The PINK1/Parkin pathway regulates mitochondrial morphology

Abstract

Loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) or parkin genes, which encode a mitochondrially localized serine/ threonine kinase and a ubiquitin-protein ligase, respectively, result in recessive familial forms of Parkinsonism. Genetic studies in Drosophila indicate that PINK1 acts upstream of Parkin in a common pathway that influences mitochondrial integrity in a subset of tissues, including flight muscle and dopaminergic neurons. The mechanism by which PINK1 and Parkin influence mitochondrial integrity is currently unknown, although mutations in the PINK1 and parkin genes result in enlarged or swollen mitochondria, suggesting a possible regulatory role for the PINK1/Parkin pathway in mitochondrial morphology. To address this hypothesis, we examined the influence of genetic alterations affecting the machinery that governs mitochondrial morphology on the PINK1 and parkin mutant phenotypes. We report that heterozygous loss-offunction mutations of drp1, which encodes a key mitochondrial fission-promoting component, are largely lethal in a PINK1 or parkin mutant background. Conversely, the flight muscle degeneration and mitochondrial morphological alterations that result from mutations in PINK1 and parkin are strongly suppressed by increased drp1 gene dosage and by heterozygous loss-of-function mutations affecting the mitochondrial fusion-promoting factors OPA1 and Mfn2. Finally, we find that an eye phenotype associated with increased PINK1/Parkin pathway activity is suppressed by perturbations that reduce mitochondrial fission and enhanced by perturbations that reduce mitochondrial fusion. Our studies suggest that the PINK1/Parkin pathway promotes mitochondrial fission and that the loss of mitochondrial and tissue integrity in PINK1 and parkin mutants derives from reduced mitochondrial fission.caused by the degeneration of dopaminergic neurons in the midbrain. The molecular mechanisms underlying neurodegeneration in PD remain unclear, although substantial evidence suggests that mitochondrial dysfunction is a major contributor: Several mitochondrial toxins induce PD-like symptoms in humans and animal models (1, 2); systemic mitochondrial dysfunction appears to be a feature of a large proportion of PD sufferers (3); and several genes involved in rare heritable forms of Parkinsonism have been implicated in mitochondrial biology, including the PTEN-induced kinase 1 (PINK1) and parkin genes (4, 5).The PINK1 and parkin genes encode a mitochondrially localized serine/threonine kinase and an E3 ubiquitin-protein ligase, respectively (6-13). Although a number of substrates of PINK1 and Parkin have been described, these advances have led to dramatically varying models of pathogenesis (5,(14)(15)(16)(17)(18)(19), making it unclear precisely how PINK1 and Parkin influence neuronal integrity. Genetic studies of highly conserved Drosophila orthologs of parkin and PINK1 indicate that PINK1 acts upstream of Parkin in a common pathway that influences the integrity of flight muscle, sperm, and a subset of dopaminer...

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

“…Moreover, further genetic analyses using mitochondrial fusionfission regulators demonstrated that PINK1 and parkin mutant phenotypes are successfully rescued by the overexpression of Drp1, a dynamin-related GTPase that promotes mitochondrial fission, or the downeregulation of Opa1 or Marf, which are other dynamin-related GTPases that induce mitochondrial fusion (Deng et al, 2008;Park et al, 2009;Poole et al, 2008;Yang et al, 2008). These findings suggest that PINK1 and Parkin balance mitochondrial dynamics by promoting mitochondrial fission to properly maintain mitochondrial function.…”

The pathways of mitophagy for quality control and clearance of mitochondria

“…A genetic interaction between the PINK1/Parkin pathway and the fission/fusion machinery was discovered in flies where overexpression of Drp1 led to suppression of mitochondrial defects in PINK1 and Parkin mutants. 66 Although similar studies in mammalian systems have produced contradictory results, 64,67 the findings in the fly indicate that PINK1 and Parkin promote fission. Consistent with this conclusion, mammalian and fly studies indicate that upon mitochondrial depolarization, Parkin translocates to mitochondria and causes polyubiquitination of Mitofusin, targeting it for removal from the mitochondrial membrane by the p97 AAA-ATPase and subsequent proteosomal degradation [55][56][57] ( Figure 4bi).…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Therefore, defective mitophagy due to a lack of parkin recruitment to impaired mitochondria by PINK1 causes the accumulation of dysfunctional mitochondria and a subsequent enhanced ROS levels and proapoptotic proteins [257]. In addition, overexpression of PINK1 promotes mitochondrial fission, while inhibition of the protein causes an excessive fusion [258,259]. Fibroblasts from PD patients carrying homozygous PINK1 mutations had truncated mitochondria networks compared to control fibroblasts, when cultured in medium with low glucose, or in the presence of galactose to favor mitochondrial energy metabolism over glycolysis [243,260].…”