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We explore how autophagy eliminates protein aggregates from within mitochondria and the role of mitochondrial fission in mitophagy. We show that PINK1 recruits Parkin onto mitochondrial subdomains after actinonin-induced mitochondrial proteotoxicity and that PINK1 recruits Parkin proximal to focal misfolded aggregates of the mitochondrial-localized mutant ornithine transcarbamylase (\u0394OTC). Parkin colocalizes on polarized mitochondria harboring misfolded proteins in foci with ubiquitin, optineurin, and LC3. Although inhibiting Drp1-mediated mitochondrial fission suppresses the segregation of mitochondrial subdomains containing \u0394OTC, it does not decrease the rate of \u0394OTC clearance. Instead, loss of Drp1 enhances the recruitment of Parkin to fused mitochondrial networks and the rate of mitophagy as well as decreases the selectivity for \u0394OTC during mitophagy. These results are consistent with a new model that, instead of promoting mitophagy, fission protects healthy mitochondrial domains from elimination by unchecked PINK1\u2013Parkin activity.<\/jats:p>","DOI":"10.1083\/jcb.201612106","type":"journal-article","created":{"date-parts":[[2017,9,12]],"date-time":"2017-09-12T10:10:11Z","timestamp":1505211011000},"page":"3231-3247","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":473,"title":["Mitochondrial fission facilitates the selective mitophagy of protein aggregates"],"prefix":"10.1083","volume":"216","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1132-6933","authenticated-orcid":true,"given":"Jonathon L.","family":"Burman","sequence":"first","affiliation":[{"name":"Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Pickles","sequence":"additional","affiliation":[{"name":"Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6015-6806","authenticated-orcid":true,"given":"Chunxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiori","family":"Sekine","sequence":"additional","affiliation":[{"name":"Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5529-0883","authenticated-orcid":true,"given":"Jose Norberto S.","family":"Vargas","sequence":"additional","affiliation":[{"name":"Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice M.","family":"Youle","sequence":"additional","affiliation":[{"name":"Molecular Cell Biology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine L.","family":"Nezich","sequence":"additional","affiliation":[{"name":"Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9723-7965","authenticated-orcid":true,"given":"Xufeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Molecular Cell Biology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2496-5179","authenticated-orcid":true,"given":"John A.","family":"Hammer","sequence":"additional","affiliation":[{"name":"Molecular Cell Biology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9117-5241","authenticated-orcid":true,"given":"Richard J.","family":"Youle","sequence":"additional","affiliation":[{"name":"Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2017,9,11]]},"reference":[{"key":"2023072309094225700_bib1","doi-asserted-by":"publisher","first-page":"2789","DOI":"10.1038\/ncomms3789","article-title":"Involvement of mitochondrial dynamics in the segregation of mitochondrial matrix proteins during stationary phase mitophagy","volume":"4","author":"Abeliovich","year":"2013","journal-title":"Nat. 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