Mitochondrial PINK1—A Novel Cardioprotective Kinase?

Siddall, Hilary K.; Warrell, Clare E.; Davidson, Sean M.; Mocanu, Mihaela M.; Yellon, Derek M.

doi:10.1007/s10557-008-6136-5

Cited by 11 publications

(11 citation statements)

References 10 publications

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“…Data from our study suggested significantly decreased Pink1 levels in PTEN knockout mice, implicating a possible role of lost Pink1 signaling in PTEN deletion. This finding is consistent with an earlier report in haploinsufficient PTEN hearts where decreased Pink1 was seen [36]. Perhaps the most intriguing data from our study was decreased AMPK phosphorylation following PTEN deletion.…”

Section: Discussionsupporting

confidence: 94%

Targeted deletion of PTEN in cardiomyocytes renders cardiac contractile dysfunction through interruption of Pink1–AMPK signaling and autophagy

Roe

Kandadi

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Phosphatase and tensin homolog deleted from chromosome 10 (PTEN) has been implicated in the maintenance of cardiac homeostasis although the underlying mechanism(s) remains elusive. We generated a murine model of cardiomyocyte-specific knockout of PTEN to evaluate cardiac geometry and contractile function, as well as the effect of metformin on PTEN deficiency-induced cardiac anomalies, if any. Cardiac histology, autophagy and related signaling molecules were evaluated. Cardiomyocyte-specific PTEN deletion elicited cardiac hypertrophy and contractile anomalies (echocardiographic and cardiomyocyte contractile dysfunction) associated with compromised intracellular Ca2+ handling. PTEN deletion-induced cardiac hypertrophy and contractile anomalies were associated with dampened phosphorylation of PTEN-inducible kinase 1 (Pink1) and AMPK. Interestingly, administration of AMPK activator metformin (200 mg/kg/d, in drinking H2O for 4 weeks) rescued against PTEN deletion-induced geometric and functional defects as well as interrupted autophagy and autophagic flux in the heart. Moreover, metformin administration partially although significantly attenuated PTEN deletion-induced accumulation of superoxide. RNA interference against Pink1 in H9C2 myoblasts overtly increased intracellular ATP levels and suppressed AMPK phosphorylation, confirming the role of AMPK as a downstream target for PTEN-Pink1. Further scrutiny revealed that activation of AMPK and autophagy using metformin and rapamycin, respectively, rescued against PTEN deletion-induced mechanical anomalies with little additive effect. These data demonstrated that cardiomyocyte-specific deletion of PTEN leads to the loss of Pink1-AMPK signaling, development of cardiac hypertrophy and contractile defect. Activation of AMPK rescued against PTEN deletion-induced cardiac anomalies associated with restoration of autophagy and autophagic flux.

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Section: Discussionsupporting

confidence: 94%

Targeted deletion of PTEN in cardiomyocytes renders cardiac contractile dysfunction through interruption of Pink1–AMPK signaling and autophagy

Roe

Kandadi

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…While the necessity for a helix-breaking residue, such as proline, for substrate recognition is not unprecedented with rhomboid proteins (33), this is the first observation that PARL may utilize this mechanism. While we were able to confirm that endogenous PINK1 interacts with PARL in human neuroblastoma cells by mass spectrometry, we are currently unable to assess aberrant PINK1 cleavage in the PARL KO MEFs due to the absence of reliable antibodies capable of detecting both full-length and cleaved PINK1 at the endogenous level (42,43). The inability to examine PINK1 cleavage events using the current PINK1 antibodies is highlighted by the study of Narendra et al .…”

Section: Discussionmentioning

confidence: 83%

PINK1 cleavage at position A103 by the mitochondrial protease PARL

Deas

Plun‐Favreau

Gandhi

et al. 2010

Human Molecular Genetics

416

313

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Mutations in PTEN-induced kinase 1 (PINK1) cause early onset autosomal recessive Parkinson's disease (PD). PINK1 is a 63 kDa protein kinase, which exerts a neuroprotective function and is known to localize to mitochondria. Upon entry into the organelle, PINK1 is cleaved to produce a ∼53 kDa protein (ΔN-PINK1). In this paper, we show that PINK1 is cleaved between amino acids Ala-103 and Phe-104 to generate ΔN-PINK1. We demonstrate that a reduced ability to cleave PINK1, and the consequent accumulation of full-length protein, results in mitochondrial abnormalities reminiscent of those observed in PINK1 knockout cells, including disruption of the mitochondrial network and a reduction in mitochondrial mass. Notably, we assessed three N-terminal PD-associated PINK1 mutations located close to the cleavage site and, while these do not prevent PINK1 cleavage, they alter the ratio of full-length to ΔN-PINK1 protein in cells, resulting in an altered mitochondrial phenotype. Finally, we show that PINK1 interacts with the mitochondrial protease presenilin-associated rhomboid-like protein (PARL) and that loss of PARL results in aberrant PINK1 cleavage in mammalian cells. These combined results suggest that PINK1 cleavage is important for basal mitochondrial health and that PARL cleaves PINK1 to produce the ΔN-PINK1 fragment.

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“…In this regard, the mitochondrial serine-threonine protein kinase, PTEN (phosphatase and tensin homologue on chromosome 10)-induced kinase 1 (PINK1), may provide a novel therapeutic target for cardioprotection [1]. Mutations in the PINK1 gene are responsible for the autosomal recessive PARK6 inherited form of early onset Parkinson disease, a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra [2].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, PINK1 protein is highly expressed in the myocardium [12] but its role in the heart, is not clear [1], [13]. Given its beneficial effects on mitochondrial function and neuroprotective properties, we investigated whether PINK1 could also protect the heart against acute IRI.…”

Section: Introductionmentioning

confidence: 99%

Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury

et al. 2013

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ObjectivesMutations in PTEN inducible kinase-1 (PINK1) induce mitochondrial dysfunction in dopaminergic neurons resulting in an inherited form of Parkinson’s disease. Although PINK1 is present in the heart its exact role there is unclear. We hypothesized that PINK1 protects the heart against acute ischemia reperfusion injury (IRI) by preventing mitochondrial dysfunction.Methods and ResultsOver-expressing PINK1 in HL-1 cardiac cells reduced cell death following simulated IRI (29.2±5.2% PINK1 versus 49.0±2.4% control; N = 320 cells/group P<0.05), and delayed the onset of mitochondrial permeability transition pore (MPTP) opening (by 1.3 fold; P<0.05). Hearts excised from PINK1+/+, PINK1+/− and PINK1−/− mice were subjected to 35 minutes regional ischemia followed by 30 minutes reperfusion. Interestingly, myocardial infarct size was increased in PINK1−/− hearts compared to PINK1+/+ hearts with an intermediate infarct size in PINK1+/− hearts (25.1±2.0% PINK1+/+, 38.9±3.4% PINK1+/− versus 51.5±4.3% PINK1−/− hearts; N>5 animals/group; P<0.05). Cardiomyocytes isolated from PINK1−/− hearts had a lower resting mitochondrial membrane potential, had inhibited mitochondrial respiration, generated more oxidative stress during simulated IRI, and underwent rigor contracture more rapidly in response to an uncoupler when compared to PINK1+/+ cells suggesting mitochondrial dysfunction in hearts deficient in PINK1.ConclusionsWe show that the loss of PINK1 increases the heart's vulnerability to ischemia-reperfusion injury. This may be due, in part, to increased mitochondrial dysfunction. These findings implicate PINK1 as a novel target for cardioprotection.

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Mitochondrial PINK1—A Novel Cardioprotective Kinase?

Cited by 11 publications

References 10 publications

Targeted deletion of PTEN in cardiomyocytes renders cardiac contractile dysfunction through interruption of Pink1–AMPK signaling and autophagy

Targeted deletion of PTEN in cardiomyocytes renders cardiac contractile dysfunction through interruption of Pink1–AMPK signaling and autophagy

PINK1 cleavage at position A103 by the mitochondrial protease PARL

Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury

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