Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress

Gautier, Camille; Kitada, Tohru; Shen, Jie

doi:10.1073/pnas.0802076105

Cited by 616 publications

(585 citation statements)

References 39 publications

(48 reference statements)

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“…The resulting mitochondrial damage may also further translate to the activation of signaling pathways involved in the development of cardiac hypertrophy and subsequent reduced contractility. Indeed, this premise is supported by observations made by others, in that a role for PINK1 has been linked to the maintenance of mitochondrial function (6,7,23,24). However, if we are to understand exactly how PINK1 affects mitochondria, the identity of potential substrates and/or interacting partners within the mitochondrion would be important to define if a kinase activity is indeed required for PINK1 function.…”

Section: Discussionmentioning

confidence: 75%

PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function

Billia

Hauck

Konecny

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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324

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Oxidative stress is caused by an imbalance between reactive oxygen species (ROS) production and the ability of an organism to eliminate these toxic intermediates. Mutations in PTEN-inducible kinase 1 (PINK1) link mitochondrial dysfunction, increased sensitivity to ROS, and apoptosis in Parkinson's disease. Whereas PINK1 has been linked to the regulation of oxidative stress, the exact mechanism by which this occurs has remained elusive. Oxidative stress with associated mitochondrial dysfunction leads to cardiac dysfunction and heart failure (HF). We hypothesized that loss of PINK1 in the heart would have deleterious consequences on mitochondrial function. Here, we observed that PINK1 protein levels are markedly reduced in end-stage human HF. We also report that PINK1 localizes exclusively to the mitochondria. PINK1 −/− mice develop left ventricular dysfunction and evidence of pathological cardiac hypertrophy as early as 2 mo of age. Of note, PINK1 −/− mice have greater levels of oxidative stress and impaired mitochondrial function. There were also higher degrees of fibrosis, cardiomyocyte apoptosis, and a reciprocal reduction in capillary density associated with this baseline cardiac phenotype. Collectively, our in vivo data demonstrate that PINK1 activity is crucial for postnatal myocardial development, through its role in maintaining mitochondrial function, and redox homeostasis in cardiomyocytes. In conclusion, PINK1 possesses a distinct, nonredundant function in the surveillance and maintenance of cardiac tissue homeostasis.mitochondrial swelling | mitochonopathy | mitochondrial energetics H eart failure (HF) is the inability of the heart to adequately pump blood to meet the demands of the body. It is the leading cause of morbidity and mortality in North America (1). The quality of life and the prognosis for this group of patients remains poor with 1-y survival rates less than 40% (1). Conventional pharmacological therapy, which only slows the progression of the disease by alleviating the workload of the heart, does not directly target the disease process itself. Alternatives to medical therapy are limited to transplantation or mechanical assist devices; approaches that are themselves associated with significant morbidity and mortality. As such, it is exceedingly important to discover alternate strategies that will effectively treat this disease entity.Oxidative stress is created by the imbalance between production of reactive oxygen species (ROS) and the elimination of toxic intermediates by antioxidant systems. The heart with its high metabolic state and limited capacity for regeneration is particularly sensitive to oxidative stress. Upon exposure to ROS, the heart undergoes hypertrophic growth, a process that involves cell enlargement, myofibrillar disarray, and reexpression of fetal genes (2). Although cardiac hypertrophy is considered an initial adaptive response, prolonged hypertrophy is ultimately detrimental and leads to progressive HF.The discovery of recessively inherited mutations in PTENinducible ...

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Section: Discussionmentioning

confidence: 75%

PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function

Billia

Hauck

Konecny

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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324

277

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“…Factors that regulate mitochondrial morphology have been shown to interact genetically with pink1 (5-7), and the pink1-deficient phenotype in Drosophila can be rescued by a component of the mitochondrial electron transport chain complex or a mitochondrial electron carrier (8,9). Respiratory chain defects have been reported in Pink1 Ϫ/Ϫ mouse embryonic fibroblasts (10), and some morphological and functional defects of mitochondria have been observed in the striatum of Pink1 null mice; Pink1 knock-out mice, however, do not exhibit any obvious morphological changes or loss of dopaminergic neurons in the substantia nigra (11,12). These findings indicate that PINK1 contributes to mitochondrial integrity.…”

mentioning

confidence: 99%

A Dimeric PINK1-containing Complex on Depolarized Mitochondria Stimulates Parkin Recruitment

Okatsu

Uno

Koyano

et al. 2013

Journal of Biological Chemistry

191

166

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Background: PINK1 functions on depolarized mitochondria. However, details regarding its mechanism remain limited. Results: We reveal the formation of a high molecular weight complex composed of two phosphorylated PINK1 molecules that stimulates Parkin recruitment. Conclusion:The dimeric PINK1-containing complex is important for mitochondrial quality control. Significance: The PINK1 molecular process is reminiscent of receptor kinase dimerization in signal transduction.

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“…The endogenous role of PINK1 at this site is unknown. However, PINK1-deficient cells display altered calcium homeostasis at the mitochondria as well as altered mitochondrial function (14). Processed PINK1 at the inner mitochondrial membrane has also been proposed to be shuttled to the cytosol, where it is degraded by the proteasome (15).…”

mentioning

confidence: 99%

BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

Hage

Don-Carolis

et al. 2015

Journal of Biological Chemistry

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Emerging evidence has demonstrated a growing genetic component in Parkinson disease (PD). For instance, loss-of-function mutations in PINK1 or PARKIN can cause autosomal recessive PD. Recently, PINK1 and PARKIN have been implicated in the same signaling pathway to regulate mitochondrial clearance through recruitment of PARKIN by stabilization of PINK1 on the outer membrane of depolarized mitochondria. The precise mechanisms that govern this process remain enigmatic. In this study, we identify Bcl2-associated athanogene 2 (BAG2) as a factor that promotes mitophagy. BAG2 inhibits PINK1 degradation by blocking the ubiquitination pathway. Stabilization of PINK1 by BAG2 triggers PARKIN-mediated mitophagy and protects neurons against 1-methyl-4-phenylpyridinium-induced oxidative stress in an in vitro cell model of PD. Collectively, our findings support the notion that BAG2 is an upstream regulator of the PINK1/PARKIN signaling pathway. Parkinson disease (PD)2 is the second most common neurodegenerative disorder, characterized by selective loss of the pigmented dopaminergic neurons of the substantia nigra pars compacta (1). Although most PD cases are sporadic in nature (2), mutations in several genes have been linked to familial forms of PD (reviewed in Ref.3). Indeed, these familial genes serve as important vehicles to study the potential mechanisms of pathogenesis in PD. In this regard, increasing evidence suggests that mitochondrial dysfunction may play a critical role in both the inherited and sporadic forms of PD, although the precise role of mitochondrial dysfunction in PD is unclear (4). Recently, two familial recessive PD genes, PTEN-induced putative kinase 1 (PINK1), a mitochondrially localized serine/threonine kinase gene, and PARKIN, an E3 ubiquitin ligase gene, have been identified as acting along similar pathways in regulating mitochondrial quality control in mammalian systems (5-8). These findings are supported by genetic studies in Drosophila models of PD that show that PARKIN and PINK1 function in a common pathway, with PARKIN being a downstream player of PINK1 (9 -11). A third recessive PD gene, DJ-1, associated with the regulation of oxidative stress, also regulates PINK1/PARKIN-mediated control of mitochondrial health (12).PINK1 is normally shuttled to the inner mitochondrial membrane where it is processed by multiple proteases (13). The endogenous role of PINK1 at this site is unknown. However, PINK1-deficient cells display altered calcium homeostasis at the mitochondria as well as altered mitochondrial function (14). Processed PINK1 at the inner mitochondrial membrane has also been proposed to be shuttled to the cytosol, where it is degraded by the proteasome (15). However, under conditions of mitochondrial stress such as treatment with the mitochondrial uncoupler carbonyl cyanide p-chlorophenylhydrazone (CCCP) or with the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP ϩ ), PINK1 can also regulate mitophagy in a PARKIN-dependent fashion (12, 16 -19). The framework by which this mitochondrial ...

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Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress

Cited by 616 publications

References 39 publications

PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function

PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function

A Dimeric PINK1-containing Complex on Depolarized Mitochondria Stimulates Parkin Recruitment

BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

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