Dr Jim Stewart

Senior Lecturer


My fascination with mitochondria began when I was taught about the endosymbiotic origin of these organelles in undergraduate cell biology classes. My graduate studies used mitochondria to study animal phylogenetics and molecular evolution, using these organelles in arthropods and other invertebrates, where a staggering diversity of mitochondrial genome forms and functions can be found. The sequencing experience led me to a post-doctoral position analysing mitochondrial DNA mutations in the now famous “mtDNA mutator mouse”, where I studied both mitochondrial DNA mutations and their transmission through the female germline.

In 2014 I started my own group at the Max Planck Institute for the Biology of Ageing in Cologne, Germany, where our work on generating mouse models with pathogenic mtDNA mutations led me closer to pre-clinical and experimental therapy research for mitochondrial disease. My lab within the Wellcome Center for Mitochondrial Research will continue to generate these relevant animal models, and to apply them to the search for novel therapies for mitochondrial disease.

Research Focus

Models of mitochondrial DNA disease.

Mitochondrial diseases encompass a complex genetic landscape, with 1140 protein gene-products encoded by the nuclear genome. Yet the tiny mitochondrial DNA itself encodes genes vital to life and mitochondrial biogenesis and account for ¾ of all mitochondrial-disease mutations.  The diseases show a surprisingly diverse array of variable physical manifestations, age of onset, and severity in patients – even for mutations within the same gene. This tissue and cell-specific variability in the disease presentation necessitates animal model research to understand these phenomena and lead to translational breakthroughs for mitochondrial disease patients.

Despite advances in nuclear genome-engineering, animal mitochondrial-DNA has remained resistant to transgenic manipulation. Our team among only three labs in the world who have generated these pathogenic mitochondrial-DNA mouse models. Work continues on charactering the pathophysiology of these models, and on pre-clinical experimental therapies for these disorders.

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 or through the study of mtDNA mutations from genome sequencing databases. We were among the first to demonstration that deleterious mitochondrial-DNA mutations transmitted through the female germline undergo rapid purifying selection. We have continued to work in this area in an attempt to unravel the various molecular events and selective forces that affect the dynamics of mitochondrial transmission.