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

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