Loss of PINK1 Function Promotes Mitophagy through Effects on Oxidative Stress and Mitochondrial Fission

Mitochondrial dysregulation is strongly implicated in Parkinson disease. Mutations in PTEN-induced kinase 1 (PINK1) are associated with familial parkinsonism and neuropsychiatric disorders. Although overexpressed PINK1 is neuroprotective, less is known about neuronal responses to loss of PINK1 function. We found that stable knockdown of PINK1 induced mitochondrial fragmentation and autophagy in SH-SY5Y cells, which was reversed by the reintroduction of an RNA interference (RNAi)-resistant plasmid for PINK1. Moreover, stable or transient overexpression of wild-type PINK1 increased mitochondrial interconnectivity and suppressed toxin-induced autophagy/mitophagy. Mitochondrial oxidant production played an essential role in triggering mitochondrial fragmentation and autophagy in PINK1 shRNA lines. Autophagy/mitophagy served a protective role in limiting cell death, and overexpressing Parkin further enhanced this protective mitophagic response. The dominant negative Drp1 mutant inhibited both fission and mitophagy in PINK1-deficient cells. Interestingly, RNAi knockdown of autophagy proteins Atg7 and LC3/Atg8 also decreased mitochondrial fragmentation without affecting oxidative stress, suggesting active involvement of autophagy in morphologic remodeling of mitochondria for clearance. To summarize, loss of PINK1 function elicits oxidative stress and mitochondrial turnover coordinated by the autophagic and fission/fusion machineries. Furthermore, PINK1 and Parkin may cooperate through different mechanisms to maintain mitochondrial homeostasis. Mitochondrial dysregulation is strongly implicated in Parkinson disease. Mutations in PTEN-induced kinase 1 (PINK1) are associated with familial parkinsonism and neuropsychiatric disorders. Although overexpressed PINK1 is neuroprotective, less is known about neuronal responses to loss of PINK1 function. We found that stable knockdown of PINK1 induced mitochondrial fragmentation and autophagy in SH-SY5Y cells, which was reversed by the reintroduction of an RNA interference (RNAi)-resistant plasmid for PINK1. Moreover, stable or transient overexpression of wild-type PINK1 increased mitochondrial interconnectivity and suppressed toxin-induced autophagy/mitophagy. Mitochondrial oxidant production played an essential role in triggering mitochondrial fragmentation and autophagy in PINK1 shRNA lines. Autophagy/mitophagy served a protective role in limiting cell death, and overexpressing Parkin further enhanced this protective mitophagic response. The dominant negative Drp1 mutant inhibited both fission and mitophagy in PINK1-deficient cells. Interestingly, RNAi knockdown of autophagy proteins Atg7 and LC3/Atg8 also decreased mitochondrial fragmentation without affecting oxidative stress, suggesting active involvement of autophagy in morphologic remodeling of mitochondria for clearance. To summarize, loss of PINK1 function elicits oxidative stress and mitochondrial turnover coordinated by the autophagic and fission/fusion machineries. Furthermore, PINK1 and Parkin may cooperate through different mechanisms to maintain mitochondrial homeostasis. Parkinson disease is an age-related neurodegenerative disease that affects ∼1% of the population worldwide. The causes of sporadic cases are unknown, although mitochondrial or oxidative toxins such as 1-methyl-4-phenylpyridinium, 6-hydroxydopamine (6-OHDA), 3The abbreviations used are: 6-OHDA, 6-hydroxydopamine; AV, autophagic vacuole; Drp1, dynamin-related protein-1; Drp1-DN, dominant negative Drp1; LC3, microtubule-associated protein light chain 3; PD, Parkinson disease/parkinsonian disorder; PINK1, PTEN-induced kinase 1; ROS, reactive oxygen species; siRNA, small interfering RNA; RNAi, RNA interference; shRNA, short hairpin RNA; HA, hemagglutinin; GFP, green fluorescent protein; RFP, red fluorescent protein; DAPI, 4′,6-diamidino-2-phenylindole; ERK, extracellular signal-regulated kinase; MnTBAP, manganese(III) tetrakis(4-benzoic acid)porphyrin. and rotenone reproduce features of the disease in animal and cell culture models (1Bove J. Prou D. Perier C. Przedborski S. NeuroRx. 2005; 2: 484-494Crossref PubMed Scopus (575) Google Scholar). 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To of mitochondrial was for for from the The green of cells with or was to to as and to The mitochondrial The was as an of mitochondrial with used as a of mitochondrial as of mitochondrial fission and are as from of with of and the mechanisms associated with in PINK1 a of SH-SY5Y cell that or exhibit decreased of PINK1. a the a and a of PINK1. the a and a are by with the or by shRNA to PINK1 of PINK1 with mitochondria with in the and stable of PINK1 a C-terminal and overexpressed PINK1 and PINK1 is also observed in both and and 1 is in the mitochondrial and cytosolic was not observed but increased in of the with or with not The of PINK1 knockdown in stable PINK1 shRNA was and protein by and not PINK1 shRNA in both the and of PINK1 with cell of PINK1 in PINK1 shRNA with cell by and of PINK1 Mitochondrial and that stable mitochondrial and a of knockdown of PINK1 short hairpin and mitochondrial with The of of mitochondrial was in PINK1 knockdown cells to in disease (4Zhu J.-H. Guo F. 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PubMed Scopus Google transient or stable overexpression of wild-type PINK1 increased mitochondrial interconnectivity and with stable cells and stable knockdown of PINK1 induced a fragmentation of the mitochondrial with cells mitochondrial an of of of mitochondria that PINK1-deficient exhibit mitochondria with cells, which a of and overexpression of PINK1 increased mitochondrial PINK1 of and fluorescent and of autophagy to the of PINK1 knockdown C.T. PubMed Scopus Google Scholar). of the protein protein light chain is essential for N. Y. T. 27: PubMed Scopus Google Scholar). The is in the is localized to and by Y. N. T. A. T. T. E. Y. T. J. PubMed Scopus Google Scholar). knockdown of PINK1 increased the to in PINK1 shRNA that loss of PINK1 autophagy The of was in cells with a of or which in S. T. T. 2007; PubMed Scopus Google Scholar). of PINK1 increased the of and and that and are in cell lines. of which A. Y. T. Y. R. Y. PubMed Scopus Google Scholar), autophagic in the PINK1-deficient PINK1 shRNA stable cell with and for of with as an of mitophagy J. Chu C.T. 2008; PubMed Scopus Google Scholar, S. I. 2006; 2: PubMed Scopus Google Scholar). We found that stable knockdown of PINK1 induced autophagic mitochondrial and and to and decreased of mitochondria as by for mitochondrial and proteins and about a in mitochondrial in shRNA overexpression of PINK1 an cells with or RNAi of Atg7 or proteins reversed the loss of mitochondrial autophagic of mitochondria in PINK1-deficient cells PINK1 Overexpression PINK1 J. Chu C.T. 2008; PubMed Scopus Google Scholar). stable knockdown of PINK1 stable PINK1 overexpression suppressed induced autophagy and mitophagy with stable and shRNA that transient of which the sequence by the shRNA, reversed the increased autophagy observed in PINK1 and is also active in against C. S. T. P. A. D.S. Proc. Natl. Acad. Sci. U. S. A. 2008; 105: PubMed Scopus Google Scholar), which is associated with autophagic cell C. Guo F. Watkins S. Y. Chu C.T. J. Pathol. 2007; PubMed Scopus Google Scholar). of PINK1 Mitochondrial and the mechanisms the of PINK1 knockdown mitochondrial used a mitochondrially fluorescent knockdown of PINK1 increased mitochondrial as by that loss of PINK1 mitochondrial and and Moreover, which to affect both and extracellular to of through the and MnTBAP, a that to mitochondria and 2003; 2: PubMed Scopus Google Scholar), reversed mitochondrial induced by loss of PINK1 to to in cells with and of Drp1-DN, which reversed the of PINK1 knockdown mitochondrial not in cell suggesting that of mitochondrial fragmentation in PINK1-deficient cells. shRNA PINK1 knockdown with and with or to the of autophagy induced by PINK1 inhibited autophagy induced by PINK1 also a autophagy and that production is for both mitochondrial fragmentation and autophagy but that its may important for autophagy Mitochondrial for Mitochondrial and in PINK1-deficient mitochondrial fragmentation observed in PINK1 shRNA cell was by We stable and PINK1 shRNA with the activity for in increased mitochondrial interconnectivity in SH-SY5Y cells of mitochondrial interconnectivity and that fission is for the mitochondrial remodeling observed in PINK1-deficient and Interestingly, with as a of autophagy in decreased and mitophagy in to to observed in wild-type and that the mitochondrial fission/fusion regulates mitochondrial induced by PINK1 for Mitochondrial in PINK1 shRNA but for Mitochondrial the of autophagy mitochondrial production and mitochondrial targeting the essential autophagy proteins Atg7 and J. Chu C.T. 2008; PubMed Scopus Google Scholar, C. Guo F. Watkins S. Y. Chu C.T. J. Pathol. 2007; PubMed Scopus Google Scholar, Chu C.T. J. Neurochem. 2008; 105: PubMed Scopus Google Scholar). knockdown of proteins inhibited autophagy in PINK1-deficient but the increased mitochondrial that autophagy of mitochondrial oxidative stress Interestingly, for or Atg7 also reversed the mitochondrial fragmentation observed in cell to to found in cells with of PINK1 and with the in that autophagy is involved in remodeling mitochondria for a role of Thus, fission/fusion and autophagic cooperate in the of mitochondrial remodeling and induced by PINK1 of and Mitochondrial in PINK1 with the that loss of PINK1 is in neuronal cells A. S. Z. A.S. E.A. G. L. I. K. E. J. L. P. J. S. Latchman D. Wood N.W. 2008; PubMed Scopus Google Scholar), found that knockdown of PINK1 a in cell in SH-SY5Y cells associated with an in cell in culture The role of autophagy in cell in PINK1-deficient cells was to autophagy and a of to autophagic further in cell was observed in PINK1 shRNA cells with or Atg7 siRNA, the of which the of stable cell mitochondrial induced by increased cell in cell suggesting that mitochondrial fission is also a protective in the of PINK1 mitophagic responses a role for autophagy in the of PINK1 as a to Parkin and in PINK1-deficient the that Parkin is to mitochondria and autophagy D. A. R.J. J. 2008; PubMed Scopus Google Scholar), the of Parkin in PINK1 knockdown cells. and that transient of a in SH-SY5Y cells increased the of and the of that with mitochondria cell in PINK1 knockdown cell the transient of Parkin mitochondrial morphologic to that transient of Parkin reversed cell induced by loss of PINK1 are to the of PD and Although the of cases are the of genes to parkinsonian pathways oxidative stress, mitochondrial and protein R. Brain Pathol. PubMed Scopus Google Scholar, Science. 2003; PubMed Scopus Google Scholar). the role of proteins implicated in autosomal recessive of PD of for the mechanisms that to or disease The that PINK1 a role in mitochondrial mitochondrial oxidative stress, and and that coordinated of and Parkin pathways are important protective responses for the of the with the that PINK1 is for mitochondrial and homeostasis (2Hoepken H.H. Gispert S. Morales B. Wingerter O. Del Turco D. Mulsch A. Nussbaum R.L. Muller K. Drose S. Brandt U. Deller T. Wirth B. Kudin A.P. Kunz W.S. Auburger G. Neurobiol. Dis. 2007; 25: 401-411Crossref PubMed Scopus (170) Google Scholar, 3Exner N. Treske B. Paquet D. Holmstrom K. Schiesling C. Gispert S. Carballo-Carbajal I. Berg D. Hoepken H.H. Gasser T. Kruger R. Winklhofer K.F. Vogel F. Reichert A.S. Auburger G. Kahle P.J. Schmid B. Haass C. J. Neurosci. 2007; 27: 12413-12418Crossref PubMed Scopus (435) Google Scholar, E.M. Abou-Sleiman P.M. Caputo V. Muqit M.M. Harvey K. Gispert S. Ali Z. Del Turco D. Bentivoglio A.R. Healy D.G. Albanese A. Nussbaum R. Gonzalez-Maldonado R. Deller T. Salvi S. Cortelli P. Gilks W.P. Latchman D.S. Harvey R.J. Dallapiccola B. Auburger G. Wood N.W. Science. 2004; 304: 1158-1160Crossref PubMed Scopus (2701) Google Scholar), found that stable knockdown of PINK1 mitochondrial and mitochondrial and overexpression of PINK1 mitochondrial a role of PINK1 in to a for PINK1 mitochondrial and that both the fission and autophagy are essential for the mitochondrial remodeling that of PINK1-deficient mitochondria and that this mitophagic response a protective mitochondrial as a coordinated of mitochondrial fission and autophagy to of mitochondria Parkin to and the autophagy of mitochondria D. A. R.J. J. 2008; PubMed Scopus Google Scholar). this to mitochondria by PINK1 Parkin the mitophagic response in PINK1 shRNA cell mitochondrial and cell of mitochondrial fission cell by Parkin is not to the mitochondrial a of mechanisms of in which PINK1 mitochondrial and Parkin mitochondria for clearance. Although and cell mitochondrial fragmentation in PINK1-deficient cells N. Treske B. Paquet D. Holmstrom K. Schiesling C. Gispert S. Carballo-Carbajal I. Berg D. Hoepken H.H. Gasser T. Kruger R. Winklhofer K.F. Vogel F. Reichert A.S. Auburger G. Kahle P.J. Schmid B. Haass C. J. Neurosci. 2007; 27: 12413-12418Crossref PubMed Scopus (435) Google Scholar), in the of for mitochondria in mutant loss of function PINK1 Proc. Natl. Acad. Sci. U. S. A. 2008; 105: PubMed Scopus Google Scholar, Y. Y. L. Beal A. Vogel H. B. Proc. Natl. Acad. Sci. U. S. A. 2008; 105: PubMed Scopus Google Scholar). of PINK1 also a in mitochondrial T. J. Proc. Natl. Acad. Sci. U. S. A. 2008; 105: PubMed Scopus Google Scholar). Although mitochondria are small and in PINK1-deficient SH-SY5Y cells, also mitochondrial and mitochondria by this a or the of Parkin to mitochondrial morphologic in PINK1-deficient cells to or through of mitochondrial by that may and N. Treske B. Paquet D. Holmstrom K. Schiesling C. Gispert S. Carballo-Carbajal I. Berg D. Hoepken H.H. Gasser T. Kruger R. Winklhofer K.F. Vogel F. Reichert A.S. Auburger G. Kahle P.J. Schmid B. Haass C. J. Neurosci. 2007; 27: 12413-12418Crossref PubMed Scopus (435) Google Scholar, A. S. Z. A.S. E.A. G. L. I. K. E. J. L. P. J. S. Latchman D. Wood N.W. 2008; PubMed Scopus Google Scholar). is also that fission observed in RNAi in response to mitochondrial to PINK1 which is not observed in to its is that both fission and are induced in response to stress and but the the of and mechanisms in a a role in mitochondrial homeostasis in D. Google Scholar). is known about the of Mitochondrial fission mitophagy in G. A. H. G. L. S. G. J. M. J. J. 2008; 27: PubMed Scopus Google Scholar), and found that loss of PINK1 both mitochondrial fission and the autophagic is not for of mitochondria to but also to mitochondrial fragmentation and of autophagy to increased of but mitochondria autophagy as a of of the autophagy reversed the fragmentation induced by PINK1 and Interestingly, cell in that of different and of mitochondria I. S. Biochem. 2007; PubMed Scopus Google Scholar). Thus, coordinated of fission and autophagic to mitochondrial remodeling for autophagic turnover in PINK1-deficient cells. disease tissues is mitochondrial autophagy associated with increased mitochondrial kinase (4Zhu J.-H. Guo F. Shelburne J. Watkins S. Chu C.T. Brain Pathol. 2003; 13: 473-481Crossref PubMed Scopus (211) Google Scholar). The that overexpression of PINK1 mitochondrial the that mitochondrially localized may a role in mitochondrial The that protein kinase of Drp1 fission S. 2007; PubMed Scopus Google Scholar, C. J. 2007; PubMed Scopus Google that may also mitochondrial fission/fusion although of the PINK1 is known to affect mitochondrial H. K. N. S. S. D. Harvey K. E. Harvey R.J. N. Wood N.W. J. 2007; PubMed Scopus Google Scholar, L. 2007; PubMed Scopus Google Scholar). mitochondrial is strongly implicated in the pathogenesis of PD, mitophagy may a to by may are mitochondrial respiration Chu C.T. 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