PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy

Matsuda, Noriyuki; Sato, Shigeto; Shiba, Kahori; Okatsu, Kei; Saisho, Keiko; Gautier, Camille; Sou, Yu‐shin; Saiki, Sachio; Kawajiri, Sumihiro; Sato, Fumiaki; Kimura, Mayumi; Komatsu, Masaaki; Hattori, Nobutaka; Tanaka, Keiji

doi:10.1083/jcb.200910140

Cited by 1,680 publications

(1,646 citation statements)

References 33 publications

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“…Later studies have supported Narendra's findings showing that PINK1 acts upstream from Parkin, and that both proteins are recruited to depolarized mitochondria (Kim et al, 2008;Kawajiri et al, 2010;Matsuda et al, 2010;Vives-Bauza et al, 2010). The DJ-1 protein, already known by its antioxidant, chaperone-like and transcriptional modulator functions, has been recently proposed to act in parallel with PINK1 and…”

Section: Linking Oxidative Stress and Mitochondrial Dynamics In Pd Amentioning

confidence: 72%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

144

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For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

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Section: Linking Oxidative Stress and Mitochondrial Dynamics In Pd Amentioning

confidence: 72%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

144

View full text Add to dashboard Cite

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“…The serine/threonine kinase PTEN‐induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin play indispensable roles in mitophagy 49, 50. Disruption of either leads to the failure of selective degradation of impaired mitochondria 51, 52.…”

Section: Discussionmentioning

confidence: 99%

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Wang

Zhao

Feng

et al. 2018

J Cellular Molecular Medi

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Mitophagy eliminates dysfunctional mitochondria and thus plays a cardinal role in diabetic cardiomyopathy (DCM). We observed the favourable effects of melatonin on cardiomyocyte mitophagy in mice with DCM and elucidated their underlying mechanisms. Electron microscopy and flow cytometric analysis revealed that melatonin reduced the number of impaired mitochondria in the diabetic heart. Other than decreasing mitochondrial biogenesis, melatonin increased the clearance of dysfunctional mitochondria in mice with DCM. Melatonin increased LC3 II expression as well as the colocalization of mitochondria and lysosomes in HG‐treated cardiomyocytes and the number of typical autophagosomes engulfing mitochondria in the DCM heart. These results indicated that melatonin promoted mitophagy. When probing the mechanism, increased Parkin translocation to the mitochondria may be responsible for the up‐regulated mitophagy exerted by melatonin. Parkin knockout counteracted the beneficial effects of melatonin on the cardiac mitochondrial morphology and bioenergetic disorders, thus abolishing the substantial effects of melatonin on cardiac remodelling with DCM. Furthermore, melatonin inhibited Mammalian sterile 20‐like kinase 1 (Mst1) phosphorylation, thus enhancing Parkin‐mediated mitophagy, which contributed to mitochondrial quality control. In summary, this study confirms that melatonin rescues the impaired mitophagy activity of DCM. The underlying mechanism may be attributed to activation of Parkin translocation via inhibition of Mst1.

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“…UbVS experiments show that the reactivity of C431 in RING2(Rcat) is slightly diminished in the presence of UbcH7‐Ub (compared to its absence in pParkin:pUb), suggesting possible rearrangement and protection might impede its reactivity in this assay. Further, the region immediately preceding the RING2(Rcat) domain contains a ubiquitin‐binding motif (Chaugule et al , 2011) that harbours at least one ARJP substitution (T415N) that impairs all ubiquitination activity (Matsuda et al , 2010). A similar ubiquitin‐binding motif has been observed for HHARI, and substitutions in this region show significant decreases in Ub affinity and ubiquitination activity (Dove et al , 2016).…”

Section: Discussionmentioning

confidence: 99%

Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation

et al. 2018

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The E3 ligase parkin ubiquitinates outer mitochondrial membrane proteins during oxidative stress and is linked to early‐onset Parkinson's disease. Parkin is autoinhibited but is activated by the kinase PINK1 that phosphorylates ubiquitin leading to parkin recruitment, and stimulates phosphorylation of parkin's N‐terminal ubiquitin‐like (pUbl) domain. How these events alter the structure of parkin to allow recruitment of an E2~Ub conjugate and enhanced ubiquitination is an unresolved question. We present a model of an E2~Ub conjugate bound to the phospho‐ubiquitin‐loaded C‐terminus of parkin, derived from NMR chemical shift perturbation experiments. We show the UbcH7~Ub conjugate binds in the open state whereby conjugated ubiquitin binds to the RING1/IBR interface. Further, NMR and mass spectrometry experiments indicate the RING0/RING2 interface is re‐modelled, remote from the E2 binding site, and this alters the reactivity of the RING2(Rcat) catalytic cysteine, needed for ubiquitin transfer. Our experiments provide evidence that parkin phosphorylation and E2~Ub recruitment act synergistically to enhance a weak interaction of the pUbl domain with the RING0 domain and rearrange the location of the RING2(Rcat) domain to drive parkin activity.

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PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy

Abstract: Defective mitochondrial quality control is shown to be a mechanism for neurodegeneration in some forms of Parkinson's disease.

Cited by 1,680 publications

References 33 publications

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation

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