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. Mitochondria and lysosomes form dynamic inter-organelle membrane contact sites, which are independent from mitophagy.GTP-bound Rab7 promotes mitochondria–lysosome contact site formation and tethering, while mitochondrial TBC1D15 (Rab7-GAP) recruited to mitochondria via Fis1 drives lysosomal Rab7 GTP hydrolysis at mitochondria–lysosome contact sites, leading to contact untethering.Mitochondria regulate lysosomal dynamics at contact sites by modulating Rab7 GTP-binding, which is a master regulator of lysosomal dynamics via Rab7 effector proteins.Lysosomes conversely regulate mitochondrial dynamics at contact sites by marking the majority of mitochondrial fission sites.Mitochondria–lysosome contact sites may mediate inter-organelle transfer of metabolites and contribute to the pathogenesis in diseases linked to dysfunction of both organelles.