Mitochondria-lysosome contacts regulate mitochondrial Ca(2+) dynamics via lysosomal TRPML1.

1. Proc Natl Acad Sci U S A. 2020 Aug 11;117(32):19266-19275. doi: 10.1073/pnas.2003236117. Epub 2020 Jul 23. Mitochondria-lysosome contacts regulate mitochondrial Ca(2+) dynamics via lysosomal TRPML1. Peng W(1), Wong YC(1), Krainc D(2). Author information: (1)Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611. (2)Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 dkrainc@nm.org. Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria-lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified 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 was mediated by tethering of mitochondria-lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria-lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria-lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria-lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes. DOI: 10.1073/pnas.2003236117 PMCID: PMC7430993 PMID: 32703809 [Indexed for MEDLINE] Conflict of interest statement: Competing interest statement: D.K. is the Founder and Scientific Advisory Board Chair of Lysosomal Therapeutics Inc. and Vanqua Bio. D.K. serves on the scientific advisory boards of The Silverstein Foundation, Intellia Therapeutics, and Prevail Therapeutics, and is a Venture Partner at OrbiMed.