title: The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria.
abstract: Defective mitochondria exert deleterious effects on host cells. To manage this risk, mitochondria display several lines of quality control mechanisms: mitochondria-specific chaperones and proteases protect against misfolded proteins at the molecular level, and fission/fusion and mitophagy segregate and eliminate damage at the organelle level. An increase in unfolded proteins in mitochondria activates a mitochondrial unfolded protein response (UPR(mt)) to increase chaperone production, while the mitochondrial kinase PINK1 and the E3 ubiquitin ligase PARK2/Parkin, whose mutations cause familial Parkinson disease, remove depolarized mitochondria through mitophagy. It is unclear, however, if there is a connection between those different levels of quality control (QC). Here, we show that the expression of unfolded proteins in the matrix causes the accumulation of PINK1 on energetically healthy mitochondria, resulting in mitochondrial translocation of PARK2, mitophagy and subsequent reduction of unfolded protein load. Also, PINK1 accumulation is greatly enhanced by the knockdown of the LONP1 protease. We suggest that the accumulation of unfolded proteins in mitochondria is a physiological trigger of mitophagy.
authors.affiliation: Biochemistry Section; Surgical Neurology Branch; National Institute of Neurological Disorders and Stroke; National Institutes of Health; Bethesda, MD USA.
authors.forename: Seok Min
authors.initials: SM
authors.lastname: Jin
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
mesh_terms: D017353:Gene Deletion; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy; D009954:Ornithine Carbamoyltransferase / Q000378:metabolism; D017510:Protein Folding; D011494:Protein Kinases / Q000378:metabolism*; D058767:Protein Unfolding; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D056811:Unfolded Protein Response; D000099202:PTEN-Induced Putative Kinase
chemical_list: D009954:Ornithine Carbamoyltransferase; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
keywords: LONP; PARK2/Parkin; PINK1; mitochondria; mitophagy; unfolded protein response