Mitochondria-lysosome contacts regulate mitochondrial fission via Rab7 GTP hydrolysis Yvette C. Wong1*, Daniel Ysselstein1, Dimitri Krainc1* 1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL *Co-Corresponding Authors
Both mitochondria and lysosomes are critical for maintaining cellular homeostasis and dysfunction of both organelles has been observed in multiple diseases. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network which drives cellular metabolism_ENREF_6. Lysosomes similarly undergo constant dynamic regulation by Rab7 GTPase, which cycles from active GTP-bound state into inactive GDP-bound state upon GTP hydrolysis. Here, we investigated the formation and regulation of mitochondria-lysosome membrane contact sites using EM, structured illumination microscopy, FRET and high spatial and temporal confocal live cell imaging. Mitochondria-lysosome contacts dynamically formed in healthy untreated cells and were distinct from damaged mitochondria targeted into lysosomes for degradation. Contact formation was regulated by active GTP-bound lysosomal Rab7, while contact untethering was mediated by Fis1 recruitment of TBC1D15/Rab7-GAP to mitochondria to drive Rab7 GTP hydrolysis to release contacts. Functionally, lysosomal contacts mark sites of mitochondrial fission allowing for lysosomal regulation of mitochondrial networks, while conversely, mitochondrial contacts regulate lysosomal Rab7 hydrolysis via TBC1D15. Mitochondria-lysosomecontacts thus allow for bidirectional regulation of mitochondrial and lysosomal dynamics, and may explain the dysfunction observed in both organelles in various human diseases.
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