Nuclear mechanisms underpinning mitochondrial vulnerability in different cell-types

Mitochondria play a central role in the homeostasis of nucleated cells, but mitochondrial insults preferentially affect some cell-types and not others. The reasons for this are not clear. Our over-arching aim is to define the principal mechanisms underpinning cell-type-specific mitochondrial vulnerability. We will take a reductionist approach, focussed on genetic disorders of intra-mitochondrial translation caused by mutations affecting mitochondrial DNA (mtDNA) transfer RNA genes and their corresponding nuclear-encoded mitochondrial aminoacyl tRNA synthetases (mt-aaRS). Our five specific inter-related aims are: Aim-1: To discover the key nuclear genes regulating mtDNA-heteroplasmy and mtDNA-levels in different cell types using single-cell functional genomic screens. Aim-2: To define cell-type-specific nuclear transcriptional signatures that modulate mitochondrial function throughout life in health and disease. Aim-3: To determine the role of canonical and non-canonical functions of mt-aaRS in cell-type-specific vulnerability. Aim-4: To characterise cell-type-specific downstream consequences of disrupting mitochondrial protein synthesis, focussing on the integrated stress response (ISR). Aim-5: To discover new mtDNA-nuclear DNA interactions in undiagnosed patients with tissue-specific mitochondrial disorders using genomics. Given emerging evidence that mitochondria contribute to many common late-onset diseases, our findings will have broader relevance for understanding tissue and cell vulnerability in many human disorders, potentially identifying new cell-type-specific therapeutic targets.