title: PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix.
abstract: Loss-of-function mutations in PINK1, which encodes a mitochondrially targeted serine/threonine kinase, result in an early-onset heritable form of Parkinson's disease. Previous work has shown that PINK1 is constitutively degraded in healthy cells, but selectively accumulates on the surface of depolarized mitochondria, thereby initiating their autophagic degradation. Although PINK1 is known to be a cleavage target of several mitochondrial proteases, whether these proteases account for the constitutive degradation of PINK1 in healthy mitochondria remains unclear. To explore the mechanism by which PINK1 is degraded, we performed a screen for mitochondrial proteases that influence PINK1 abundance in the fruit fly Drosophila melanogaster. We found that genetic perturbations targeting the matrix-localized protease Lon caused dramatic accumulation of processed PINK1 species in several mitochondrial compartments, including the matrix. Knockdown of Lon did not decrease mitochondrial membrane potential or trigger activation of the mitochondrial unfolded protein stress response (UPRmt), indicating that PINK1 accumulation in Lon-deficient animals is not a secondary consequence of mitochondrial depolarization or the UPRmt. Moreover, the influence of Lon on PINK1 abundance was highly specific, as Lon inactivation had little or no effect on the abundance of other mitochondrial proteins. Further studies indicated that the processed forms of PINK1 that accumulate upon Lon inactivation are capable of activating the PINK1-Parkin pathway in vivo. Our findings thus suggest that Lon plays an essential role in regulating the PINK1-Parkin pathway by promoting the degradation of PINK1 in the matrix of healthy mitochondria.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Thomas
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Andrews
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Jonathon L
authors.initials: JL
authors.lastname: Burman
authors.affiliation: Department of Biology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Wen-Yang
authors.initials: WY
authors.lastname: Lin
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Pallanck
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049070:Protease La / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D049070:Protease La; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase