ESR4: “Mitophagy in neuronal physiology and neurodegeneration during ageing”

FORTH (N. Tavernarakis group): Mitophagy in neuronal physiology and neurodegeneration during ageing

i. Objective of research: To elucidate the role of mitophagy in neuronal physiology and neurodegeneration during ageing.

ii. Current state of the art: Maintenance of mitochondrial function and energy homeostasis requires both generation of newly synthesized and elimination of dysfunctional mitochondria. We have recently shown that mitophagy, a selective type of autophagy targeting mitochondria for degradation, interfaces with mitochondrial biogenesis to regulate mitochondrial content and longevity in the nematode Caenorhabditis elegans. In addition we have identified key mediators of mitophagy and mitogenesis under conditions of stress in C. elegans and have developed tools for monitoring mitophagy in vivo. Moreover, we have established multiple C. elegans models of neurodegeneration. We propose to exploit these resources to dissect the involvement of mitophagy in neuronal physiology and neurodegeneration during ageing.

iii. Research methodology and approach: Our research plan involves five specific tasks with defined endpoints, as follows: (1) Generation of transgenic C. elegans strains expressing mitophagy reporters in specific neuronal types. (2) Monitoring mitochondrial turnover during ageing in nematode neurons. (3) Assessment of the influence of genetic pathways and interventions known to affect C. elegans ageing on neuronal mitophagy and neurodegeneration. (4) Monitoring mitochondrial fate during neurodegeneration in C. elegans. (5) RNAi screening for modifiers of neuronal mitophagy and susceptibility to age-associated neurodegeneration.

iv. Originality and innovative aspects of the ESR project: The project combines innovative and highly effective approaches of manipulating and monitoring mitophagy in the nematode, with genome-wide, RNAi-based genetic screening methodologies that should deliver novel, key regulators of neuronal energy homeostasis and quality control, with relevance to age-associated neurodegeneration.

v. Integration of the ESR project to the overall research programme: Our ESR will work jointly with the Scorrano and Auwerx groups, to dissect the molecular mechanisms that control mitophagy and mitochondrial biogenesis in mouse models of neurodegeneration.