Loss of PINK1 Function Promotes Mitophagy through Effects on Oxidative Stress and Mitochondrial Fission

Dagda, Ruben K.; Cherra, Salvatore J.; Kulich, Scott; Tandon, Anurag; Park, David; Chu, Charleen T.

doi:10.1074/jbc.m808515200

Cited by 848 publications

(949 citation statements)

References 59 publications

(28 reference statements)

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“…Inhibition of Pink1 induces fragmented mitochondria, altered cristae morphology and reduced membrane potential 34 . Overexpression of Pink1 rescues mitochondrial fragmentation 35 , increases mitochondrial interconnectivity 12 and reduces mitochondrial dysfunction and apoptosis as well 36 . Our present study for the first time reveals that Pink1 can maintain the cardiac structure and function through its protective effect on the mitochondria.…”

Section: Pink1 Inhibits Mitochondrial Fragmentation and Apoptosismentioning

confidence: 98%

“…The dysfunction of this signalling usually leads to neurodegeneration. Pink1 loss of function increases mitochondrial fission in Drosophila and mammalian neurons 12 . Recent study has also shown that overexpression of Pink1 in HL-1 cardiac cells reduces cell death post ischaemia/reperfusion (I/R), and Pink1-knockout (KO) mice are more susceptible to I/R injury compared with wild-type (WT) mice 13 .…”

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confidence: 99%

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E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

Wang

Zhou

et al. 2015

Nat Commun

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Mitochondrial fragmentation plays an important role in the progression of cardiac diseases, such as myocardial infarction and heart failure. Mitochondrial network is controlled by many factors in different cell types. Here we show that the interplay between E2F1, miR-421 and Pink1 regulates mitochondrial morphology and cardiomyocyte cell death. Pink1 reduces mitochondrial fragmentation and protects cardiomyocyte from apoptosis. On the other hand, miR-421 promotes cardiomyocyte mitochondrial fragmentation, apoptosis and myocardial infarction by suppressing Pink1 translation. Finally, we show that transcription factor E2F1 activates miR-421 expression. Knocking down E2F1 suppresses mitochondrial fragmentation, apoptosis and myocardial infarction by affecting miR-421 levels. Collectively, these data identify the E2F1/miR-421/Pink axis as a regulator of mitochondrial fragmentation and cardiomyocyte apoptosis, and suggest potential therapeutic targets in treatment of cardiac diseases.

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Section: Pink1 Inhibits Mitochondrial Fragmentation and Apoptosismentioning

confidence: 98%

mentioning

confidence: 99%

E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

Wang

Zhou

et al. 2015

Nat Commun

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“…However, the link between mitochondrial dysfunction and PD is not yet clearly elucidated (Xie et al, 2010). In the last years, mutations in genes encoding proteins related directly or indirectly to mitochondrial function, PINK1, PARKIN, DJ-1, LRRK2 and SNCA, have been reported and implicated in the appearance of PD (Albrecht, 2005;Andres-Mateos et al, 2007;Dodson and Guo, 2007;Devi et al, 2008;Ramsey and Giasson, 2008;Dagda et al, 2009). …”

Section: In Parkinson´s Diseasementioning

confidence: 99%

“…The reason for this emerging research field was the discovery of mutations in PD-related genes such as Park2, which encodes the E3ubiquitin ligase Parkin; PINK1 (Park6), encoding the PTEN-induced kinase 1, and DJ-1 (also called Park7), which causes familial PD (Andres-Mateos et al, 2007;Dodson and Guo, 2007;Devi et al, 2008;Ramsey and Giasson, 2008;Dagda et al, 2009). The proteins encoded by these genes have been implicated in the maintenance of a healthy mitochondria population through a combined system of mitochondrial dynamics and autophagy that involves the specific elimination of some mitochondria, a process that was termed mitophagy (Lemasters, 2005;Kim et al, 2007;Twig et al, 2008a;Twig et al, 2008b).…”

Section: Linking Oxidative Stress and Mitochondrial Dynamics In Pd Amentioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

136

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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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“…In this way dysfunctional mitochondria become spatially separated from the intact network and, importantly, distinguishable from intact mitochondria. This is needed to prime them for their selective degradation by autophagy (mitophagy) and several reports have confirmed that mitochondrial fission is indeed required for the selective removal of mitochondria in mammals [37,38,[47][48][49][50]. Damaged mitochondria are subsequently marked by stabilization of PINK1 at the outer membrane and by recruitment of PARKIN [17,18] which represent early steps in mitophagy.…”

Section: Introductionmentioning

confidence: 99%

Quality control of mitochondria during aging: Is there a good and a bad side of mitochondrial dynamics?

2013

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Maintenance of functional mitochondria is essential in order to prevent degenerative processes leading to disease and aging. Mitochondrial dynamics plays a crucial role in ensuring mitochondrial quality but may also generate and spread molecular damage through a population of mitochondria. Computational simulations suggest that this dynamics is advantageous when mitochondria are not or only marginally damaged. In contrast, at a higher degree of damage, mitochondrial dynamics may be disadvantageous. Deceleration of fusion‐fission cycles could be one way to adapt to this situation and to delay a further decline in mitochondrial quality. However, this adaptive response makes the mitochondrial network more vulnerable to additional molecular damage. The “mitochondrial infectious damage adaptation” (MIDA) model explains a number of inconsistent and counterintuitive data such as the “clonal expansion” of mutant mitochondrial DNA. We propose that mitochondrial dynamics is a double‐edged sword and suggest ways to test this experimentally.

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Loss of PINK1 Function Promotes Mitophagy through Effects on Oxidative Stress and Mitochondrial Fission

Abstract: Mitochondrial dysregulation is strongly implicated in

Cited by 848 publications

References 59 publications

E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Quality control of mitochondria during aging: Is there a good and a bad side of mitochondrial dynamics?

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