Investigating the link between mitochondrial dysfunction and the integrated stress response in CNS pathology

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Mitochondria are critical for ATP provision and play other essential roles in cells such as buffering calcium and lipid synthesis (Devine & Kittler, 2018). The tight regulation of mitochondrial transport, distribution and turnover are crucial for neuronal health and disruption of mitochondrial dynamics leading to cellular stress is increasingly implicated in CNS disroders. But we still know very little about the underlying mechanisms by which damaged mitochondria lead to neuronal death. Recently, evidence suggests that disruption of mitochondrial homeostasis can lead to ISR activation. But how mitochondrial dysfunction is sensed to trigger the ISR in neurons, whether this activation contributes to neuronal pathology and if cross-talk between these two pathways can be therapeutically targeted remains a major open question. The central aim of this project is to further elucidate the mechanisms by which damaged mitochondria activate a pathological ISR in neurons. We will leverage the expertise in mitochondrial biology and mouse models of mitochondrial pathology in the Kittler lab along with expertise and tool ISR inhibitor compounds from the Crowther group at AstraZeneca. Using this approach we will be uniquely placed to further explore cross-talk between pathological mitochondrial dynamics and ISR activation with the aim of achieving the following key objectives:1) to identify the key signalling mechansims and stress-sensing proteases, chaperones and kinases through which mitochondrial damage leads to ISR activation;2) to determine which disease specific forms of mitochondrial damage can activate the ISR (e.g. altered fission/fusion, disrupted trafficking, altered mitophagy).3) to determine if blocking ISR activation leads to neuronal protection from mitochondrial insults in vitro and in vivo.