Variability in mitochondrial genetics and functionality and its cell physiological effects

Lead Research Organisation: Imperial College London
Department Name: Dept of Mathematics

Abstract

Mitochondria are organelles that produce the energy that is necessary for life within our cells. This energy is produced in the form of ATP, a molecule that is used as an energy source in countless cellular processes. The importance of mitochondria in ensuring a sufficient energy supply within organisms means that variability in mitochondrial performance -- and subsequent changes in their capacity to produce ATP -- can have profound consequences for an organism. Many diseases with great societal impact are associated with damage to the protein machinery of mitochondria and subequent decrease in mitochondrial performance, including Alzheimer's, Parkinson's, and a host of inherited diseases. Increasing damage to the mitochondrial system in organisms is postulated to be a key cause of ageing. In addition, differences in the mitochondrial content of cells can affect fundamental biological behaviour, such as how stem cells differentiate into other cell types (a key question in current stem cell research) and how tumour cells respond to anti-cancer drugs.

Despite the importance of mitochondrial variability in these situations of medical and biological interest, and a recent explosion of experimental data showing that mitochondria form a rich physical system within cells, there has been little theoretical work to provide a quantitative understanding of the mitochondrial system. This lack of quantitative understanding makes it very difficult, for example, to make statements of clinical relevance such as the probability of inheriting a mitochondrial disease. This project aims to address this imbalance by producing mathematical and computational models of several key causes and effects of mitochondrial variability. First, damage to the mitochondrial genome -- which encodes the proteins that are responsible for ATP production -- and to the proteins themselves will be explored quantitatively, providing a mathematical foundation to help describe probabilities and time behaviour of mitochondrial damage. Second, the effects of this and other sources of mitochondrial variability -- including uneven inheritance of mitochondria from a parent cell to a daughter cell -- will be incorporated into a model for the variation in ATP levels between cells in a population. Thirdly, the effects of this variability on two key biological phenomena: the differentiation pathways of stem cells, and the response of tumour cells to anti-cancer drugs, will be explored by linking these models with existing approaches in the mathematical biology literature.

Technical Summary

This project will address the existing disconnect between experimental and theoretical understanding of mitochondrial systems by using existing and novel statistical modelling approaches to describe sources of mitochondrial variability, and combining this with computational models to explore mitochondrial effects on downstream processes.

A birth-death-mutation model incorporating stochastic partitioning effects will be developed to statistically describe the time evolution of the mitochondrial makeup of cells. A model for oxidative damage, including oxidative phosphorylation and ROS production, mtDNA mutation, cardiolipin and protein damage, will be developed to provide a systems-level view of mitochondrial time behaviour. These models will be parameterised using recent advances in statistical inference for stochastic kinetic systems, notably from approximate Bayesian computation. This part of the project will be the first example of a rigorously parameterised statistical description of mitochondrial damage and quality control, enabling quantitative statements and predictions to be made about damage buildup and subsequent disease onset.

Existing control theory-based models for ATP homeostasis will be examined and adapted with input from new computational models of mitochondria and oxidative phosphorylation to model the effects of mitochondrial variability on the ATP content of cells. Existing inferential techniques for stochastic kinetic models will be adapted to allow the statistical inference of rate parameters that may vary with time, to incorporate the possibility of varying ATP levels in cellular models. Combining these approaches, terms representing mitochondrial variability will be incorporated into existing mathematical models for stem cell differentiation and TRAIL response to explore the implications of mitochondrial variability in these systems of medical interest.

Planned Impact

This research will benefit academic communities in the fields of mitochondrial biology, cellular noise, and mathematical biology, as well as applied statistics. Its implications and the models it produces will be of use to medical practitioners concerned with approaches to mitochondrial disease and diseases associated with mitochondrial damage. Through its quantitative approach to this important medical system, clinical approaches to the management of these diseases will be improved, benefitting public health. In addition, public dissemination of the elucidation of causes and effects of stochasticity in cellular biology will help raise the understanding of stochastic biology in the public eye and potentially inform the public about how random effects play a role in medical treatments.

Perhaps the most important result of this research will be a improved quantitative understanding of mitochondrial variability. The current lack of a quantitative foundation in this field has been noted as a significant factor hindering the clinical management of mitochondrial disease. Contributions from this project have the potential to make quantitative predictions about mitochondrial disease inheritance and onset timescales, which will improve medical approaches to managing these diseases. As the number of diseases in which mitochondrial variability is implicated as a causal factor increases -- from those resulting from inherited mtDNA mutations to the more ubiquitous examples of Parkinson's and Alzheimer's -- this quantitative understanding will be invaluable.

The stem cell project within this research also has the potential to increase understanding in a biological system of fundamental medical relevance. With the ongoing development of stem cell therapy, and high level of interest in developmental biology, a quantitative understanding of the influences on differentiation pathways is of profound importance. Advances made in this research will investigate mitochondrial influences on these pathways -- an effect of potentially fundamental importance. The increased understanding resulting from this work will be of immediate relevance to researchers in stem cell biology and development, potentially translating into advantages in stem cell therapy approaches.

The TRAIL response project likewise has the potential to contribute positively to public health. An understanding of the factors that result in different tumour cells responding differently to drug treatment will be of great benefit to the further development and application of this clinical approach.

Academically, the project will be of benefit both in providing a quantitative description of what is at present a qualitatively understood system, and in developing new stochastic models and inferential techniques for the description of stochastic systems in cellular biology (see Academic Beneficiaries).

Publications

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Aryaman J (2017) Mitochondrial heterogeneity, metabolic scaling and cell death. in BioEssays : news and reviews in molecular, cellular and developmental biology

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Greenbury SF (2014) A tractable genotype-phenotype map modelling the self-assembly of protein quaternary structure. in Journal of the Royal Society, Interface

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Hoitzing H (2015) What is the function of mitochondrial networks? A theoretical assessment of hypotheses and proposal for future research. in BioEssays : news and reviews in molecular, cellular and developmental biology

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Johnston IG (2014) Efficient parametric inference for stochastic biological systems with measured variability. in Statistical applications in genetics and molecular biology

 
Description HFEA Advisory Panel 2014
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
URL http://www.hfea.gov.uk/8964.html
 
Description HFEA Scientific Review March 2013
Geographic Reach National 
Policy Influence Type Citation in systematic reviews
 
Title Bottleneck model 
Description Mathematical description of the mammalian mtDNA bottleneck, allowing prediction of perturbations, elucidation of dynamics, and statistical identification of the argued mechanism 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2014 
Provided To Others? Yes  
Impact eLife paper 
 
Title Heteroplasmy Dynamics Model 
Description Based on rigorous population genetics and statistical inference, I have developed a new analysis technique for the time behaviour of mtDNA heteroplasmy in intracellular populations. This technique assign a single metric to profilerative differences between mtDNA haplotypes and can be used to cross-compare data from different organisms, in different tissues, and through time. It dramatically increases the power of mtDNA heteroplasmy analysis. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2012 
Provided To Others? Yes  
Impact Identification of new segregation regimes; chemical treatments to modulate heteroplasmy; new factors influencing mtDNA segregation (to be detailed in forthcoming publications) 
 
Description Jo Poulton 
Organisation John Radcliffe Hospital
Department Department of Obstetrics and Gynaecology
Country United Kingdom 
Sector Hospitals 
PI Contribution Our ongoing collaboration involves the use of mathematical models to answer pertinent questions surrounding the inheritance and onset of mitochondrial disease. My role in this collaboration is the construction of mathematical formalisms to describe, and make predictions regarding, the changing presence of mutant mtDNA within and between generations.
Collaborator Contribution My collaborator Prof Jo Poulton at the JR is an expert on mitochondrial disease and a clinician directly involved with patient treatment. She has provided invaluable expertise in constructing these models, and the important questions that they should attempt to answer. We are currently writing grants to explore the role of mitophagy in modulating mutant mtDNA content, a possible clinical strategy identified through our collaboration.
Impact Article in preparation: Physical modelling and Bayesian inference elucidates the debated mechanism of the mtDNA bottleneck Various conference talks (MitOX, IoP Quantitative Methods in Gene Regulation) The collaboration is highly multidisciplinary, with advanced tools from maths, statistics and computational modelling combined with biological data to answer pertinent clinical questions.
Start Year 2012
 
Description Joerg Burgstaller 
Organisation University of Vienna
Department Veterinary Medicine
Country Austria 
Sector Academic/University 
PI Contribution Developmental and use of mathematical models to explore the details of mtDNA segregation in heteroplasmic mice.
Collaborator Contribution Construction of novel wild-derived mouse models of mtDNA heteroplasmy to explore mtDNA dynamics without reliance on inbred laboratory strains.
Impact Forthcoming publication (submitted); new mouse models to study mtDNA dynamics that possess a controlled spectrum of genetic diversity and are much more comparable to the mtDNA content of human populations than existing mouse models are.
Start Year 2011
 
Description Karl Morten 
Organisation John Radcliffe Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Mathematical modelling of oxygen consumption data in cells
Collaborator Contribution Experimental measurements of oxygen consumption in cells
Impact Paper -- Monitoring intracellular oxygen concentration - implications for hypoxia studies and real time oxygen monitoring -- interdisciplinary (maths and cell biology)
Start Year 2013
 
Description Logan 
Organisation University of Angers
Country France 
Sector Academic/University 
PI Contribution Mathematical modelling and analysis of new experimental findings in mitochondria in Arabidopsis.
Collaborator Contribution Experimental elucidation of Arabidopsis mitochondrial behaviour.
Impact Plant Physiology paper
Start Year 2014
 
Description Tonio Enriques 
Organisation Spanish Ministry of Health and Consumer Affairs
Department National Center for Cardiovascular Research (CNIC)
Country Spain 
Sector Public 
PI Contribution I am collaborating with the research group of Tonio Enriques to explore the time behaviour and possible modulating factors of mtDNA segregation in mice. My new approach for the mathematical and statistical analysis of mtDNA population data has enabled the identification of several previously unobserved phenomena and has found several drug treatments that yielded significant changes to mtDNA dynamics.
Collaborator Contribution Tonio's research group performs the construction of and measurements on the heteroplasmic mice that this project entails.
Impact Forthcoming publication detailing our findings, and possible intervention strategies for modulating mtDNA segregation. Highly multidisciplinary: using new mathematical and statistical treatments to explore fundamental biology and identify possible medical interventions.
Start Year 2012
 
Description Academic Soiree (Oxford) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Several dozen interdisciplinary postgraduate students attended a talk about mitochondrial disease, which sparked questions and discussion afterwards.

Many of the audience had never come across mitochondrial disease before and expressed interest in further exploration.
Year(s) Of Engagement Activity 2013
 
Description Caladis 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Caladis is an online tool designed to help non-technical audiences deal with statistics in everyday questions more rigorously. Briefly, it allows one to quantify the uncertainty in one or more factors that influence a quantity of interest, then presents the uncertainty in the final answer. It was designed to underline the fact that taking uncertainties and variability in quantities into account is of great importance in "back-of-the-envelope" calculations.

Caladis experiences several thousand hits a month and substantial usage for a variety of problems. We are preparing a publication detailing its use and application in biology.
Year(s) Of Engagement Activity 2012,2013
URL http://caladis.org/
 
Description DynaMito Conference (Okinawa) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Several hundred delegates attended a poster presentation detailing my work modelling mitochondrial genetic variation in organisms.

Encouragingly (given the heavy molecular biology focus of the conference), substantial interest was apparent in this interdisciplinary approach. New contacts were made with American, German, and Finnish research groups studying mtDNA dynamics.
Year(s) Of Engagement Activity 2013
URL http://www.fbs.osaka-u.ac.jp/DynaMito2013/DynaMito2013/Welcome.html
 
Description HFEA Presentation 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Our research on issues with proposed gene therapies were presented to the governmental advisory panel and included in subsequent reports and recommendations

Our research is included in current recommendation documentation on these therapies
Year(s) Of Engagement Activity 2014
 
Description JR Hospital 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Clinicians and researchers in the obs&gyn department of the John Radcliffe hospital attended a talk detailing new mathematical approaches for modelling mtDNA dynamics, and insights that these approaches have produced.

Clinicians were made aware of new findings and of new tools which dramatically increase the potential power of experimental analyses and clinical sampling of mtDNA.
Year(s) Of Engagement Activity 2013
 
Description MASAMB Conference (London) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Several hundred researchers with a general interest in applying mathematical and statistical approaches to biological problems attended a talk on modelling the inheritance of mitochondrial disease using new maths and statistics tools.

I was invited to submit a paper detailing the tools I invented for this project, and substantial interest in mitochondrial genetics was provoked in discussion through the conference.
Year(s) Of Engagement Activity 2013
URL http://www.theosysbio.bio.ic.ac.uk/masamb/programme.html
 
Description MitOX conferences 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talks at the MitOX conferences in Oxford -- substantial followup discussion and new collaborations resulted

New collaborations and grant planning with new contacts
Year(s) Of Engagement Activity 2013,2014
 
Description NIH Bethesda 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Poster presentation on the mathematical modelling of the mitochondrial bottleneck and implications for clinical interventions

International colleagues were informed about this, the first rigorous mathematical treatment of the mtDNA bottleneck. Substantial enthusiasm for this interdisciplinary approach led to formation of currently informal partnerships.
Year(s) Of Engagement Activity 2012
URL http://www.cvent.com/events/nhlbi-mitochondrial-biology-symposium-2013/archived-26f05e0e129748c8b816...
 
Description Research Blog 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Several non-technical articles were written describing the approaches and results used in recent research topics to assist public dissemination of research findings.

The blog (which also includes details of the research performed by other members of the research group) experiences several hundred hits every week.
Year(s) Of Engagement Activity 2012,2013
URL http://systems-signals.blogspot.co.uk/
 
Description Sixth Form Talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Presentation of research to Sixth Form students as part of taster days and scientific events at Imperial College.

Positive student feedback; substantial subsequent communication with interested students
Year(s) Of Engagement Activity 2014,2015
 
Description Twitter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Members of the public and from interest groups related to mitochondrial disease (charities, fundraisers etc.) follow this Twitter feed, which details recent advances both in my work and in the wider academic sphere. These are frequently retweeted, "spreading the word", and I have been contacted for further details by several interested parties.

(see above)
Year(s) Of Engagement Activity 2012,2013
URL https://twitter.com/mitomaths