Modulating inter-mitochondrial contacts to increase membrane potential for mitigating blue light damage

Abstract

Mitochondrial membrane potential (MMP) is essential for mitochondrial functions, yet current methods for modulating MMP lack precise spatial and temporal control. Here, we developed an optogenetic mitochondrial tethering system, termed OptoMitoTether, that enables reversible control of inter-mitochondrial proximity with high spatiotemporal precision. Blue light activation induced CRY2PHR oligomerization between adjacent mitochondrial outer membranes, reduced mitochondrial nearest-neighbor distances, and promoted inter-mitochondrial tethering. OptoMitoTether activation was associated with elevated MMP and was associated with lower reactive oxygen species (ROS) and preserved ATP production during prolonged blue light stress. Moreover, OptoMitoTether expression preserved mitochondrial bioenergetic function in human retinal cells and extended lifespan in C. elegans during chronic blue light exposure. These findings establish OptoMitoTether as a tool for manipulating mitochondrial proximity and reveal a link between inter-mitochondrial tethering and mitochondrial bioenergetic state during blue light stress.

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