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Using live super-resolution microscopy, we found that lysosomal tethering events rarely undergo lysosomal fusion, but rather untether over time to reorganize the lysosomal network. Inter-lysosomal untethering events are driven by a mitochondrial Mid51\/Fis1 complex that undergoes coupled oligomerization on the outer mitochondrial membrane. Importantly, Fis1 oligomerization mediates TBC1D15 (Rab7-GAP) mitochondrial recruitment to drive inter-lysosomal untethering via Rab7 GTP hydrolysis. Moreover, inhibiting Fis1 oligomerization by either mutant Fis1 or a Mid51 oligomerization mutant potentially associated with Parkinson\u2019s disease prevents lysosomal untethering events, resulting in misregulated lysosomal network dynamics. In contrast, dominant optic atrophy\u2013linked mutant Mid51, which does not inhibit Mid51\/Fis1 coupled oligomerization, does not disrupt downstream lysosomal dynamics. As Fis1 conversely also regulates Mid51 oligomerization, our work further highlights an oligomeric Mid51\/Fis1 mitochondrial complex that mechanistically couples together both Drp1 and Rab7 GTP hydrolysis machinery at mitochondria\u2013lysosome contact sites. These findings have significant implications for organelle networks in cellular homeostasis and human disease.<\/jats:p>","DOI":"10.1083\/jcb.202206140","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T13:43:22Z","timestamp":1661953402000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":34,"title":["Mid51\/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics"],"prefix":"10.1083","volume":"221","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3188-4342","authenticated-orcid":true,"given":"Yvette C.","family":"Wong","sequence":"first","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6519-1651","authenticated-orcid":true,"given":"Soojin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine","family":"Cisneros","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine G.","family":"Molakal","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingping","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7103-6671","authenticated-orcid":true,"given":"Steven J.","family":"Lubbe","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 1"},{"name":"Simpson Querrey Center for Neurogenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4716-1886","authenticated-orcid":true,"given":"Dimitri","family":"Krainc","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 1"},{"name":"Simpson Querrey Center for Neurogenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2022,8,31]]},"reference":[{"key":"2022090113013939400_bib1","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/s41580-019-0185-4","article-title":"Lysosomes as dynamic regulators of cell and organismal homeostasis","volume":"21","author":"Ballabio","year":"2020","journal-title":"Nat. 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