What drives disease caused by inherited heteroplasmic pathogenic mtDNA variants?

Disease caused by inherited mitochondrial (mt)DNA mutations is clinically heterogeneous; individuals carrying the same pathogenic variant can have very different phenotypic presentations and disease severity. This is exemplified by the most common heteroplasmic disease-causing variant, m.3243A>G. The precise pathogenic mechanisms of m.3243A>G remain elusive, creating a substantial knowledge gap.

My hypothesis is that m.3243A>G-disease is influenced by nuclear genetic and environmental factors that determine the cellular response to this variant.

This is further complicated by heteroplasmy: the presence of variable levels of wild-type and mutant mtDNA within the same cell.

I aim to exploit the natural cell-to-cell variability afforded by heteroplasmy, employing single-cell methods, population genetics and cell-models, to determine and define the drivers of disease associated with m.3243A>G.

I will: 1) Characterise the cellular response to m.3243A>G in patient cells with single-cell multiomics; 2) Identify nuclear genetic and environmental factors that contribute to disease within a large patient cohort; 3) Characterise nuclear factors using iPSC-derived disease-specific cell models.

Understanding disease heterogeneity associated with m.3243A>G is of paramount importance for patients and healthcare providers. Solving this holds the key to improving patient prognosis and developing targeted treatments. Furthermore, this investigation serves as a paradigm for comprehending other, rarer, mtDNA variants.