Inhibiting Drp1-mediated mitochondrial fission selectively prevents the release of cytochrome c during apoptosis

Estaquier, Jérǒme; Arnoult, Damien

doi:10.1038/sj.cdd.4402107

Cited by 293 publications

(242 citation statements)

References 38 publications

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“…Disruption of mitochondrial morphological dynamics sensitizes cells to apoptotic cell death (9,24,25), and recent studies have reported that disturbances within the balance of these two processes can implicate the outcome of cardiovascular disease and neurodegenerative disease (20). In this study, we show that ischemic challenge in myocytes promotes translocation of Drp1 to His-Pim-1 (wild-type, kinase dead) was expressed in Escherichia coli and affinitypurified for use in the kinase assay.…”

Section: Discussionmentioning

confidence: 87%

“…In addition to steadystate activity, Drp1 is also associated with early apoptosis (4,(7)(8)(9)(10). Cellular stress increases Drp1 shuttling, which leads to fragmented mitochondrial networks, whereas prolonged or severe insult promotes stabilization of Drp1 to the mitochondria, which increases the likelihood of progression to apoptotic cell death (7,8,(11)(12)(13).…”

mentioning

confidence: 99%

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Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Din

Mason

Völkers

et al. 2013

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

116

121

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Mitochondrial morphological dynamics affect the outcome of ischemic heart damage and pathogenesis. Recently, mitochondrial fission protein dynamin-related protein 1 (Drp1) has been identified as a mediator of mitochondrial morphological changes and cell death during cardiac ischemic injury. In this study, we report a unique relationship between Pim-1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemic stress. Transgenic hearts overexpressing cardiac Pim-1 display reduction of total Drp1 protein levels, increased phosphorylation of Drp1-S637 , and inhibition of Drp1 localization to the mitochondria. Consistent with these findings, adenoviral-induced Pim-1 neonatal rat cardiomyocytes (NRCMs) retain a reticular mitochondrial phenotype after simulated ischemia (sI) and decreased Drp1 mitochondrial sequestration. Interestingly, adenovirus Pimdominant negative NRCMs show increased expression of Bcl-2 homology 3 (BH3)-only protein p53 up-regulated modulator of apoptosis (PUMA), which has been previously shown to induce Drp1 accumulation at mitochondria and increase sensitivity to apoptotic stimuli. Overexpression of the p53 up-regulated modulator of apoptosis-dominant negative adenovirus attenuates localization of Drp1 to mitochondria in adenovirus Pim-dominant negative NRCMs promotes reticular mitochondrial morphology and inhibits cell death during sI. Therefore, Pim-1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to sI.

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Section: Discussionmentioning

confidence: 87%

mentioning

confidence: 99%

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Din

Mason

Völkers

et al. 2013

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

116

121

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“…For instance, downregulation of Drp1 partially inhibits the release of cytochrome c, but does not inhibit the release of Smac/DIABLO. Subsequently, it only delays but not inhibits apoptosis 39 . Overexpression of OPA1 does not protect ischaemia-induced apoptosis, although it alters mitochondrial dynamics 40 .…”

Section: Pink1 Inhibits Mitochondrial Fragmentation and Apoptosismentioning

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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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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“…Mitochondrial fission critically depends on the GTPase dynaminrelated protein 1 (Drp1) (14), which oligomerizes on the outer mitochondrial membrane to constrict mitochondria at division sites (15). Mitochondrial fission also occurs during apoptosis and may be required for apoptosis progression under specific circumstances (16), although it does not induce apoptosis per se (17)(18)(19).…”

mentioning

confidence: 99%

Listeria monocytogenes transiently alters mitochondrial dynamics during infection

Stavru

Bouillaud

Sartori

et al. 2011

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

211

214

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Mitochondria are essential and highly dynamic organelles, constantly undergoing fusion and fission. We analyzed mitochondrial dynamics during infection with the human bacterial pathogen Listeria monocytogenes and show that this infection profoundly alters mitochondrial dynamics by causing transient mitochondrial network fragmentation. Mitochondrial fragmentation is specific to pathogenic Listeria monocytogenes, and it is not observed with the nonpathogenic Listeria innocua species or several other intracellular pathogens. Strikingly, the efficiency of Listeria infection is affected in cells where either mitochondrial fusion or fission has been altered by siRNA treatment, highlighting the relevance of mitochondrial dynamics for Listeria infection. We identified the secreted pore-forming toxin listeriolysin O as the bacterial factor mainly responsible for mitochondrial network disruption and mitochondrial function modulation. Together, our results suggest that the transient shutdown of mitochondrial function and dynamics represents a strategy used by Listeria at the onset of infection to interfere with cellular physiology.bacterial infection | calcium influx | bioenergetics

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Inhibiting Drp1-mediated mitochondrial fission selectively prevents the release of cytochrome c during apoptosis

Cited by 293 publications

References 38 publications

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

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

Listeria monocytogenes transiently alters mitochondrial dynamics during infection

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