Deciphering the interplay between mitophagy, epigenetic regulation, and neurodegeneration in ageing

Objective

"The ""MitoEpigeNeAge"" research proposal seeks to uncover the molecular mechanisms of age-related neurodegeneration by focusing on the interplay between mitophagy, redox-regulated histone methylation, and neuronal death. Brain ageing is characterized by the accumulation of damaged mitochondria and epigenetic changes, leading to neurodegeneration. Mitophagy, the process that clears damaged mitochondria, declines with age but extends lifespan and offers neuroprotection when activated. However, its impact on the epigenome remains unclear. The project will utilize Caenorhabditis elegans due to its well-defined nervous system and evolutionary conservation of neuronal ageing mechanisms. Advanced technologies will analyse chromatin accessibility and gene expression in redox-sensitive neurons. Super-resolution imaging and optogenetics will allow precise manipulation of mitochondrial damage and mitophagy in live animals. Key objectives include: 1) Monitoring chromatin accessibility, histone methylation, and gene expression in wild-type and mitophagy-deficient worms; 2) Developing in vivo reporters to track chromatin modifications during ageing and mitophagy induction; 3) Using optogenetics to assess the effects of mitochondrial damage on histone methylation in neurons; 4) Exploring if mitophagy-inducing interventions provide neuroprotection through changes in histone methylation linked to redox homeostasis; 5) Conducting a genetic screen to find mitophagy modulators that enhance mitochondrial quality control, histone methylation, and resistance to neurodegeneration. This project supports the researcher’s long-term goals and the MSCA's mission to promote innovative research. Its successful completion will greatly enhance understanding of age-related neuronal decline, with significant benefits for human health. The MSCA grant would be transformative, providing essential resources to advance the research and establish the researcher as a group leader in the ageing field."