession with gauging accuracy of individual posts is misguided. To strengthen information ecosystems, focus on narratives and why people share what they do.)
• Rodolphi 2017 Thesis  + (Anabolic androgenic steroids (AAS) such as … Anabolic androgenic steroids (AAS) such as nandrolone decanoate (ND) are synthetic hormones derived from testosterone. It is known that one of the most important adverse effects of abusive administration of these steroids is the increase in aggressive behavior. Evidence indicates that high doses of AAS alter morphology and cause hyperactivation of glutamatergic synapses which correlates with an aggressive exacerbated phenotype. Physiologically, glutamate is considered the main excitatory neurotransmitter in the mammalian brain. At high glutamate levels, occurs neuronal hyperexcitability mainly through the ionotropic N-methyl-d-aspartate (NMDAr) type of glutamatergic receptors and, consequently, changes in mitochondrial metabolism. Existing transporters in astrocytes predominantly perform the termination of glutamatergic excitatory signaling. In this sense, the GLT-1 glutamate astrocytic transporter is responsible for more than 90% of glutamate removal from the synaptic cleft, contributing significantly to the maintenance of glutamatergic signaling homeostasis. Administration of the β-lactam antibiotic ceftriaxone (CEF) increases GLT-1 expression and decreases glutamatergic hyperexcitability, which could potentially counteract brain mechanisms associated to increased aggressive phenotype mediated by nandrolone decanoate (ND). However, a possible molecular and behavioral interaction has not yet been explored in context. Thus, the primary objective of this work was to investigate whether increased expression of the GLT-1 astrocyte transporter modulates the glutamatergic mechanisms involved in ND-induced aggressive phenotype, and mitochondrial activity. Sixty-day-old male CF-1 mice were divided into 4 groups: oil vehicle (VEH), nandrolone (ND), ceftriaxone (CEF) and nandrolone + ceftriaxone (ND / CEF). Nandrolone was injected subcutaneously (15mg / kg) for 19 days. Ceftriaxone (200mg / kg) or saline solution were administered intraperitoneally for 5 days. After the last injection, the latency for the first attack and the number of attacks on the intruder test were evaluated. The animals were sacrificed after the test, and homogeinized cortex were used for immunoquantification of GLT-1 and phosphorylation of the NMDAr pNR2B^ser1232 subunit. Mitochondrial activity was evaluated in total brain sinaptossomes. Glutamate levels were measured in the cerebrospinal fluid. Compared to the vehicle group, treatment with ND significantly decreased the expression of GLT-1, increased glutamate levels and expression of the pNR2B^ser1232 which was mechanistically associated with an increase in the aggressive phenotype; decrease in the latency and increase in the number of attacks. Also, ND decreased mitochondrial respiratory control. Administration of CEF significantly increased GLT-1 expression and decreased glutamate levels relative to the ND group, whereas pNR2B^ser1232 levels and aggressive phenotype were similar to the control group. In the ND / CEF group the expression of GLT-1 and pNR2B^ser1232, glutamate levels and aggressive phenotype were significantly lower than in the ND group, and similar to the control group. Furthermore, CEF was able to attenuate the alteration in the mitochondrial respiratory control caused by ND. Our results demonstrated that the levels of glutamate astrocytic transporter GLT-1 and pNR2B^ser1232 are important mechanism behind the increased aggressive phenotype induced by ND, and decreased mitochondrial respiratory control. Also, this model reinforces the importance of glutamate levels and astrocytic molecular targets in the regulation of the aggressive phenotype.ce of glutamate levels and astrocytic molecular targets in the regulation of the aggressive phenotype.)
• Putzer 1985 Comp Biochem Physiol  + (Anaerobic processes were studied in ''Tubi … Anaerobic processes were studied in ''Tubifex'' and other aquatic invertebrates. After the aerobic-anoxic transition of Tubifex, succinate accumulated up to about 25 μmol/g W_d within the first hour of anoxia, but steady-state levels were established after 4hr at only 10 μmol/g W_d in an open-flow system.</br></br>Proprionate accumulated after a lag of 30 min and reached steady-state concentrations of about 30 μmol/g W_d after 5 h of anoxia.</br></br>Lactate concentrations did not increase above 4 μmol/g W_d under anoxia. Its accumulation was not induced by exposure to a blood extract, although ''Tubifex'' has the potential for lactate production.</br></br>The initial rates of glycolytic endproduct accumulation were increased in the presence of the deproteinized blood extract by 60% (succinate, 0–30 min anoxia) and by 50% and 90% (proprionate, 30–60 min anoxia; 1% and 2% blood extract, respectively). The maximum and steady state levels of these metabolites were not influenced by the hydrolysate of blood.</br></br>Aerobic and anaerobic heat dissipation of ''Lumbriculus variegatus'' was stimulated by the addition to the medium of a deproteinized hydrolysate of bovine blood. Oxygen uptake of ''Cyclops abyssorum'' increased similarly upon the addition of the blood extract under hypoxia.lops abyssorum'' increased similarly upon the addition of the blood extract under hypoxia.)
• Keys 2014 Int J Epidemiol  + (Analyses are reported on the correlation w … Analyses are reported on the correlation with height and with subcutaneous fat thickness of relative weight expressed as per cent of average weight at given height, and of the ratios weight/height, weight/height squared, and the ponderal index (cube root of weight divided by height) in 7424 ‘healthy’ men in 12 cohorts in five countries. Analyses are also reported on the relationship of those indicators of relative weight to body density in 180 young men and in 248 men aged 49–59. Judged by the criteria of correlation with height (lowest is best) and to measures of body fatness (highest is best), the ponderal index is the poorest of the relative weight indices studied. The ratio of weight to height squared, here termed the body mass index, is slightly better in these respects than the simple ratio of weight to height. The body mass index seems preferable over other indices of relative weight on these grounds as well as on the simplicity of the calculation and, in contrast to percentage of average weight, the applicability to all populations at all times.icability to all populations at all times.)
• Kuznetsov 2008 Nat Protoc  + (Analysis of mitochondrial function is cent … Analysis of mitochondrial function is central to the study of intracellular energy metabolism, mechanisms of cell death and pathophysiology of a variety of human diseases, including myopathies, neurodegenerative diseases and cancer. However, important properties of mitochondria differ ''in vivo'' and ''in vitro''. Here, we describe a protocol for the analysis of functional mitochondria ''in situ'', without the isolation of organelles, in selectively permeabilized cells or muscle fibers using digitonin or saponin. A specially designed substrate/inhibitor titration approach allows the step-by-step analysis of several mitochondrial complexes. This protocol allows the detailed characterization of functional mitochondria in their normal intracellular position and assembly, preserving essential interactions with other organelles. As only a small amount of tissue is required for analysis, the protocol can be used in diagnostic settings in clinical studies. The permeabilization procedure and specific titration analysis can be completed in 2 h.itration analysis can be completed in 2 h.)
• Doerrier 2016 Mitochondrion  + (Analysis of mitochondrial function is cruc … Analysis of mitochondrial function is crucial to understand their involvement in a given disease. High-resolution respirometry of permeabilized myocardial fibers in septic mice allows the evaluation of the bioenergetic system, maintaining mitochondrial ultrastructure and intracellular interactions, which are critical for an adequate functionality. OXPHOS and electron transport system (ET-pathway) capacities were assessed using different substrate combinations. Our findings show severe septic-dependent impairment in OXPHOS and ET capacities with mitochondrial uncoupling at early and late phases of sepsis. Moreover, sepsis triggers complex III (CIII)-linked alterations in supercomplexes structure, and loss of mitochondrial density. In these conditions, melatonin administration to septic mice prevented sepsis-dependent mitochondrial injury in mitochondrial respiration. Likewise, melatonin improved cytochrome b content and ameliorated the assembly of CIII in supercomplexes. These results support the use of permeabilized fibers to identify properly respiratory deficits and specific melatonin effects in sepsis. and specific melatonin effects in sepsis.)

• Analytica China 2020 Shanghai CN  + (Analytica China Exhibition, Shanghai, China, 2020)

• Bousseau 2019 FASEB J  + (Angiogenesis is a complex process leading … Angiogenesis is a complex process leading to the growth of new blood vessels from existing vasculature, triggered by local proangiogenic factors such as VEGF. An excess of angiogenesis is a recurrent feature of various pathologic conditions such as tumor growth. Phostines are a family of synthetic glycomimetic compounds that exhibit anticancer properties, and the lead compound 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-2λ5-[1,2]oxaphosphinane (PST 3.1a) shows antiglioblastoma properties both ''in vitro'' and ''in vivo''. In the present study, we assessed the effect of PST 3.1a on angiogenesis and endothelial metabolism. ''In vitro'', PST 3.1a (10 µM) inhibited all steps that regulate angiogenesis, including migration, proliferation, adhesion, and tube formation. ''In vivo'', PST 3.1a reduced intersegmental vessel formation and vascularization of the subintestinal plexus in zebrafish embryos and also altered pathologic angiogenesis and glioblastoma progression ''in vivo''. Mechanistically, PST 3.1a altered interaction of VEGF receptor 2 and glycosylation-regulating protein galectin-1, a key component regulating angiogenesis associated with tumor resistance. Thus, these data show that use of PST 3.1a is an innovative approach to target angiogenesis.nnovative approach to target angiogenesis.)
• Atallah 2022 Biomedicines  + (Angiogenesis is an essential process by wh … Angiogenesis is an essential process by which new blood vessels develop from existing ones. While adequate angiogenesis is a physiological process during, for example, tissue repair, insufficient and excessive angiogenesis stands on the pathological side. Fine balance between pro- and anti-angiogenic factors in the tissue environment regulates angiogenesis. Identification of these factors and how they function is a pressing topic to develop angiogenesis-targeted therapeutics. During the last decade, exciting data highlighted non-metabolic functions of intermediates of the mitochondrial Krebs cycle including succinate. Among these functions is the contribution of succinate to angiogenesis in various contexts and through different mechanisms. As the concept of targeting metabolism to treat a wide range of diseases is rising, in this review we summarize the mechanisms by which succinate regulates angiogenesis in normal and pathological settings. Gaining a comprehensive insight into how this metabolite functions as an angiogenic signal will provide a useful approach to understand diseases with aberrant or excessive angiogenic background, and may provide strategies to tackle them.and may provide strategies to tackle them.)
• Chergova 2015 Abstract MiPschool London 2015  + (Angiogenesis is the process of new blood v … Angiogenesis is the process of new blood vessel formation from preexisting vasculature [1]. Endothelial cells (ECs) are responsible for the development of the vascular plexus. This process is very active during embryonic development whereas ECs are quiescent during adulthood. Reactivation of angiogenesis is related to various pathological states such as tumor growth. Angiogenesis requires remodeling and new tissue formation and therefore a higher demand in ATP. Mitochondria are essential cell organelles with pivotal role in processes of life and death and they are the main source of ATP in the cell. Nevertheless, it has been shown that VEGF, a key pro-angiogenic factor, is involved in mitochondrial biogenesis [2]. However, the role of mitochondria in the endothelium is poorly understood. Mitochondria are extremely dynamic structures. Their morphology is modulated through processes of fusion and fission in order to fulfill their diverse functions [3]. Mitochondrial morphology is orchestrated by a number of dynamin-like GTPases. Mitochondrial fusion depends on mitofusin 1 (MFN1), mitofusin 2 (MFN2) and Optic Atrophy 1 (OPA1). DRP1 is the key regulator of mitochondrial fission. The emerging of mitochondrial function in diverse cellular processes provoked our interest to study mitochondrial dynamics and the role of DRP1 in endothelial cells during angiogenesis.</br></br>''In vitro'' we are approaching DRP1’s function in HUVEC cells (Human Umbilical Cord Endothelial Cells) under angiogenic stimulation or ablation. ''In vivo'' we will evaluate physiological angiogenesis using the mouse retinal neovascularization model [4] in the conditional endothelial knock out for DRP1.</br></br>Our results show that VEGF treatment of HUVECs decreases DRP1 levels. Parallel to this inhibition of angiogenesis by the anti-angiogenic factor 16K prolactin causes an increase of DRP1 expression. Furthermore, we evaluated angiogenesis by measuring cell migration, proliferation and permeability in HUVECs with down-regulation of DRP1 (siRNAs) and we observed an upregulation of angiogenic parameters.</br></br>Our preliminary data are suggesting a key role of mitochondrial dynamics in angiogenesis and a new function for DRP1 in endothelial cells. Our goal is to identify how pro and anti-angiogenic agents affect DRP1 and which are the molecular pathways through which DRP1 is affecting angiogenesis.ough which DRP1 is affecting angiogenesis.)
• Kivelae 2014 EMBO Mol Med  + (Angiogenic growth factors have recently be … Angiogenic growth factors have recently been linked to tissue metabolism. We have used genetic gain- and loss-of function models to elucidate the effects and mechanisms of action of vascular endothelial growth factor-B (VEGF-B) in the heart. A cardiomyocyte-specific VEGF-B transgene induced an expanded coronary arterial tree and reprogramming of cardiomyocyte metabolism. This was associated with protection against myocardial infarction and preservation of mitochondrial complex I function upon ischemia-reperfusion. VEGF-B increased VEGF signals via VEGF receptor-2 to activate Erk1/2, which resulted in vascular growth. Akt and mTORC1 pathways were upregulated and AMPK downregulated, readjusting cardiomyocyte metabolic pathways to favor glucose oxidation and macromolecular biosynthesis. However, contrasting with a previous theory, there was no difference in fatty acid uptake by the heart between the VEGF-B transgenic, gene-targeted or wildtype rats. Importantly, we also show that VEGF-B expression is reduced in human heart disease. Our data indicate that VEGF-B could be used to increase the coronary vasculature and to reprogram myocardial metabolism to improve cardiac function in ischemic heart disease.ardiac function in ischemic heart disease.)
• Vorotnikov 2022 Biomedicines  + (Angiopathy is a common complication of dia … Angiopathy is a common complication of diabetes mellitus. Vascular endothelium is among the first targets to experience blood-borne metabolic alterations, such as hyperglycemia and hyperlipidemia, the hallmarks of type 2 diabetes. To explore mechanisms of vascular dysfunction and eventual damage brought by these pathologic conditions and to find ways to protect vasculature in diabetic patients, various research approaches are used including in vitro endothelial cell-based models. We present an analysis of the data available from these models that identifies early endothelial cell apoptosis associated with oxidative stress as the major outcome of mimicking hyperglycemia and hyperlipidemia in vitro. However, the fate of endothelial cells observed in these studies does not closely follow it in vivo where massive endothelial damage occurs mainly in the terminal stages of diabetes and in conjunction with comorbidities. We propose that the discrepancy is likely in missing essentials that should be available to cultured endothelial cells to adjust the metabolic state and withstand the immediate apoptosis. We discuss the role of carnitine, creatine, and AMP-activated protein kinase (AMPK) in suiting the endothelial metabolism for long-term function in diabetic type milieu in vitro. Engagement of these essentials is anticipated to expand diabetes research options when using endothelial cell-based models. when using endothelial cell-based models.)
• Havird 2019 Mitochondrion  + (Angiosperm mitochondrial (mt) genes are ge … Angiosperm mitochondrial (mt) genes are generally slow-evolving, but multiple lineages have undergone dramatic accelerations in rates of nucleotide substitution and extreme changes in mt genome structure. While molecular evolution in these lineages has been investigated, very little is known about their mt function. Some studies have suggested altered respiration in individual taxa, although there are several reasons why mt variation might be neutral in others. Here, we develop a new protocol to characterize respiration in isolated plant mitochondria and apply it to species of ''Silene'' with mt genomes that are rapidly evolving, highly fragmented, and exceptionally large (~11 Mbp). This protocol, complemented with traditional measures of plant fitness, cytochrome c oxidase activity assays, and fluorescence microscopy, was also used to characterize inter- and intraspecific variation in mt function. Contributions of the individual "classic" OXPHOS complexes, the alternative oxidase, and external NADH dehydrogenases to overall mt respiratory flux were found to be similar to previously studied angiosperms with more typical mt genomes. Some differences in mt function could be explained by inter- and intraspecific variation. This study suggests that ''Silene'' species with peculiar mt genomes still show relatively normal mt respiration. This may be due to strong purifying selection on mt variants, coevolutionary responses in the nucleus, or a combination of both. Future experiments should explore such questions using a comparative framework and investigating other lineages with unusual mitogenomes.</br></br><small>Copyright © 2019 Elsevier B.V. and Mitochondria Research Society. All rights reserved.</small>a Research Society. All rights reserved.</small>)
• Havird 2018 bioRxiv  + (Angiosperm mitochondrial (mt) genes are ge … Angiosperm mitochondrial (mt) genes are generally slow-evolving, but multiple lineages have undergone dramatic accelerations in rates of nucleotide substitution and extreme changes in mt genome structure. While molecular evolution in these lineages has been investigated, very little is known about their mt function. Here, we develop a new protocol to characterize respiration in isolated plant mitochondria and apply it to species of ''Silene'' with mt genomes that are rapidly evolving, highly fragmented, and exceptionally large (~11 Mbp). This protocol, complemented with traditional measures of plant fitness, cytochrome c oxidase activity assays, and fluorescence microscopy, was used to characterize inter- and intraspecific variation in mt function. Contributions of the individual "classic" OXPHOS complexes, the alternative oxidase, and external NADH dehydrogenases to overall mt respiratory flux were found to be similar to previously studied angiosperms with more typical mt genomes. Some differences in mt function could be explained by inter- and intraspecific variation, possibly due to local adaptation or environmental effects. Although this study suggests that these ''Silene'' species with peculiar mt genomes still show relatively normal mt function, future experiments utilizing the protocol developed here can explore such questions in a more detailed and comparative framework.a more detailed and comparative framework.)
• Liu 2016 Apoptosis  + (Angiotensin II (AngII) is an important fac … Angiotensin II (AngII) is an important factor that promotes the proliferation of cancer cells, whereas celastrol exhibits a significant antitumor activity in various cancer models. Whether celastrol can effectively suppress AngII mediated cell proliferation remains unknown. In this study, we studied the effect of celastrol on AngII-induced HepG2 cell proliferation and evaluated its underlying mechanism. The results revealed that AngII was able to significantly promote HepG2 cell proliferation via up-regulating AngII type 1 (AT₁) receptor expression, improving mitochondrial respiratory function, enhancing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, increasing the levels of reactive oxygen species (ROS) and pro-inflammatory cytokines. The excess ROS from mitochondrial dysfunction is able to cause the apoptosis of tumor cells via activating caspase3 signal pathway. In addition, the reaction between NO and ROS results in the formation of peroxynitrite (ONOO^-), and then promoting cell damage. Celastrol dramatically enhanced ROS generation, thereby causing cell apoptosis through inhibiting mitochodrial respiratory function and boosting the expression levels of AngII type 2 (AT₂) receptor without influencing NADPH oxidase activity. PD123319 as a special inhibitor of AT2R was able to effectively decrease the levels of inflammatory cytokines and endothelial nitric oxide synthase (eNOS) activity, but only partially attenuate the effect of celastrol on AnII mediated HepG2 cell proliferation. Thus, celastrol has the potential for use in liver cancer therapy. ROS derived from mitochondrial is an important factor for celastrol to suppress HepG2 cell proliferation.ial is an important factor for celastrol to suppress HepG2 cell proliferation.)
• Menze 2009 J Biol Chem  + (Anhydrobiotic animals survive virtually co … Anhydrobiotic animals survive virtually complete loss of cellular water. The mechanisms that explain this phenomenon are not fully understood but often include the accumulation of low molecular weight solutes such as trehalose and macromolecules like Late Embryogenesis Abundant (LEA) proteins. Here we report for the first time the occurrence of a mitochondria-targeted LEA gene (Afrlea3m) product in an animal species. The deduced molecular mass of the 307-amino acid polypeptide from the brine shrimp ''Artemia franciscana'' is 34 kDa. Bioinformatic analyses reveal features typical of a Group 3 LEA protein, and subcellular localization programs predict targeting of the mature peptide to the mitochondrial matrix, based on an N-terminal, amphipathic presequence. Real-time quantitative PCR shows that ''Afralea3m'' mRNA is expressed manyfold higher in desiccation-tolerant embryonic stages when compared with intolerant nauplius larvae. Mitochondrial localization of the protein was confirmed by transfection of human hepatoma cells (HepG2/C3A) with a nucleotide construct encoding the first 70 N-terminal amino acids of ''AfrLEA3m'' in-frame with the nucleotide sequence for green fluorescence protein. The chimeric protein was readily incorporated into mitochondria of these cells. Successful targeting of a protein to human mitochondria by use of an arthropod signaling sequence clearly reveals the highly conserved nature of such presequences, as well as of the import machinery. Finally, mitochondria isolated from A. franciscana embryos, which naturally contain ''AfrLEA3m'' and trehalose, exhibit resistance to water stress (freezing) as evidenced by an unchanged capacity for oxidative phosphorylation on succinate + rotenone, a resistance that is absent in mammalian mitochondria lacking AfrLEA3m.n mammalian mitochondria lacking AfrLEA3m.)
• Zhang 2022 Mol Med Rep  + (Animal models for Parkinson's disease (PD) … Animal models for Parkinson's disease (PD) are very useful in understanding the pathogenesis of PD and screening for new therapeutic approaches. The present study compared two commonly used neurotoxin‑induced mouse models of chronic PD to guide model selection, explore the pathogenesis and mechanisms underlying PD and develop effective treatments. The chronic PD mouse models were established via treatment with rotenone or 1‑methyl‑4‑phenyl‑1,2,3,6-tetrahydropyridine (MPTP) for 6 weeks. The effects of rotenone and MPTP in the mice were compared by assessing neurobehavior, neuropathology and mitochondrial function through the use of the pole, rotarod and open field tests, immunohistochemistry for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), ionized calcium‑binding adapter molecule 1 (Iba‑1), neuronal nuclear antigen (NeuN) and (p)S129 α‑synuclein, immunofluorescence for GFAP, Iba‑1 and NeuN, western blotting for TH, oxygen consumption, complex I enzyme activity. The locomotor activity, motor coordination and exploratory behavior in both rotenone and MPTP groups were significantly lower compared with the control group. However, behavioral tests were no significant differences between the two groups. In the MPTP group, the loss of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta, the reduction of the tyrosine hydroxylase content in the SN and striatum and the astrocyte proliferation and microglial activation in the SN were more significant compared with the rotenone group. Notably, mitochondrial‑dependent oxygen consumption and complex I enzyme activity in the SN were significantly reduced in the rotenone group compared with the MPTP group. In addition, Lewy bodies were present only in SN neurons in the rotenone group. Although no significant differences in neurobehavior were observed between the two mouse models, the MPTP model reproduced the pathological features of PD more precisely in terms of the loss of DA neurons, decreased dopamine levels and neuroinflammation in the SN. On the other hand, the rotenone model was more suitable for studying the role of mitochondrial dysfunction (deficient complex I activity) and Lewy body formation in the SN, which is a characteristic pathological feature of PD. The results indicated that MPTP and rotenone PD models have advantages and disadvantages, therefore one or both should be selected based on the purpose of the study.elected based on the purpose of the study.)
• Tsilidis 2013 PLOS Biol  + (Animal studies generate valuable hypothese … Animal studies generate valuable hypotheses that lead to the conduct of preventive or therapeutic clinical trials. We assessed whether there is evidence for excess statistical significance in results of animal studies on neurological disorders, suggesting biases. We used data from meta-analyses of interventions deposited in Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies (CAMARADES). The number of observed studies with statistically significant results (O) was compared with the expected number (E), based on the statistical power of each study under different assumptions for the plausible effect size. We assessed 4,445 datasets synthesized in 160 meta-analyses on Alzheimer disease (n = 2), experimental autoimmune encephalomyelitis (n = 34), focal ischemia (n = 16), intracerebral hemorrhage (n = 61), Parkinson disease (n = 45), and spinal cord injury (n = 2). 112 meta-analyses (70%) found nominally (p≤0.05) statistically significant summary fixed effects. Assuming the effect size in the most precise study to be a plausible effect, 919 out of 4,445 nominally significant results were expected versus 1,719 observed (p<10−9). Excess significance was present across all neurological disorders, in all subgroups defined by methodological characteristics, and also according to alternative plausible effects. Asymmetry tests also showed evidence of small-study effects in 74 (46%) meta-analyses. Significantly effective interventions with more than 500 animals, and no hints of bias were seen in eight (5%) meta-analyses. Overall, there are too many animal studies with statistically significant results in the literature of neurological disorders. This observation suggests strong biases, with selective analysis and outcome reporting biases being plausible explanations, and provides novel evidence on how these biases might influence the whole research domain of neurological animal literature.rch domain of neurological animal literature.)
• Lau 2017 Dissertation  + (Animals are highly dependent on oxygen (O& … Animals are highly dependent on oxygen (O₂). The use of O₂, however, comes with both advantages and disadvantages. On one hand, O₂ is key to the process that produces chemical energy within mitochondria inside the cell, on the other hand the use of O₂ generates reactive oxygen species (ROS), which are harmful byproducts. In this thesis, I investigated these two aspects of O₂ use at mitochondria from a group of sculpin fishes that are distributed along the marine intertidal zone and are naturally exposed to daily fluctuations of O₂. I found that more hypoxia tolerant sculpins improved O₂ binding at the level of mitochondria. However, this increased O₂ binding was not associated with increased aerobic energy production, and counterintuitively, there was higher ROS generation in more hypoxia tolerant sculpins. It is possible that higher ROS generation in hypoxia tolerant sculpins is part of the strategy in surviving the O₂ variable intertidal.ssible that higher ROS generation in hypoxia tolerant sculpins is part of the strategy in surviving the O₂ variable intertidal.)
• Tian 2017 Front Genet  + (Animals that are able to sustain life unde … Animals that are able to sustain life under hypoxic conditions have long captured the imagination of biologists and medical practitioners alike. Although the associated morphological modifications have been extensively described, the mechanisms underlying the evolution of hypoxia tolerance are not well understood. To provide such insights, we investigated genes in four major energy metabolism pathways, and provide evidence of distinct evolutionary paths to mammalian hypoxia-tolerance. Positive selection of genes in the oxidative phosphorylation pathway mainly occurred in terrestrial hypoxia-tolerant species; possible adaptations to chronically hypoxic environments. The strongest candidate for positive selection along cetacean lineages was the citrate cycle signaling pathway, suggestive of enhanced aerobic metabolism during and after a dive. Six genes with cetacean-specific amino acid changes are rate-limiting enzymes involved in the gluconeogenesis pathway, which would be expected to enhance the lactate removal after diving. Intriguingly, 38 parallel amino acid substitutions in 29 genes were observed between hypoxia-tolerant mammals. Of these, 76.3% were radical amino acid changes, suggesting that convergent molecular evolution drives the adaptation to hypoxic stress and similar phenotypic changes. This study provides further insights into life under low oxygen conditions and the evolutionary trajectories of hypoxia-tolerant species. trajectories of hypoxia-tolerant species.)
• Salin 2016 J Exp Biol  + (Animals, especially ectotherms, are highly … Animals, especially ectotherms, are highly sensitive to the temperature of their surrounding environment. Extremely high temperature, for example, induces a decline of average performance of conspecifics within a population, but individual heterogeneity in the ability to cope with elevating temperatures has rarely been studied. In this study, we examined inter-individual variation in feeding ability and consequent growth rate of juvenile brown trout Salmo trutta acclimated to a high temperature (19°C), and investigated the relationship between these metrics of whole-animal performances and among-individual variation in mitochondrial respiration capacity. Food was provided ''ad libitum'' yet intake varied ten-fold amongst individuals, resulting in some fish losing weight whilst others continued to grow. Almost half of the variation in food intake was related to variability in mitochondrial capacity: low intake (and hence growth failure) was associated with high LEAK respiration rates within liver and muscle mitochondria, and a lower coupling of muscle mitochondria. These observations, combined with the inability of fish with low food consumption to increase their intake despite ''ad libitum'' food levels, suggest a possible insufficient capacity of the mitochondria for maintaining ATP homeostasis. Individual variation in thermal performance is likely to confer variation in the upper limit of an organism's thermal niche and in turn affect the structure of wild populations in warming environments.</br></br>© 2016. Published by The Company of Biologists Ltd.ublished by The Company of Biologists Ltd.)
• ESCI 2014  + (Annual Scientific Meeting of the European Society for Clinical Investigation , Utrecht, The Netherlands; [http://www.esci.eu.com/meetings/ ESCI 2014])
• Ravasz 2024 Sci Rep  + (Anoxia halts oxidative phosphorylation (OX … Anoxia halts oxidative phosphorylation (OXPHOS) causing an accumulation of reduced compounds in the mitochondrial matrix which impedes dehydrogenases. By simultaneously measuring oxygen concentration, NADH autofluorescence, mitochondrial membrane potential and ubiquinone reduction extent in isolated mitochondria in real-time, we demonstrate that Complex I utilized endogenous quinones to oxidize NADH under acute anoxia. 13C metabolic tracing or untargeted analysis of metabolites extracted during anoxia in the presence or absence of site-specific inhibitors of the electron transfer system showed that NAD+ regenerated by Complex I is reduced by the 2-oxoglutarate dehydrogenase Complex yielding succinyl-CoA supporting mitochondrial substrate-level phosphorylation (mtSLP), releasing succinate. Complex II operated amphidirectionally during the anoxic event, providing quinones to Complex I and reducing fumarate to succinate. Our results highlight the importance of quinone provision to Complex I oxidizing NADH maintaining glutamate catabolism and mtSLP in the absence of OXPHOS.bolism and mtSLP in the absence of OXPHOS.)
• Komlodi 2018b EBEC2018  + (Anoxia leads to over-reduction of mitochon … Anoxia leads to over-reduction of mitochondrial coenzyme Q (Q, quinone) pools rendering Complex I unable to oxidize NADH, leading to a profound decrease in the matrix NAD⁺/NADH ratio. As a consequence, the function of matrix dehydrogenases is impaired. Yet, under certain anoxic conditions catabolism of metabolites converging through the α-ketoglutarate dehydrogenase Complex (KGDHC) is known to occur, yielding succinyl-CoA, in turn supporting substrate-level phosphorylation substantiated by succinate-CoA ligase [1].</br></br>Mitochondrial respiration and NADH autofluorescence were measured simultaneously with the NextGen-O2k (Oroboros Instruments, Innsbruck, Austria), and the redox state of the Q-pool was detected with a three-electrode system implanted into the O2k (Oroboros Q2k).</br></br>We show that in isolated mouse liver mitochondria Complex I utilizes endogenous quinones oxidizing NADH during anoxia. Untargeted metabolomic analysis of matrix metabolites of mitochondria subjected to respiratory arrest due to anoxia and in the presence of specific inhibitors of respiratory complexes infer showed that NAD⁺ arising from Complex I is utilized by KGDHC yielding succinyl-CoA for succinate-CoA ligase, thus maintaining substrate-level phosphorylation during anoxia. Finally, by using custom-made 3D-printed plugs designed for standard fluorometric cuvettes, we show that under no conditions of respiratory arrest due to anoxia and/or pharmacological inhibition of the complexes did the mitochondria undergo swelling, which could potentially confound matrix metabolite estimations or bioenergetic parameters due to permeability transition.</br>Our results highlight the importance of the availability of quinones in conjunction with the operation of Complex I in maintaining substrate-level phosphorylation during anoxia.ex I in maintaining substrate-level phosphorylation during anoxia.)
• Ravasz 2019 Abstract IOC141  + (Anoxia leads to over-reduction of mitochon … Anoxia leads to over-reduction of mitochondrial quinone pools hampering Complex I from oxidizing NADH, leading to a profound decrease in the matrix NAD+/NADH ratio. As a consequence of this, the function of matrix dehydrogenases is impaired. Yet, under certain anoxic conditions catabolism of metabolites converging through the ketoglutarate dehydrogenase complex (KGDHC) is known to occur yielding succinyl-CoA, in turn supporting substrate-level phosphorylation substantiated by succinate-CoA ligase. Here, by measuring simultaneously oxygen partial pressure and NADH autofluorescence or quinone redox state we show that in isolated mitochondria Complex I utilizes endogenous quinones oxidizing NADH during anoxia. Untargeted metabolomic analysis of matrix metabolites of anoxic mitochondria and in the presence of ETS inhibitors inferred that NAD+ arising from Complex I is utilized by KGDHC yielding succinyl-CoA for succinate-CoA ligase, thus maintaining substrate-level phosphorylation during anoxia. The amount of endogenous quinones was estimated to be in the millimolar range and was unaffected by dietary intake of vitamin K3 (menadione). The quinone pools could be reduced by Complexes I and II and the electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) system during anoxia, exhibiting a descending order of affinity and reciprocally, increasing order of capacity. Our results highlight the importance of quinone availability in conjunction to Complex I-mediated NADH oxidation in maintaining substrate-level phosphorylation during anoxia.trate-level phosphorylation during anoxia.)
• Ravasz 2018 Abstract The evolving concept of mitochondria  + (Anoxia leads to over-reduction of mitochon … Anoxia leads to over-reduction of mitochondrial quinone pools hampering Complex I from oxidizing NADH, leading to a profound decrease in the matrix NAD+/NADH ratio. As a consequence of this, the function of matrix dehydrogenases is impaired. Yet, under certain anoxic conditions catabolism of metabolites converging through the ketoglutarate dehydrogenase Complex (KGDHC) is known to occur yielding succinyl-CoA, in turn supporting substrate-level phosphorylation substantiated by succinate-CoA ligase. Here, by measuring simultaneously oxygen partial pressure and NADH autofluorescence or quinone redox state we show that in isolated mitochondria Complex I utilizes endogenous quinones oxidizing NADH during anoxia. Untargeted metabolomic analysis of matrix metabolites of anoxic mitochondria and in the presence of ETC inhibitors inferred that NAD+ arising from Complex I is utilized by KGDHC yielding succinyl-CoA for succinate-CoA ligase, thus maintaining substrate-level phosphorylation during anoxia. The amount of endogenous quinones was estimated to be in the millimolar range and was unaffected by dietary intake of vitamin K3 (menadione). The quinone pools could be reduced by Complexes I and II and the electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) system during anoxia, exhibiting a descending order of affinity and reciprocally, increasing order of capacity. Our results highlight the importance of quinone availability in conjunction to Complex I-mediated NADH oxidation in maintaining substrate-level phosphorylation during anoxia.trate-level phosphorylation during anoxia.)
• Buck 2012 Adv Exp Med Biol  + (Anoxia rapidly elicits hyper-excitability … Anoxia rapidly elicits hyper-excitability and cell death in mammal brain but this is not so in anoxia-tolerant turtle brain where spontaneous electrical activity is suppressed by anoxia (i.e. spike arrest; SA). In anoxic turtle brain extracellular GABA concentrations increase dramatically and impact GABAergic synaptic transmission in a way that results in SA. Here we briefly review what is known about the regulation of glutamatergic signalling during anoxia and investigate the possibility that in anoxic turtle cortical neurons GABA(A/B) receptors play an important role in neuroprotection. Both AMPA and NMDA receptor currents decrease by about 50% in anoxic turtle cerebrocortex and therefore exhibit channel arrest, whereas GABA-A receptor currents increase twofold and increase whole-cell conductance. The increased post synaptic GABA-A receptor current is contrary to the channel arrest hypothesis but it does serve an important function. The reversal potential of the GABA-A receptor (E(GABA)) is only slightly depolarized relative to the resting membrane potential of the neuron and not sufficient to elicit an action potential. Therefore, when GABA-A receptors are activated, membrane potential moves to E(GABA) and prevents further depolarization by glutamatergic inputs during anoxia by a process termed shunting inhibition. Furthermore we discuss the presynaptic role of GABA-B receptors and show that increased endogenous GABA release during anoxia mediates SA by activating both GABA-A and B receptors and that this represents a natural oxygen-sensitive adaptive mechanism to protect brain from anoxic injury.anism to protect brain from anoxic injury.)
• Gnaiger 1987 Physiol Zool  + (Anoxic heat dissipation of ''Lumbriculus v … Anoxic heat dissipation of ''Lumbriculus variegatus'', as measured by direct calorimetry, is reduced by up to 85 % relative to aerobic rates. The decrease of anoxic heat dissipation and the diminution of activity peaks in the calorimetric output coincide with the disappearance of peristaltic movements under anoxia. A transfer from aerobic conditions with food to anoxia without food results in cessation of defecation when the gut is half emptied, whereas the gut is completely emptied under aerobic conditions within 6 and 8-10 h at 20 and 11 °C, respectively. The aerobic retention time of the food is independent of worm length (10-50 mm). After aerobic feeding the gut content is higher than after anoxic feeding at 6 °C. On return to aerobic conditions, heat dissipation increases immediately, whereas defecation is resumed only after a lag of 2 h. An anoxic component to the aerobic heat dissipation becomes apparent in relation to simultaneous respirometric measurements when feces accumulate in the calorimetric chamber. When the guts are completely emptied before the experiment, the theoretical oxycaloric equivalent yields an accurate estimate of heat dissipation, indicating that no significant net formation of anoxic end products occurs under aerobic conditions. Anoxic catabolism of glycogen may not fully explain the directly measured rates of heat dissipation under environmental anoxia. This has been suggested earlier for ''Lumbriculus'' and has since been confirmed for ''Tubifex'' on the basis of simultaneous calorimetric and biochemical measurements. Direct calorimetry is required to assess total rates of metabolic energy expenditure in anoxic oligochaetes.energy expenditure in anoxic oligochaetes.)
• Martinez 2013 Marine Biol  + (Antarctic fauna are highly adapted to the … Antarctic fauna are highly adapted to the frigid waters of the Southern Ocean. This study describes the ''in vitro'' temperature sensitivity of oxygen consumption rates measured in liver mitochondria from the pelagic notothenioid ''Pleuragramma antarcticum'' between 5 and 35 °C. Oxygen fluxes were measured after the addition of millimolar levels of pyruvate, malate, succinate and glutamate (LEAK) and saturating levels of ADP [oxidative phosphorylation (OXPHOS)]. OXPHOS respiration significantly decreased above 18.7 °C. A comparison of the oxidative capacities among ''P. antarcticum'' and other notothenioids showed significant differences in OXPHOS respiration, where benthic species exhibited about 50% lower OXPHOS capacities than ''P. antarcticum''. In addition, OXPHOS capacities normalized per milligram of mitochondrial protein of ''P''. antarcticum'' were up to eight times higher than those reported in the literature for other notothenioids. The comparatively high respiration rates measured in this study may be explained by our approach, which engaged both Complexes I and II under conditions of oxidative phosphorylation. OXPHOS capacities of independently activated Complexes I and II were found to range from 42 to 100% of rates obtained when both complexes were activated simultaneously in the same species. The remarkable tolerance of ''P. antarcticum'' OXPHOS toward warmer temperatures was unexpected for an Antarctic stenotherm and may indicate that thermal sensitivity of their mitochondria is not the driving force behind their stenothermy.he driving force behind their stenothermy.)
• Strobel 2013 PLoS One  + (Antarctic notothenioid fish are characteri … Antarctic notothenioid fish are characterized by their evolutionary adaptation to the cold, thermostable Southern Ocean, which is associated with unique physiological adaptations to withstand the cold and reduce energetic requirements but also entails limited compensation capacities to environmental change. This study compares the capacities of mitochondrial acclimation to ocean warming and acidification between the Antarctic nototheniid ''Notothenia rossii'' and the sub-Antarctic ''Lepidonotothen squamifrons'', which share a similar ecology, but different habitat temperatures. After acclimation of ''L. squamifrons'' to 9 °C and ''N. rossii'' to 7 °C (normocapnic/hypercapnic, 0.2 kPa CO2/2000 ppm CO2) for 4-6 weeks, we compared the capacities of their mitochondrial respiratory complexes I (CI) and II (CII), their P/O ratios (phosphorylation efficiency), proton leak capacities and mitochondrial membrane fatty acid compositions. Our results reveal reduced CII respiration rates in warm-acclimated ''L. squamifrons'' and cold hypercapnia-acclimated ''N. rossii''. Generally, ''L. squamifrons'' displayed a greater ability to increase CI contribution during acute warming and after warm-acclimation than N. rossii. Membrane unsaturation was not altered by warm or hypercapnia-acclimation in both species, but membrane fatty acids of warm-acclimated ''L. squamifrons'' were less saturated than in warm normocapnia-/hypercapnia-acclimated ''N. rossii''. Proton leak capacities were not affected by warm or hypercapnia-acclimation of ''N. rossii''. We conclude that an acclimatory response of mitochondrial capacities may include higher thermal plasticity of CI supported by enhanced utilization of anaplerotic substrates (via oxidative decarboxylation reactions) feeding into the citrate cycle. ''L. squamifrons'' possesses higher relative CI plasticities than N. rossii, which may facilitate the usage of energy efficient NADH-related substrates under conditions of elevated energy demand, possibly induced by ocean warming and acidification. The observed adjustments of electron transport system complexes with a higher flux through CI under warming and acidification suggest a metabolic acclimation potential of the sub-Antarctic ''L. squamifrons'', but only limited acclimation capacities for ''N. rossii''. acclimation capacities for ''N. rossii''.)
• Skemiene 2020 J Bioenerg Biomembr  + (Anthocyanins are considered as bioactive c … Anthocyanins are considered as bioactive components of plant-based diets that provide protection against ischemic cardiovascular pathologies by mechanisms dependent on their antioxidant and reductive capacities. However, it is not clear whether similar anthocyanin-mediated mechanisms can provide protection against ischemia-induced brain mitochondrial injury and cell death. In this study, we compared effects of three cyanidin-3-glycosides - glucoside (Cy3G), galactoside (Cy3Gal) and rutinoside (Cy3R), with pelargonxidin-3-glucoside (Pg3G) and found that at 10-20 μM concentrations they have no direct effect on respiratory functions of mitochondria isolated from normal or ischemia-damaged rat brain slices. However, intravenous injection of Cy3Gal and Cy3G (0,025 mg/kg or 0,05 mg/kg what matches 10 μM or 20 μM respectively) but not Cy3R in rats protected against ischemia-induced caspase activation and necrotic cell death, and reduced infarct size in cerebral cortex and cerebellum. These effects correlated with cytochrome c reducing capacity of cyanidin-3-glycosides. In contrast, intravenous injection of 0,025 mg/kg Pg3G which has the lowest cytochrome c reducing capacity among investigated anthocyanins, had no effect on ischemia-induced caspase activation and necrosis but reduced brain infarct size whereas intravenous injection of 0,05 mg/kg of Pg3G slightly promoted necrosis in the brain. Our data suggest that reductive rather than antioxidant capacities of anthocyanins may be important components in providing protection against ischemic brain damage. protection against ischemic brain damage.)
• Skemiene 2015 FEBS J  + (Anthocyanins, a subclass of flavonoids, ar … Anthocyanins, a subclass of flavonoids, are known to protect against myocardial ischemia; however, little is known about their direct, acute effects on mitochondria injured by the ischemic insult. In this study, the effects of delphinidin 3-O-glucoside (Dp3G), cyanidin 3-O-glucoside (Cy3G) and pelargonidin 3-O-glucoside (Pg3G) on the activity of complex I of the mitochondrial respiratory chain were studied in mitochondria isolated from normal rat hearts and rat hearts subjected to ischemia for 45 min. Cy3G and Dp3G increased the activity of complex I, measured in the presence or absence of coenzyme Q¹ (CoQ¹ ), in ischemia-damaged mitochondria, whereas in nonischemic mitochondria the effect was observed only in the absence of CoQ¹. Dp3G and Cy3G but not Pg3G increased state 3 respiration and ATP synthesis with NADH-dependent substrates in mitochondria after ischemia. The results suggest that certain anthocyanins can act as electron acceptors at complex I, and bypass ischemia-induced inhibition, resulting in increased ATP production after ischemia. This study provides new information on a possible role of certain anthocyanins in the regulation of energy metabolism in mammalian cells.ertain anthocyanins in the regulation of energy metabolism in mammalian cells.)