Novel Functions of Mitochondria-Lysosome Contact Sites in Health and Neurological Disease


Inter-organelle contact sites have become increasingly appreciated as important regulators of cellular homeostasis, and disruption of inter-organelle contact site dynamics and function has been observed in various pathologies. Recently, inter-organelle contact sites between mitochondria and lysosomes were discovered, offering a new mechanism by which these two organelles may directly interact, and were subsequently found to regulate mitochondrial fission. However, whether mitochondria-lysosome contacts like other inter-organelle contacts may serve additional functions has not been elucidated. Moreover, while both mitochondrial and lysosomal dysfunction have been implicated in many neurological diseases, whether alterations in mitochondria-lysosome contact site dynamics and function may further contribute to disease pathogenesis has not been described. Here, we report two novel functions of mitochondria-lysosome contact sites—the regulation of inter-mitochondrial contact site tethering and direct calcium transfer from lysosomes to mitochondria—and describe dysregulation of these contact-dependent functions in two models of neurological disease. First, using super-resolution imaging, we demonstrate that inter-mitochondrial contacts frequently form and play a fundamental role in mitochondrial networks by restricting mitochondrial motility. Inter-mitochondrial contact untethering events are marked and regulated by mitochondria-lysosome contacts and moreover, inter-mitochondrial contact formation and untethering are regulated by Mfn1/2 and Drp1 GTP hydrolysis, respectively. Importantly, we find that multiple Charcot-Marie-Tooth Type 2 disease-linked mutations in Mfn2 (CMT2A), RAB7 (CMT2B) and TRPV4 (CMT2C) converge on prolonged inter-mitochondrial contacts and defective mitochondrial motility. Additionally, using high spatial and temporal resolution live-cell microscopy, we identify a role for mitochondria–lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which is mediated by tethering of mitochondria–lysosome contact sites. Mitochondrial calcium uptake at mitochondria–lysosome contact sites is further modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Importantly, mucolipidosis type IV (MLIV) patient fibroblasts harboring loss-of-function mutations in TRPML1 show both altered mitochondria-lysosome contact site dynamics and defective contact-dependent mitochondrial calcium uptake. Together, our findings highlight a role of mitochondria-lysosome contact sites in mitochondrial network regulation and interorganelle calcium dynamics and furthermore, demonstrate the potential contribution of mitochondria-lysosome contact site dysfunction to the pathophysiology of several neurological disorders.

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