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

By R. Dagda, Salvatore J Cherra, S. Kulich, A. Tandon, David S. Park, C. Chu. Journal of Biological Chemistry, 2009

958 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/92aa4af63ba903008fb7b4a29696540320b88290

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Citations in the corpus

Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, positive): “…in mitochondrial membrane potential, and respiration defects (Exner et al , 2007; Hoepken et al , 2007; Gautier et al , 2008; Piccoli et al , 2008; Dagda et al , 2009, 2011; Gegg et al , 2009; Gispert et al , 2009; Lutz et al , 2009; Sandebring et al , 2009; Cui et al , 2010; Yuan et al , 2010;…”
Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases (2009, background): “Knockdown of Pink1 in SH-SyY5Y cells induces mitochondrial fragmentation, accumulation of mitochondrially-targeted autophagosomes and increased cell death (55).”
The Role of Oxidative Stress in Parkinson’s Disease (2013, background): “PINK1 deficiency results in shortening, swelling and fragmentation of mitochondria in cultured cells [150, 316–319] associated with loss of mitochondrial enzyme activity, particularly that of Complex I [151, 320–323].”
The Interplay Between Mitochondrial Dynamics and Mitophagy (2011, background): “In an animal model of Alzheimer disease (116, 117) and a culture model of Parkinson disease (17), mitochondrial architecture was fragmented and the relative mitochondrial mass in APs was shown to be selectively increased (71).”
Autophagy-Dependent Ferroptosis: Machinery and Regulation (2020, background): “In addition, the inhibition of mitochondrial fission by the depletion of dynamin 1 like (DNM1L/DRP1) or fission, mitochondrial 1 (FIS1) reduces the levels of mitophagy, whereas mitophagy deficiency increases mitochondrial fragmentation (Dagda et al., 2009; Kageyama et al., 2014).”
Mitochondrial Dysfunction in Parkinson's Disease (2011, background): “Knockdown of PINK1 has been shown to induce mitochondrial oxidative stress, mitochondrial fragmentation, and autophagy and dysregulate calcium homeostasis in SH-SY5Y cells [76, 98].”
Autophagy gone awry in neurodegenerative diseases (2010, neutral): “Mutant forms of these proteins disrupt mitophagy at different steps—translocation, aggregation, ubiquitination and autophagic clearanc”
Mitochondria-Ros Crosstalk in the Control of Cell Death and Aging (2011, background): “Recently, it has been shown that knockdown of PINK1 expression also leads to mitophagy in SH-SY 5Y cells, due to mitochondrial fragmentation and mitochondrial ROS production [145].”
Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin (2010, background): “First, immediately after depolarization, 1377PINK1- and Parkin-mediated proteasomal degradation of Mfn1 and Mfn2 • Tanaka et al. (Exner et al., 2007; Dagda et al., 2009; Lutz et al., 2009; Sandebring et al., 2009).”
PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin (2010, background): “Mitochondria in these cells or tissues exhibit electron transport chain (ETC) dysfunction, diminished membrane potential, increased reactive oxygen species production, mitochondrial fragmentation, and calcium dysregulation, among other abnormalities [20,32,34,51].”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, positive): “Overall, it is important to quantify mitophagy at various stages (initiation, progression, and late mitophagy) to identify stimuli that elicit this process.(757,758)”
Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells (2013, methodology): “A previously characterized stable PINK1-3xFlag expressing SH-SY5Y line (#24, Dagda et al 2009 Reference 45), was treated with FCCP (2μM x 4 hrs) beginning at 72 h after transfection with siCtrl or siPLS3.”
Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. (2010, background): “A recent study has reported that the stable knockdown of PINK1 by RNAi activates autophagy/ mitophagy (28).”
Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates Mitofusin (2010, background): “However, the effects of parkin or PINK1 deficiency in mammalian cells remain unresolved since additional reports describe inconsistent phenotypes in PINK1 and parkin deficient cells (6, 14-17).”