PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

Abstract

Parkinson's disease (PD), the most prevalent neurodegenerative movement disorder, is characterized by an agedependent 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.

Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1) Mutation and TRAP1 Inhibitor Gamitrinib-triphenylphosphonium (G-TPP) Induce a Forkhead Box O (FOXO)-dependent Cell Protective Signal from Mitochondria

“…Resistance to oxidative stress is often closely related to mitochondrial function and integrity (4), and ROS sensitivity is dramatically increased in flies lacking a familial PD gene PINK1 (5,8). Under rotenone treatment, PINK1 null mutants (B9) showed decreased survival rates compared with WT controls as previously reported (Fig.…”

“…Further genetic and cell biological studies revealed that PINK1 translocates Parkin, an E3 ubiquitin ligase encoded by another familial PD gene parkin, to mitochondria and regulates mitochondrial remodeling processes such as mitochondrial fusion/fission and mitophagy. Moreover, PINK1 also regulates mitochondrial trafficking, mitochondrial protective gene expression, and complex I activity through various partners, suggesting PINK1 as a molecular checkpoint in the maintenance of mitochondrial function and integrity (8).…”

Beneficial Effects of AMP-Activated Protein Kinase Agonists in Kidney Ischemia-Reperfusion: Autophagy and Cellular Stress Markers

“…In fact, the rapidly degraded mitochondrial protein, PINK1, is stabilized by mitochondrial depolarization [38], which begins sequential steps in the selective autophagic degradation of the mitochondria, or mitophagy [39–41]. Mitophagy is an efficient mechanism for the cell to maintain quality control over aged or damaged mitochondria to avoid cell death [42–44]. As observed, the significant induction of PINK1 in IR rats was normalized with the addition of AMPK agonists (Fig.…”

PINK1 signalling in cancer biology

“…These properties of PINK1 have been shown to be implemented by both mitochondrial and cytosolic functions of PINK1, and mechanistically through proteasomal [45][46][47] and autophagic [48,49] pathways, and via PI3-kinase/Akt/mTOR [37,41,50,51], NFκB [52,53] and calcium dependent signalling [54][55][56]. Moreover, PINK1 has a primary function in mitochondrial homeostasis and dynamics, including mitophagy, bioenergetics, fission and fusion [49,54,[57][58][59][60][61][62][63][64][65][66][67][68][69][70].…”