Regulation and Function of Mitochondria-Lysosome Membrane Contact Sites in Cellular Homeostasis

Mitochondrial and lysosomal function are intricately related and critical for maintaining cellular homeostasis, as highlighted by multiple diseases linked to dysfunction of both organelles. Recent work using high-resolution microscopy demonstrates the dynamic formation of inter-organelle membrane contact sites between mitochondria and lysosomes, allowing for their direct interaction in a pathway distinct from mitophagy or lysosomal degradation of mitochondrial-derived vesicles. Mitochondria-lysosome contact site tethering is mechanistically regulated by mitochondrial proteins promoting Rab7 GTP hydrolysis, and allows for the bidirectional crosstalk between mitochondria and lysosomes and the regulation of their organelle network dynamics, including mitochondrial fission. In this review, we summarize recent advances in mitochondria-lysosome contact site regulation and function, and discuss their potential roles in cellular homeostasis and various human diseases.