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COST Action CA15203 (2016-2021): MitoEAGLE
Evolution-Age-Gender-Lifestyle-Environment: mitochondrial fitness mapping

MitoEAGLE

Summary

The objective of the MITOEAGLE network is to improve our knowledge on mitochondrial function in health and disease related to Evolution, Age, Gender, Lifestyle and Environment. Every study of mitochondrial (mt) function and disease is faced with EAGLE as the essential background conditions characterizing the individual patient, subject, study group, species, tissue or even cell line. To address the complex interrelationships of EAGLE with an initial focus on humans and rodent models, the network will enhance the value of each individual study by starting to analyse and catalog data beyond the published record. Highlighting the topic of gender and mitochondrial function, unique new information will emerge on human biology from the development of a European reference database. Protocols, technologies and standard procedures will be compared and strategies defined for improvement of quality control. An inter-laboratory ring test will be established as a world-wide innovation in the field of mitochondrial respiratory physiology. The expertise gained and new standards developed will be integrated into a strategic dissemination and education programme for mitochondrial phenotyping, aiming at an expanding European and MitoGlobal EAGLE network where researchers collaborate on mapping mitochondrial physiology and medicine, complementary to established mtDNA databases.

» e-COST:Memorandum of Understanding ~ 2016-02-26

» More details: COST Action MITOEAGLE

» Join the COST Action CA15203 MITOEAGLE

COST Action CA15203 MITOEAGLE approved

2016-02-12

We are happy to inform you that proposal OC-2015-2-19984 Mitochondrial mapping: Evolution - Age - Gender - Lifestyle - Environment was approved by the COST Committee of Senior Officials.

The European Framework COST will support trans-national cooperation and networking regarding the COST Action CA15203 MITOEAGLE for four years.

Evaluation highlights

The proposal addresses the considerable lack of uniformity and consensus on standard operating procedures in the design and implementation of research protocols involving mitochondrial physiology. This is a very real problem that can only be solved through networks on a scale such as this Action, that will work to harmonise experimental protocols across research groups.

» More details: MITOEAGLE evaluation highlights

S&T Excellence

Challenge

Main aim

Every study of mitochondrial function and disease in human tissues and cells is faced with Evolution, Age, Gender, Lifestyle and Environment (EAGLE) as essential background conditions characterizing the individual patient, subject, study group, species, tissue or – to some extent - cell line. This range of factors is too wide to be accommodated in any single project on mitochondrial respiration. Only a large and well coordinated network can manage to generate the necessary number of consistent data to address the complexity of EAGLE. The MITOEAGLE knowledge management network will be a strategic innovation to develop harmonization protocols towards generating a rigorously monitored data repository on mitochondrial respiratory function. A MITOEAGLE data management system is necessary to interrelate results of a large number of studies, to interpret pathological phenotypes, and to set results into the multidimensional context of EAGLE. Clearly, MITOEAGLE must be operated by mitochondrial specialists on a global scale. MITOEAGLE will be a gateway and milestone to better diagnose mitochondrial respiratory defects which are linked to various age-related health risks, including cardiovascular and degenerative diseases, such as type 2 diabetes, neurodegenerative diseases (Alzheimer’s, Parkinson’s, Huntington’s), and several types of cancer (Murdoch 2013 JAMA).

Relevance and timeliness

Diseases that are strongly related to a sedentary life style are spreading world-wide at an epidemic scale. Mitochondrial dysfunction is increasingly associated with the progression of such pathologies: cause or consequence? There is currently no regimented, quantitative system, or database organised to routinely test, compare and monitor mitochondrial capacities within individuals, populations, or among populations. This reflects the need for scientific innovation and represents a shortcoming in the health system of our modern, rapidly ageing society. Traditional lifestyles of ‘remote’ human populations are dwindling such that these highly significant windows into our evolutionary past are about to becoming closed, forever. While studies of mitochondrial DNA (mtDNA) have become increasingly established in the search for the evolutionary history and diversification of the human species, mitochondrial function remains comparatively unexplored, but may turn out to provide key information for preventing diseases which become prevalent upon transition to a Westernized lifestyle. The presently observed acceleration of research on cell and mitochondrial respiration represents a challenge to transform scientific information into knowledge and translate complex results on mitochondrial (dys)function into a patient-related mitochondrial score. Diagnostic standards, however, are lacking. A concerted action of the scientific community is required to implement quality control systems and optimally harmonize protocols across research groups. The primary challenge is to ‘increase value and reduce waste in research design, conduct, and analysis’, to separate the signal from the noise (Ioannidis 2005; The Lanzet 2014): ‘The signal is the truth. The noise is what distracts us from the truth’ (Silver N: The signal and the noise. The art and science of prediction. Penguin Press 2012).

Objectives

Research coordination objectives

MITOEAGLE aims at providing the first standardized measures to link mitochondrial and physiome performance (heart rate, BMI, blood pressure, blood chemistry, V_O2max) to understand the myriad of factors that play a role in mitochondrial physiology. The ambitious objective to optimally harmonize protocols across research groups cannot be achieved through projects with limited numbers of partners. Therefore, the COST framework represents an ideal instrument which allows bringing together many groups and experts in the diverse field of mitochondrial physiology. The aim of this Action is to form a unique well-coordinated network of senior researchers and young investigators, to include well established stakeholders, and to establish a spirit of mentorship and collaboration in contrast to fierce competition which characterized early decades of bioenergetics. The COST format is perfectly suited for achieving these objectives.

These objectives will be realised by using the following instruments:

1. Network meetings, workshops.
2. Working Groups (WG).
3. Short Term Scientific Missions (STSM).
4. Discussion forum and websites in order to report effectively the COST Action progress.

Members of the MITOEAGLE consortium may be active in more than one WG, thus allowing substantial crosstalk between the groups and interactions between different disciplines.

These instruments are directed towards the following aims of the MITOEAGLE COST Action:

1. Intensify the dissemination of updated knowledge and know-how among the partners;
2. Build and improve collaborative relationships among the participating groups of the Action and interested end-users;
3. Foster coordinated research activities of scientific proposals in the European Research Area;
4. Increase the number of active participants in the course of the COST Action;
5. Initiate applications for funding to support international collaborative research projects;
6. Present and publish results of collaborative research projects within the COST Action, particularly related to STSM supported by the Action.

Capacity-building objectives

• MITOEAGLE recommendations

- increase the value and reduce the noise: Enthusiastic and authentic opinion leaders can bring about a change to increase the value and reduce the noise in mitochondrial research specifically, biomedicine at large, and in our society in general. Millions of Euros are wasted on research that is lacking coherent standards. Prespecified and time-stamped protocols are needed, and researchers need to be introduced into adhering to publicly deposited protocols in practice (Begley, Ioannidis 2015). MITOEAGLE recommendations will provide practical guidelines for students, scientists and stakeholders.

• A monitored database – centres of excellence

The MITOEAGLE database will provide an invaluable tool for mitochondrial studies in the transition from exploratory preclinical research to clinical and pharmacological applications. Centres of excellence will emanate from the project’s working groups providing training programmes and diagnostic services.

• Training

Enhance the rigorous training activities particularly for PhD students and young researchers (STSM, Schools, Workshops, Conferences) in order to establish the practical guidelines introduced by MITOEAGLE and to enhance research results in the long term.

Progress beyond the state-of-the-art and innovation potential

Description of the state-of-the-art

The capacity and efficiency of energy transformation through the pathways of mitochondrial core energy metabolism represent key features of the mitochondrial phenotype. Performance parameters of oxidative phosphorylation (OXPHOS) are not available in a consistent format for cataloguing as defined ‘core variables’ and, therefore, are not represented in presently available databases. In contrast, many research groups are working on extensive documentation of genetic, epigenetic, transcriptomic, proteomic, lipidomic and metabolomic datasets in various fields of basic and clinical research, including mitochondrial medicine. Relevant techniques include next-generation sequencing to determine the genome (nDNA and mtDNA), methylome, and the transcriptome (RNA), and mass spectrometry for analysis of the proteome, lipidome, and metabolome. Such data are becoming available through various portals, some of which provide Open Access to allow researchers to use the data for their specific needs and data mining. The quality of any database is not better than the quality of the primary constituent datasets. Rigorous standards have to be applied to forge information into knowledge. Comparability of data generated by different labs on OXPHOS performance is restricted due to different laboratory protocols applied. Harmonization is clearly required along these lines, including the establishment of mitochondrial reference samples for inter-laboratory proficiency tests, and guidelines for data analysis and reporting (http://www.equator-network.org/).

Progress beyond the state-of-the-art

The COST Action MITOEAGLE aims at developing a quality management system (QMS), defining common standards for measurements in the field of mitochondrial function. The following protocols shall be defined in the course of the Action, so that the participants can finally agree on a set of well documented standard operating procedure (SOP) protocols:

1. Solution protocols: media, substrates, uncouplers, inhibitors used in SUIT protocols, permeabilization agents, etc.
2. Instrumental performance protocols
3. Mitochondrial preparation protocols, including biopsy sampling, tissue storage, cell preparation protocols, etc.
4. Respirometric OXPHOS data acquisition and analysis protocols.

The Action will elaborate definitions of fundamental terms as required by the data management system, including a review on normalization of the data (tissue mass, cell protein, mt-markers such as mt-volume, mt-protein, mt-marker enzymes, flux ratios).

A User Requirement Document will define the strategy and tools required for a MITOEAGLE database, which will be elaborated for initiation of a data repository designed to ultimately describe the linkage between the mt-phenotype and a variety of factors (Mitochondrial Fitness Mapping, Fig. 1). E in EAGLE includes genetic variables. Depending on sample selection (human studies and animal models) as well as tissues and cell types, specific SOPs are summarized for various mt-preparations (Fig. 1). Adherence to common standards is likely to increase the proportion of true findings (Ioannidis 2005; Fortier et al 2010). A data bank with harmonized datasets will advance significantly the field of human and comparative bioenergetics research and provide the level of knowledge required for helping health systems to evolve.

Innovation in tackling the challenge

Scientists may refute the challenge of comparing, optimizing and even pre-registering their protocols, when employment and assessment procedures exert stronger pressures on unhealthy competition by high-profile publication than on time-consuming quality control by collaboration. Young investigators may lack a broad perspective on methodological standards and may be reluctant to deviate from a trotten path. MITOEAGLE, however, will bring a large group of mitochondrial experts together by demonstrating the added value for each individual project, when harmonization of protocols will allow scattered data to be combined as the only means to overcome severe limitations of the traditional scientific approach (Fortier et al 2010).

• Sample size

The complexity of evolutionary background, age, gender, lifestyle and environment (EAGLE) linked to mitochondrial function cannot be addressed in the conventional small-scale studies with 20 subjects (rather than 2,000 or 200,000). To come anywhere near to large sample sizes, pooling of information between studies is essential on a global scale.

• Standardization

Rigorous standardization is the gold standard for data pooling, but may not be achievable at the present level of research in mt-physiology, where different preparation protocols, incubation media and respiratory protocols are used. Therefore, unrealistic efforts towards developing and implementing a defined standard will be replaced by a translation strategy: Major subprotocols (e.g. different respiration media) will be compared (facilitated by STSM and workshops) to allow quantitative conversion of results obtained by different groups following their specific ‘standard’ operating procedures. This will be a first evolutionary step towards harmonization and standardization.

Added value of networking

In relation to the challenge

There is no QMS commonly available in the field of mitochondrial respirometry and bioenergetics. Without networking on a large scale it is not possible to implement a widely or even generally accepted set of standards that is required for harmonization of datasets. To implement the objectives of MITOEAGLE, it is necessary to bring together a large international group of experts. Teams from 32 countries will participate in this COST Action (25: AT, BE, CH, CZ, DE, EE, ES, ET, FR, HU, IE, IT, LT, LV, NL, NO, PL, PT, RO, RS, SE, SF, SK, UK, US) or have expressed an interest in collaboration (BR, CA, IN, NZ, ZA). Among the 24 European Member States in the MITOEAGLE network, 46% are Inclusiveness target countries. Researcher mobility will be supported through staff exchanges between labs, especially Early Career Investigators who will form the next generation of team leaders for European Research in mitochondrial physiology. This large Consortium will include opinion leaders and stakeholders, who will be crucial for disseminating the developed standards (protocols, ring tests) through their contacts and networks, in a preclinical phase before advancing these standards to the level of CE and FDA certification.

In relation to existing efforts at European and/or international level

The MITOEAGLE network will operate in close contact and complementary to various European and international mitochondrial organizations. International mitochondrial societies and European bioenergetics networks are, for example:

• European Bioenergetics Conference (EBEC) organizes bi-annual conferences,
• the Mitochondrial Physiology Society (MiP) has been founded in 2003 to organize conferences and summerschools worldwide,
• the Mitochondrial European Education Training (MEET) is a project started in 2013, linking partners from 8 different countries.
• International Mito Patients is a network of national patient organizations involved in mitochondrial disease;
• DE: mitoNET - German Network for Mitochondrial Disorders;
• FR: Association Contre Les Maladies Mitochondriales;
• IT: COMETA - Coordinamento malattie metaboliche ereditarie;
• RS: The Serbian Society for Mitochondrial and Free Radical Physiology (SSMFRP) was established in 2008 as a national Society;
• UK: The Children's Mitochondrial Disease Network is the only UK charity dedicated to providing information and support for all mitochondrial disorders;
• US: The United Mitochondrial Disease Foundation (UMDF) was founded in 1996 to promote research and education for the diagnosis, treatment and cure of mitochondrial disorders.

Impact

Expected impact

Short-term and long-term scientific, technological, and/or socioeconomic impacts

The Action will build a capacity in the European Research Area and increase the reproducibility of studies in this field as well as the scientific knowledge. Networking between current and emerging groups will be initiated and sustained. This network will allow communication, exchange of ideas, and feedback between the groups involved. The research performed by the network members in the WGs will be financed independent of the COST action through local, national or international funding. MITOEAGLE will cover costs for the activities including management and meeting organization.

In the short-term perspective this COST Action will result in

1. more effective national and trans-national research systems.
2. optimal transnational cooperation and joint grant applications among the involved groups.
3. an open recruitment of Early Career Investigators for STSMs and Workshops.
4. gender balance in the Action’s research training (STSMs and in Working Groups) and membership of the Management Committee.

In the long-term perspective the involved groups may penetrate the practice in basic science in this field. With development of the quality management system (QMS), the entire research field is pushed to a new level and thus impacts are expected on the entire field and its clinical application. The most important advantages will be:

1. Added value to existing data and publications.
2. More economical research by saving resources through standardized and harmonized protocols. Measurements will not be wasted due to lack of comparability.
3. Increased quality and validity of the research.
4. New possibilities of data sharing and data mining.

Measures to maximise impact

Plan for involving the most relevant stakeholders

The MITOEAGLE consortium will emphasize the connections to established European and international mitochondrial networks, for exchange of expertise and harmonization of diagnostic approaches. Scientific societies and organizations will be approached to support the COST Action by integration of MITOEAGLE sessions into their regular conferences (Biochemical Society, FEBS, MiP Society, EUROMIT, EBEC). MITOEAGLE will encourage other research communities to join, by organizing open conferences and workshops as well as by informing about current and planned activities, and therefore increasing visibility, on the Action’s website.

Potential for innovation versus risk level

Potential for scientific, technological and/or socioeconomic innovation breakthroughs

The Action is ambitious in setting up a QMS in order to create common prospective standards and a harmonization system for post-study analysis and feeding the MITOEAGLE database. The successful completion of this COST Action will lead to a deeper understanding of the biological interactions in the field of mitochondrial function, making research in this area more effective and fruitful. However, standardizing is difficult (e.g. tissue-specific protocols) and the comparability of results obtained with different instruments might suffer from varying quality control standards. An ‘absolute‘ gold standard may remain inherently unattainable, as is the case in most fields of contemporary bioscience. Practically, the least common denominator that can be agreed upon may remain disappointingly fragmented, particularly in a large and diverse consortium involving stakeholders represented by university-based and industry-based scientists. Senior stakeholders may be biased by a commitment to their established - scientifically published or commercially sold - procedural protocols, which appear to be ‘accepted’ (by peer review) or ‘accredited’ (by revenues).

Without generous project management, a large consortium may fail by default to agree on highly specific standards. In contrast, a minimally selected consortium is bound to reach consensus, however, without any chance of impacting on the larger scientific community. Even in the case of successful establishment of the QMS and hormonization protocols, the presently available amount of matching data for any specific mitochondrial variable may be small after filtering by the QMS. The MITOEAGLE COST Action may be merely a first small (but important) step, and is certainly a project that requires extension and persistence. MITOEAGLE may be seen as too ambitious in the short term, but indispensable at large.

Implementation

Working Groups

Four Working Groups (WG) are planned to interact closely: WG1 elaborates the overall strategy, with input into Working Groups specializing on muscle tissue (WG2), fat tissue (WG3), blood cells and cultured cell lines (WG4). Feeding the data repositories, WG2-4 will implement the strategies, providing feedback to WG1, with feedforward in optimization cycles. These will lead to summaries of recommendations and a ‘Training and knowledge management concept’ (Fig. 2).

WG1

Standard operating procedures and user requirement document: Protocols, terminology, documentation

» More details: MITOEAGLE protocols, terminology, documentation

WG 2

MITOEAGLE data repository in muscle and other tissues

» More details: MITOEAGLE data: muscle

WG3

MITOEAGLE data repository on fat tissues and other tissues

» More details: MITOEAGLE data: fat

WG4

MITOEAGLE data repository for blood cells and clutured cells

» More details: MITOEAGLE data: blood and cultured cells

WG5

MITOEAGLE dissemination and training (suggested by the COST reviewers)

» More details: MITOEAGLE dissemination and training

MITOEAGLE data repositories (from WG 2-4)

1. Deposit post-hoc datasets related to articles already published on topics of WG 2-4 by Consortium members on locations accessible for the Consortium.
2. Connect published articles to deposited datasets, using generally accessible tools such as PubMed Commons (http://www.ncbi.nlm.nih.gov/pubmedcommons/).
3. Along with development of SOPs, implement advance public deposition of protocols (Begley, Ioannidis 2015).
4. Deposit datasets with submitted manuscripts and finally connect these using tools such as PubMed Commons.

Risk and contingency plans

Even in the very large consortium the availability of data, e.g. on mitochondrial respiratory function in human adipose tissue, may be limited and not yet suitable for a data repository. In this case, the consortium might decide for WG3 to (a) focus on model organisms, or (b) select a different tissue or tissues, or (c) be cancelled in favour of strengthening the other WGs. Depending on the expertise and specific interests of members in the Consortium, WG2 and WG3 may decide to include different tissues in their work plan. Later, fluctuations in the consortium may change such a focus. To secure a critical mass, additional funds may be required to achieve the goal of the Action, if additional tissues should be included (which is certainly a long-term aim beyond the Action).

Management structures and procedures

This COST Action will be coordinated by a management structure with defined goals, timelines and specialist WGs. A Management Committee (MC) will coordinate the Action and inform partners at a regular interval, prepare progress reports and manage the budget. The Action Management Committee will design a plan to initiate the activities of the four Working Groups.

The MC plays a key element regarding the coordination of this COST Action; it will direct and structure the Working Groups and define, organise and monitor the progress and the outcome of the collaborative interactions in the network continuously. The executive Board of the MC includes the coordinators of the 4 WGs. The responsibility of the Chairman will be a day-to-day management of this COST Action. He will form the network link to the Commission, will receive/disburse funds and maintain formal accounts through a Research Accountant.

MC tasks will be:

1. Appointment of the Action Chair, Vice-chair and Action evaluation;
2. establishment and maintenance of a COST website: visibility of the Action itself, conferences, workshops, dissemination of working opportunities (PhD, Postdoc positions), interactions with other scientific societies, reports;
3. planning and organizing MC meetings, scientific meetings, workshops;
4. assessment of progress reports by the different WGs, monitoring the progress of their objectives;
5. reviewing and approving STSM and Workshop applications;
6. invitation of new participants to the COST Action;
7. enforcing cooperation between the WGs;
8. preparation of reports;
9. networking to other EU programmes and stakeholders;
10. ensuring no repetition within the COST participants and with other European programmes.

MC meetings will take place at regular intervals, preferentially linked with scientific meetings. The structure of the MC meetings will be as follows: meetings in different places in Europe according to the preference of members of the COST Action. Restricted MC meetings (Chair, Vice-chairs, WG coordinators) through tele- or video-conferences will be organized between the regular MC meetings to ensure efficient coordination of the activities. Meetings will be minuted to ensure transparency. To monitor the achievements of objectives and milestones, annual reports of the WGs will be prepared and submitted to the MC. These reports will be evaluated and discussed at MC meetings and appropriate decisions will be made.

Network as a whole

The enormous interest in this COST MITOEAGLE Action underlines the necessity and "having one's finger on the puls of the time" of such a project. At this stage the Action has already secured the interest of research centres in 24 different European countries, furthermore, numerous International Partner Countries (IPCs) have indicated their interest in the Action. IPCs and Near Neighbour Countries (NNCs) are needed for the success of this Action, which tries to solve a problem of global importance. All the involved countries will benefit from this Action by increasing the scientific and financial efficacy of their research through implementing international MITOEAGLE standards. The broad geographical distribution of participating countries allows an optimum exchange of information and lays a foundation for a long-term international cooperation, going beyond the timeframe of the COST Action itself.

The COST MITOEAGLE Network comprises a high number of experienced researchers as well as ECIs, giving the latter the possibility to learn from international experts and subsequently giving them the chance to start building up their own research groups. The participating countries will profit from the active exchange that will strengthen their local research and consolidate its future.

To optimize the participation possibilities for researchers of all the involved countries, network meetings and activities will be spread across Europe. A special focus will be laid on including Inclusiveness Target Countries (46% of the countries in this Action). Interaction with other COST Actions and European as well as international programmes will be stimulated throughout the duration of the Action.

Links

• CA COST Action CA15110 - Harmonising standardisation strategies to increase efficiency and competitiveness of European life-science research

OBJECTIVE: The main objective is to avoid duplication and overlap of existing standardisation activities and to achieve a breakthrough in standardisation efforts; the Action aims to bridge, combine and team up with other initiatives. This shall be achieved through a coordinated, long-term strategy by active involvement of all stakeholders from research, industry and policy.

• National Exercise Clinical Trials Network (contact Lai Nicola)

http://www.uab.edu/medicine/exercise/nextnet

To share exercise data among the different national labs we are using redcap: http://www.project-redcap.org/

• NINDS Mitochondrial Diseases Common Data Element Project - Public Review Period: November 20, 2014 - January 16, 2015

http://www.commondataelements.ninds.nih.gov/MITO.aspx#tab=Data_Standards

• Work in progress: MiPMap

MitoFit

Meetings

Organize a series of meetings of members of the consortium with a minimum of added costs, by integrating MITOEAGLE sessions in regular meetings of established mitochondrial societies. Keep a track record for information flow to attending participants.

Satellite workshops will extend the activities of the consortium, which may lead to continuing inter-laboratory studies, development of standards for quality control and teaching initiatives to disseminate and certify such standards for quality control.

Intergration with established and developing databases

Contact organizations and research groups operating comparable genomic and physiological databases, to share their expertise. Interdisciplinary expertise is required on the design of the MITOEAGLE data base, considering the complexities of the logistic, legal and financial aspects.