Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6

Hoepken, Hans-Hermann; Gispert, Suzana; Morales, Blas; Wingerter, Oliver; Turco, Domenico Del; Mülsch, Alexander; Nussbaum, Robert L.; Müller, Klaus; Dröse, Stefan; Brandt, Ulrich; Deller, Thomas; Wirth, Brunhilde; Kudin, Alexei P.; Kunz, Wolfram S.; Auburger, Georg

doi:10.1016/j.nbd.2006.10.007

Cited by 183 publications

(140 citation statements)

References 67 publications

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“…20, we showed that loss-of-function mutations in the Drosophila parkin ortholog result in profound mitochondrial pathology, leading us to argue that Parkin acts to promote mitochondrial integrity. Mitochondrial defects have subsequently been detected in Parkin-deficient worms (33), mice (34), and humans (35,36), and recent studies in Drosophila have shown that PINK1 and Parkin act in a common pathway that influences mitochondrial integrity (22)(23)(24). Our current work advances these findings by providing evidence that the PINK1/ Parkin pathway acts to promote mitochondrial fission.…”

Section: Discussionmentioning

confidence: 54%

The PINK1/Parkin pathway regulates mitochondrial morphology

Poole

Thomas

Andrews

et al. 2008

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

775

660

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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...

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Section: Discussionmentioning

confidence: 54%

The PINK1/Parkin pathway regulates mitochondrial morphology

Poole

Thomas

Andrews

et al. 2008

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

775

660

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“…Moreover, mitochondrial dysfunctions in aging and neurodegenerative disorders such as PD can be detected also in peripheral somatic cells [64][65][66]. Whether the pre-existing perturbation of mitochondrial functionality can be corrected upon iPSC generation is, thus, an essential question that needs to be addressed.…”

Section: Implications For the Use Of Human Ips Cells For In Vitro Modmentioning

confidence: 99%

The Senescence-Related Mitochondrial/Oxidative Stress Pathway is Repressed in Human Induced Pluripotent Stem Cells

et al. 2010

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The ability of stem cells to propagate indefinitely is believed to occur via the fine modulation of pathways commonly involved in cellular senescence, including the telomerase, the p53, and the mitochondrial/oxidative stress pathways. Induced pluripotent stem cells (iPSCs) are a novel stem cell population obtained from somatic cells through forced expression of a set of genes normally expressed in embryonic stem cells (ESCs). These reprogrammed cells acquire self-renewal properties and appear almost undistinguishable from ESCs in terms of morphology, gene expression, and differentiation potential. Accordingly, iPSCs exhibit alterations of the senescence-related telomerase and p53 signaling pathways. However, although treatments with antioxidants have been recently shown to enhance cellular reprogramming, detailed information regarding the state of the mitochondrial/oxidative stress pathway in iPSCs is still lacking. Mitochondria undergo specific changes during organismal development and aging. Thus, addressing whether somatic mitochondria within iPSCs acquire ESC-like features or retain the phenotype of the parental cell is an unanswered but relevant question. Herein, we demonstrate that somatic mitochondria within human iPSCs revert to an immature ESC-like state with respect to organelle morphology and distribution, expression of nuclear factors involved in mitochondrial biogenesis, content of mitochondrial DNA, intracellular ATP level, oxidative damage, and lactate generation. Upon differentiation, mitochondria within iPSCs and ESCs exhibited analogous maturation and anaerobic-to-aerobic metabolic modifications. Overall, the data highlight that human iPSCs and ESCs, although not identical, share similar mitochondrial properties and suggest that cellular reprogramming can modulate the mitochondrial/oxidative stress pathway, thus inducing a rejuvenated state capable of escaping cellular senescence.

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“…Furthermore, loss of PINK1 function in human cell lines originated morphological changes of mitochondria and impaired energy metabolism, showed by a decreased mitochondrial membrane potential [243]. Cells isolated from individuals with a PINK1 mutation that causes a G309D substitution demonstrate reduced complex I activity and evidence of increased oxidative damage compared with cells from age matched controls [246]. Furthermore, PINK1 deficiency in a Drosophila model results in the loss of dopaminergic cells, as well as increased susceptibility to oxidative stress and reduced ATP levels [247].…”

Section: Ptenǧinduced Putative Kinase 1 (Pink1)mentioning

confidence: 99%