K-Regio MitoFit

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K-Regio MitoFit

The project MitoFit highlights the benefits of mitochondrial fitness.
K-Regio MitoFit
* English - »German


MitoFit Science Camp in July 2016 in Kuehtai, Tyrol, Austria: Johannes Burtscher, Patrick Schaefer, Luiz Felipe Garcia e Souza, Pablo Garcia-Roves, Enrico Calzia, Stephen Dozier, Ignazio Prieto, Verena Laner, Erich Gnaiger, Devin Manning, Pedro Neves

MitoFit

MitoFit in health and preventive medicine

Physical inactivity is one of the greatest drivers of metabolic dysregulation and preventable diseases in modern societies, and has an impact on ageing populations in particular. It is becoming increasingly apparent that high and robust mitochondrial capacities are central for sustained metabolic health throughout life. Active lifestyles increase mitochondrial capacities and reduce the risk of degenerative diseases. Despite the clear role of high and efficient mitochondrial capacities in preventing metabolic diseases, promoting health and improving life quality in ageing populations, there is currently no regimented, quantitative system, or database organised to routinely test, compare and monitor mitochondrial capacities within individuals, populations, or among populations. The OROBOROS O2k - established in 46 countries - is the only instrument with sufficient stability and reliability for quantitative high-resolution respirometry (HRR). This world-leading technology offers the unique potential for developing the quality control tools required to establish the O2k as a calibrated and standardised in vitro diagnostic device. Overall, we aim to gain a CE Mark and FDA approval for the O2k, following the innovations on the level of a quality control system, and to transform this high-resolution research instrument into an essential medical device to monitor metabolic health – maintaining mitochondria fit and well to live a healthier, longer life.
MitoFit Science Camp in July 2016 in Kuehtai, Tyrol, Austria: MitoFit-training session with Stefan Moser (Sporttherapie Mag. Huber, AT)

K-Regio project MitoFit

MitoFit
The project MitoFit is funded by the Land Tirol within the program K-Regio of Standortagentur Tirol.
The K-Regio project MitoFit aims at developing novel laboratory standards and diagnostic monitoring of a mitochondrial fitness score. MitoFit will provide a signature to stimulate health tourism in the Alpine setting, introducing a scientific perspective on the benefits of mitochondrial fitness ranging from outdoor sports to quality of life and healthy ageing supported by physiotherapy.


Applicant: Medical University of Innsbruck, A.Univ.-Prof. Dr. Erich Gnaiger
Application: 2015-04-24; Granted: 2015-09-16
Project duration: 2015-05-01 to 2018-04-30
Total budget: € 1.26 Mill; financial support by Fonds Tiroler Zukunftsstiftung (LGBl. Nr. 88/1997) € 0.89 Mill.


 » MitoFit Science Camp 2016 Kuehtai AT
 » MitoFit K-Regio project report


Concept

MitoFit will provide a unique opportunity within fields of recreation, sports, wellness, lifestyle monitoring and preventive medicine programs. Collaborations with established regional initiatives will leverage on current research initiatives and established expertise in the measurement of mitochondrial function and competence. This will translate to tangible outcomes for the MitoFit concept as a marketable health, sports performance and medical diagnostic device. The establishment of the MitoFit-Knowledge Management Platform with a database reposited in the MitoFit Centre of Excellence (Fig. 1) will also provide a keystone to support the leadership of the mitochondrial monitoring instruments developed in translational research on mitochondrial competence (e.g. previous K-Regio project MitoCom) in close collaboration with local industrial partners.
The O2k-Core and O2k-Fluorometer, which are the gold standard for generating reliable quantitative respirometric data, will be the instruments of choice to build the MitoFit database. Standardized protocols developed by the MitoFit project will be streamlined for applications of the K-Regio project MitoFit. This will lead to a significant expansion of the world-wide market for the O2k, and drive the transition of the O2k from a well established specialized research tool to a standard health and biomedical instrument.
Figure 1: Structure of the MitoFit project. The development of the MitoFit- Knowledge Management Platform as an integrated module of the O2k technology system is in the centre of the project is. Strategies will be developed to pave the way towards obtaining a CE Mark (EU) and gaining regulatory approval by the Food and Drug Administration (FDA, US). Strategy development for hardware and software will be complemented by innovations in laboratory standards. A quality control system unique in the field of mitochondrial respirometry will be developed, from standardized protocols and sample preparation to the world-wide innovation of a proficiency ring test. These developments will be tested and applied in work packages introducing the MitoFit approach into the fields of lifestyle analyses based on diagnostic assays of mitochondrial function in blood cells. Health, sport and training programmes will be developed to improve mitochondrial fitness, with a focus on protective medicine, well-being and healthy ageing. The experience gained in implementing laboratory quality controls and during application developments will provide feedback into the structure and function of the MitoFit-Knowledge Management Platform.


Objectives

The objective is to achieve the transformation for the O2k from a research instrument to a medical device. The O2k is a high-end product for measuring mitochondrial function by high-resolution respirometry and is currently distributed in 44 countries world-wide. In an increasing number of cases, we are faced with demands on CE, FDA or equivalent approval for clinical diagnosis. Presently, there is no other instrument available on the market which meets such requirements. While continuing our strategy on Open innovation to maintain our technological leadership in mitochondrial respiratory research, the objective of the present project is to initiate an additional dimension of Strategic innovation towards standardization and comprehensive quality control as required for a medical device.

Technological and scientific innovation

The MitoFit-Knowledge Management Platform (KMP)
The MitoFit KMP will be developed as an integral component of the O2k-technology. It will provide the first standardized measures to link human mitochondrial health to physiome data (heart rate, BMI, blood pressure, blood chemistry, VO2max). The technological ‘sole source’ status will be systematically secured. An increasing amount of respirometric data on mitochondrial physiology is generated world-wide, enlarging the theoretically available data base at an increasing speed. However, due to lacking standards as to how results are reported, most published data are not available for quantitative meta-analysis.
Even within research groups, data from different projects have to be tediously re-analyzed for quantitative comparison. By extending O2k applications to monitoring personal mitochondrial fitness and diagnosing an increasing range of health conditions, the development of a knowledge management platform will become even more important and mandatory for considerations on CE and FDA approval. The design of the MitoFit-Data Management System will provide the conceptual framework for strategic innovations related to a quality control system for standardization of instrumental quality tests and mitochondrial reference protocols, establishment of reference samples for proficiency tests, and guidelines for data analysis and presentation. Based on a collection of data obtained through this platform, users will be able to search from pre-defined fields or through full-text search for data, documents and a variety of areas of interest. In combination with web-based collaboration tools implemented in the software, the platform will both broaden the actually available data base for all researchers and stimulate the development of research networks.
Reference sample of cryopreserved mitochondria
The development of a reference sample for respirometry will provide enormous benefits for scientific research and open up new perspectives on clinical applications, enabling a presently unattainable level of quality control in respiratory studies which will (1) increase the scientific potential of on-going and newly initiated mitochondrial studies in basic and applied research. (2) The reference sample will provide the possibility for quality control of quantitative data for direct comparison and evaluation of functional mitochondrial diagnosis on patients monitored over the timecourse of their disease and treatment, and diagnosed by different clinical laboratories. (3) A reference sample can contribute significantly to the substitution and reduction of experiments with sacrificed animals, by (a) replacing animal tissue used for training and routine quality control, or (b) for methodological development, and (c) reducing the number of artefacts in experiments with animal or human tissue by detecting methodological deficiencies in routine quality control using the reference sample.
Cryopreservation of human blood cells
Obtaining tissue biopsies for the study of mitochondrial function is an invasive approach that requires a clinician to obtain the samples under strictly sterile conditions and that usually goes along with the need to immediately use the samples for measurements. The possibility to measure mitochondrial function in human blood cells will help to overcome these limitations by allowing a far less invasive sampling procedure applicable by anyone proficient in blood drawing and by enabling the collection and storage of samples for later measurements and analysis. It will also allow the repeated sampling of the same individual, as the burden of sampling is dramatically reduced. Altogether, the advantages of using cryopreserved human blood cells for respirometry will immensely widen the applicability of respirometry for the study of human physiology and will provide a significant stimulus for the entire research field.
MitoFit proficiency test
A proficiency ring test, probing the performance of participating laboratories, will be applied using the reference samples developed in a previous step. Measuring the respiration of reference samples at two pre-defined time points and following strictly defined experimental protocols, it will be possible for the first time to evaluate and compare the proficiency of different labs and to assess the reproducibility of measurements conducted, thereby having a measure of quality control at hand. Based on the outcome of the test, individual labs may set adequate steps to improve their performance and to develop lab SOPs supporting compliance with defined standard requirements.
Current state-of-the-art
Figure 2: Substrate-uncoupler-inhibitor titration (SUIT) protocols.
A: Combined determination of oxygen consumption and H2O2 flux by O2k-Fluorometry in permeabilized HEK cells. Substrate and coupling states are shown in the upper and lower bars. Substrate states are limited to CI- and CI&II-linked respiration. From Makrecka- Kuka et al (2015).
B: Coupling/substrate control diagrams for experimental protocol design, including multiple substrate states for fatty acid oxidation, FAO (octanoylcarnitine & malate, OctM), CI-linked (addition of glutamate, G), CI&II-linked (addition of succinate, S), and CII-linked (addition of rotenone, Rot) respiration. Flux control ratios are normalized relative to ETS capacity with convergent CI&II (&FAO) electron input. Arrows 1, 2 and 3 indicate different SUIT protocols with partially overlapping respiratory states. From Gnaiger (2014).
Knowledge Management Platform
Many research groups are working on extensive documentation of genetic, epigenetic, transcriptomic, proteomic, lipidomic and metabolomic datasets in basic and clinical research, including mitochondrial medicine. Relevant techniques include next-generation sequencing to determine the genome (nDNA and mtDNA), methylome, and transcriptome (RNA), and mass spectrometry (proteome, lipidome, K-Regio: MitoFit 4 MitoFit www.mitofit.org metabolome). Such data are available online through various portals, some of which provide Open Access to allow researchers to use the data for addressing their specific interests and working hypotheses.
The capacity and efficiency of energy transformation through the mitochondrial pathways of core energy metabolism represent key features of the mitochondrial phenotype, but no corresponding data base is available for mapping mitochondrial health versus disease in humans. Performance parameters of OXPHOS are not available in a consistent format for cataloguing and, therefore, are not represented in presently available databases. Quantitative comparability of data generated by different labs on OXPHOS performance is restricted due to different protocols applied for preparing experimental solutions (solution protocols) and lack of standardization of procedure protocols including instrumental performance protocols, mitochondrial and cell preparation protocols and experimental titration protocols (SUIT protocols; Fig. 2).
With more than 280 and 150 O2k instruments sold in the EU and the US, respectively, it appears that we are not required to obtain a CE Mark or FDA clearance or approval for the O2k. However, this status will change when extending the applications from a research instrument to a medical device intended to report personal mitochondrial fitness disposition results for a wide range of health conditions, including the propensity for degenerative and other complex diseases. According to our knowledge of the available literature, the OROBOROS O2k is the only instrument on the world-wide market providing system accuracy criteria compatible with implementation of a Quality Control System for use as an In Vitro Diagnostic (IVD) device.


MitoFit Workpackages

Workpackages

WP1
» The O2k from research instrument to medical device - MitoFit-Medical device
WP2
» MitoFit-Knowledge Management Platform - MitoFit-KMP
WP3
» Laboratory standards for high-resolution respirometry: towards a QCS - MitoFit-QCS
WP4
» Reference sample: cryopreserved mitochondria - development for functional control assays - MitoFit-Reference sample
WP5
» Human blood cells as study model of mitochondrial respiration and H2O2 production - MitoFit-Bloodcells
WP6
» Development of the MitoFit proficiency test - MitoFit-PT
WP7
» Development of a sport module: high altitude sprint training - MitoFit-Sport module
WP8
» Development of a physiotherapy module: effects of physical activity on cardiovascular risk factors in middle-aged subjects - MitoFit-Physiotherapy module
WP9
» Development of a training module - MitoFit-Training module


Partners

Medical University Innsbruck MUI: Universitätsklinik für Visceral-, Transplantations- und Thoraxchirurgie, D. Swarovski Forschungslabor, DSL (Ao. Univ.-Prof. Dr. Erich Gnaiger)

https://www.i-med.ac.at/patienten/ukl_transplant-chirurgie.html

Medical University Innsbruck MUI: Biozentrum Innsbruck - Sektion für Bioinformatik, SBI (Univ.-Prof. Dr. Zlatko Trajanoski)

http://icbi.i-med.ac.at/

LF-University Innsbruck LFU: Institut für Sportwissenschaften, ISW (Univ.-Prof. DDr. Martin Burtscher, Verena Menz, Dr. Hannes Gatterer)

http://www.uibk.ac.at/isw/

OROBOROS SME: OROBOROS INSTRUMENTS GmbH, Innsbruck, ORO (Dr. Erich Gnaiger, Mag.a. Verena Laner)

http://wiki.oroboros.at/index.php/OROBOROS_INSTRUMENTS

WGT SME: WGT-Elektronik GmbH & Co KG, Kolsass, Tyrol, WGT (Philipp Gradl)

http://www.wgt.at

HLZ Kuehtai SME: Höhenleistungszentrum Betriebsg.m.b.H., Innsbruck, HLZ (Geschäftsführer Mag. Andreas Brix, Robert Valentini)

http://www.hoehentraining-kuehtai.at/

Sporttherapie Huber SME: Sporttherapie Mag. Huber GmbH, Innsbruck, STH (Mag. Reinhard Huber)

http://www.sporttherapie-huber.at

MUI = Medical University Innsbruck; LFU = Leopold-Franzens-University Innsbruck; SME = Small and medium-sized enterprise

External consultants

  • MUI: Department für Medizinische Statistik, Informatik und Gesundheitsökonomie, MSIG (Univ.-Doz. Dr. Georg Göbel)
https://www.i-med.ac.at/msig/
  • software security networks - ssn (Lukas Gradl)
http://www.ssn.at/
  • fancy tree films (Johannes Aitzetmüller)
http://www.fancytreefilms.com/
  • en.co.tec Schmid KG, Technisches Büro für Elektrotechnik (Dipl.- Ing. Martin Schmid)
http://www.encotec.at/

International strategic partners - Europe

ES Barcelona Garcia-Roves PM
DE Ulm Karabatsiakis A
SK Bratislava Sumbalova Z

International strategic partners - overseas

  • Goodpaster Bret H, Prof. Dr: Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Sanford/Burnham Institute, Orlando, FL, US
US FL Orlando Goodpaster BH
NZ Auckland Hickey AJ
  • Molina Anthony JA, PhD: J. Paul Sticht Center on Aging, Dept Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, US
US NC Winston-Salem Molina AJA
US NC Greenville Neufer PD
ZA Cape Town Ojuka EO


Becoming ‘MitoFit’ – a trend towards a new lifestyle?

With its innovative approach, MitoFit arouses a new awareness of preventive medicine, to which a physically active and calorie-balanced lifestyle can contribute significantly. Of particular importance is “healthy aging”, a generally improved quality of life and a reduced risk of a multiplicity of degenerative diseases influenced by the mitochondria: e.g. obesity, diabetes II, various forms of cancer and dementias. Mitochondrial competence will be made a reality to a larger proportion of the population and the regional identity strengthened both amongst our own population and amongst tourists through the offer of exercise-orientated leisure packages in the Alpine landscape of Tyrol.
Making our mitochondria fit – MitoFit and well – may strengthen the trend to a less sedentary, healthier and balanced lifestyle, supported by the growing evidence of the central role of mitochondrial function for an improved and prolonged quality of life.


Related projects

  1. COST Action » MITOEAGLE
  2. Tiroler Innovationsförderung » NextGen-O2k (Feb 2015 - Jan 2017)
  3. K-Regio MitoCom: » MitoCom (completed 2014)