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Staff Profile

Dr Jim Stewart

Senior Lecturer

Background

BACKGROUND

It has now been 35 years since the first disease alleles on the mitochondrial DNA have been described. In addition, the accumulation of mitochondrial dysfunction with age is one of the nine classic hallmarks of the ageing process. The lab focuses on the following research questions – how do the mitochondria acquire these mutations? How do they clonally expand to lead to mitochondrial deficiency in somatic cells and when transmitted through the female germline? Can we generate animal models to model aspects of human mtDNA disease? What effects do these sporadic deficient cells have on organismal health and ageing?


AFFILIATION

I am a member of the Biosciences Institute and work in the Mitochondrial and Neuromuscular Diseases research theme. I am also affiliated with the Cells, Genes, Molecules Theme.

I am also a member of The Genetics Society.


PREVIOUS POSITIONS

Research Group Leader, Max Planck Institute for Biology of Ageing, Cologne, Germany. (Feb 2014 – Oct 2020).

Senior Postdoctoral Fellow, Max Planck Institute for Biology of Ageing, Cologne, Germany. (Mar 2009 – Jan 2014).

Postdoctoral Fellow Karolinska Institutet, Division of Metabolic Diseases Stockholm, Sweden. (Nov 2005 – Dec 2009).


EDUCATION

PhD. Department of Molecular Biology and Biochemistry, Simon Fraser University, BC, Canada (Jan 2002 – Feb 2006).

MSc. Department of Molecular Biology and Biochemistry, Simon Fraser University, BC, Canada (Sep 1997 – Feb 2002).

BSc (Hons). Biology w/ Chemistry minor. University of Waterloo, ON, CANADA (Sep 1992 – May 1997)

 

FUNDING

"Purging mutant mitochondrial DNA: from mechanisms to therapies" - UKRI - MRC. (co-I) (2022-2026).

"Towards eradicating mitochondrial DNA deletions: from mechanisms to small molecule therapies" - Champ Foundation. (co-I) (072022-072025).

"MitoCluster: an integrated phenotyping and mouse model generation platform for mitochondrial disease and dysfunction". MRC National Mouse Genetics Network. (04/2022-04/2027).

PAST FUNDING

"Wellcome Centre for Mitochondrial Research". - The Wellcome Trust. (PI within the center) (04/2022-04/2024).

"Enhancing mitochondrial DNA fidelity to improve mammalian lifespan and healthspan" - Human Frontier Science Program (09/2019 - 06/2023).

 

OTHER LINKS

- ORCID

- ResearchGate

- ResearcherID / Publons

Research

Animal models of mitochondrial-DNA disease - Mitochondrial diseases encompass a complex genetic landscape, affecting 1:4,300 adults. While >1140 protein gene-products within mitochondria are nuclear-encoded, mutations of the 13 protein, 22 tRNA and 2 rRNAs mitochondrial-DNA genes account for ¾ of all mitochondrial-disease patients. The diseases show a surprisingly diverse array of variable physical manifestation, age of onset and severity in patients, even for mutations within the same gene. In an effort to understand this disease complexity, and aid in pre-clinical research towards treatments for mitochondrial disorders, animal models are highly sought after. Despite advances in nuclear genome-engineering, animal mitochondrial-DNA has remained resistant to transgenic manipulation (Stewart, JIMD, 2020). Our team has previously developed mouse models of mitochondrial-DNA dysfunction via random mutagenesis and screening (Kauppila et al, Cell Reports, 2016, Burr et al. Cell.2023), and are among only three labs in the world who have generated these mitochondrial-DNA mouse models. Work continues on charactering the pathophysiology of these models (Burr et al. Cell.2023), and on pre-clinical experimental therapies for these disorders (Bacman et al. Nature Medicine, 2018, Gammage et al, Nature Medicine 2018, Filograna et al, Scientific Advances, 2019, Zekonyte et al. Nature Communications 2021).

Method to detect and quantify mitochondrial-DNA mutations – The mosaic, cell-to-cell variability of mitochondrial-DNA mutations due to the multi-copy nature of this genome leads to specific challenges in the study of mitochondrial-DNA mutational dysfunction. We work on and refine various sequencing methods to detect, quantify and characterize mitochondrial-DNA mutations (Ross et al, Nature 2013; Kaupilla et al. Cell Reports, 2016; Kauppila et al. NAR, 2018). We also develop methods to detect mitochondrial dysfunction in tissue samples (Simard et al. Journal of Pathology, 2018). We have also studied the roles of suspected Base-Excision DNA repair enzymes within the mitochondria to determine what (if any) role they have on mitochondrial mutagenesis (Kauppila et al, NAR, 2018, Kauppilla & Stewart, BBA-bioenergetics, 2015).

Mitochondria-DNA mutations to reveal functional elements – The inability to manipulate animal mitochondrial-DNA has limited reverse genetics approaches to uncover and study regulatory elements. We have developed methods to study various mitochondrial processes by the study of the behaviour of mutations after random mutagenesis in the mouse (Wanrooij et al. EMBO Reports, 2012) or through the study of mtDNA mutations from cancer genomics databases (Stewart et al. PLoS Genetics, 2015).

Germline transmission and Selection on mitochondrial-DNA mutations – We were among the first to demonstration that deleterious mitochondrial-DNA mutations transmitted through the female germline undergo rapid purifying selection. (Stewart et al. PLoS Biology, 2008; Stewart et al. Nature Reviews Genetics, 2008, Stewart & Larsson, PLoS Genetics, 2014). We have continue to work in this area in an attempt to unravel the various molecular events and selective forces that affect the dynamics of mitochondrial transmission (Kauppila et al. Cell Reports, 2016; Jokinen et al. Human Molecular Genetics, 2016)

Teaching

Module Lead : MCR 8013 - Designing a Research Proposal (E-learning)


Lectures for MMB8034 - MRes in Mitochondrial Medicine

Project Supervisor - CMB3000 - Research Project

Project Supervisor - MRes and MSci projects


Fellow of the Medical Sciences Graduate School

Publications