Decoding mitochondrial selective autophagy in synaptic homeostasis during ageing

Introduction

Age-dependent accumulation of damaged mitochondria and synaptic loss represent early pathological hallmarks of brain ageing leading to neuronal death. Mitochondria-selective autophagy (mitophagy) is triggered to eliminate defective organelles promoting cellular and organismal survival. Mitophagy declines with age, while its induction extends lifespan and confers neuroprotection across diverse species. Although the pivotal role of mitophagy in neuronal physiology is steadily emerging, its contribution to synaptic homeostasis remains elusive.

Project Overview

Building on our previous pioneering studies, SynaptoMitophagy aims to reveal the molecular underpinnings of age-dependent synaptic impairment, focusing on mitochondrial maintenance and turnover. We will combine the nematode Caenorhabditis elegans, which offers a well-defined nervous system, with cutting-edge technologies, such as super resolution imaging, microfluidics, and optogenetics, to manipulate spatiotemporally mitochondrial damage and monitor synaptic mitophagy at nanoscale resolution, in vivo. Mammalian neurons will be used to address the functional conservation of synaptic mitophagy components.

Objectives

The objectives are four-fold:

1. Establish mitophagy reporters for in vivo monitoring of mitochondrial fate at synapses during ageing and under neuroprotective conditions.
2. Use optogenetic tools to stimulate synapse-restricted mitochondrial damage and, thereby, to detect mitophagy induction and its contribution to neurotransmission.
3. Characterize the synaptic defects and assess behavioral deficits arising from mitophagy impairment.
4. Conduct forward genetic screening for synaptic mitophagy modulators, towards augmenting mitochondrial quality control and resistance to age-related synaptic failure.

Expected Outcomes

The cumulative results of this proposal will decode the molecular mechanisms of neuronal mitophagy compartmentalization at synapses during ageing, providing critical insights with broad relevance to human health and quality of life.