Mitochondrial defects kill some cell types while leaving others untouched, and this project aims to find out why. Mitochondria are the power plants inside nearly every human cell, but when they malfunction—due to genetic mutations or ageing—the damage is not uniform. Some tissues, like nerve or muscle, are far more vulnerable than others. The reasons for this selective vulnerability are unknown. This project will focus on rare genetic disorders where mitochondrial protein production breaks down, using those as a model to uncover the fundamental rules governing which cells survive a mitochondrial insult. The research is fundamental science. It will map the nuclear genes that control mitochondrial behaviour in different cell types, identify the stress responses triggered when mitochondrial protein synthesis fails, and search for new genetic interactions in undiagnosed patients. There is no immediate clinical application. However, because mitochondrial dysfunction is now linked to common late-onset diseases such as Parkinson’s and Alzheimer’s, understanding why certain cells are vulnerable could eventually point toward cell-type-specific treatments—targeting only the tissues that need protection, not every cell in the body.
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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.
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