Inducing mitophagy by an optogenetic bimodular system

Autophagy-mediated selective degradation of damaged mitochondria (mitophagy) is a key process in cellular quality control. Although mitophagy impairment is involved in several pathophysiological conditions, such as neurodegeneration, muscle dystrophy and aging, valuable methods to safely induce mitophagy in vivo are still lacking. Here we describe a new optogenetic bi-modular tool to stimulate mitophagy, based on the blue light-dependent recruitment of the pro-autophagy protein AMBRA1 to the mitochondrial surface. Upon irradiation, AMBRA1-RFP-sspB is massively relocated from cytosol to mitochondria, where it mediates mito-aggresomes formation and reduction of mitochondrial mass. When a dark state is restored, mitochondrial markers return to the pre-irradiation levels, indicating that the observed effect is, indeed, reversible. Finally, as a proof of concept of the biomedical relevance for this method, we induced mitophagy in an experimental model of Parkinson’s Disease, and were able to fully prevent cell death. Given the unique features of this tool, we think it may turn out to be very useful for a wide range of both therapeutic and research applications