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Review
. 2012 Jul;34(1):7-13.
doi: 10.1007/s10059-012-0100-8. Epub 2012 May 18.

PINK1 as a molecular checkpoint in the maintenance of mitochondrial function and integrity

Hyongjong Koh  1 , Jongkyeong Chung
Affiliations
Review

PINK1 as a molecular checkpoint in the maintenance of mitochondrial function and integrity

Hyongjong Koh et al. Mol Cells. 2012 Jul.

Abstract

Parkinson's disease (PD), the most prevalent neurodegenerative movement disorder, is characterized by an age-dependent selective loss of dopaminergic (DA) neurons. Although most PD cases are sporadic, more than 20 responsible genes in familial cases were identified recently. Genetic studies using Drosophila models demonstrate that PINK1, a mitochondrial kinase encoded by a PD-linked gene PINK1, is critical for maintaining mitochondrial function and integrity. This suggests that mitochondrial dysfunction is the main cause of PD pathogenesis. Further genetic and cell biological studies revealed that PINK1 recruits Parkin, an E3 ubiquitin ligase encoded by another PD-linked gene parkin, to mitochondria and regulates the mitochondrial remodeling process via the Parkin-mediated ubiquitination of various mitochondrial proteins. PINK1 also directly phosphorylates the mitochondrial proteins Miro and TRAP1, subsequently inhibiting mitochondrial transport and mitochondrial oxidative damage, respectively. Moreover, recent Drosophila genetic analyses demonstrate that the neuroprotective molecules Sir2 and FOXO specifically complement mitochondrial dysfunction and DA neuron loss in PINK1 null mutants, suggesting that Sir2 and FOXO protect mitochondria and DA neurons downstream of PINK1. Collectively, these recent results suggest that PINK1 plays multiple roles in mitochondrial quality control by regulating its mitochondrial, cytosolic, and nuclear targets.

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Figures

Fig. 1
Fig. 1
Mitochondrial protective roles of PINK1. PINK1 regulates the mitochondrial remodeling process via the Parkin-mediated ubiquitination of a number of mitochondrial proteins, including Mfn and VDAC1. PINK1 also directly phosphorylates the mitochondrial proteins Miro and TRAP1, subsequently preventing mitochondrial trafficking and mitochondrial oxidative damage, respectively. Moreover, PINK1 can induce the expression of mitochondrial protective genes such as SOD2 and 4EBP via the Sir2-FOXO pathway.
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