Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death

Wasiak, Sylwia; Zunino, Rodolfo; McBride, Heidi M.

doi:10.1083/jcb.200610042

Cited by 483 publications

(441 citation statements)

References 70 publications

(144 reference statements)

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“…Studies showed that Bax and Drp1 are binding partners, and Drp1 promotes mitochondrial translocation of Bax 51. Though both Bax and Drp1 translocate to discrete foci on the mitochondria, studies showed that mitochondrial Bax participates in apoptotic fragmentation of mitochondria by stabilizing Drp1 52, 53, 54. Mitochondrial Drp1 promotes Bax oligomerization and leads to cytochrome C release from mitochondria 55.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

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BackgroundDesmin filament proteins interlink the contractile myofibrillar apparatus with mitochondria, nuclei and the sarcolemma. Mutations in the human desmin gene cause cardiac disease, remodeling, and heart failure but the pathophysiological mechanisms remain unknown.Methods and ResultsCardiomyocyte‐specific overexpression of mutated desmin (a 7 amino acid deletion R172‐E178, D7‐Des Tg) causes accumulations of electron‐dense aggregates and myofibrillar degeneration associated with cardiac dysfunction. Though extensive studies demonstrated that these altered ultrastructural changes cause impairment of cardiac contractility, the molecular mechanism of cardiomyocyte death remains elusive. In the present study, we report that the D7‐Des Tg mouse hearts undergo aberrant mitochondrial fission associated with increased expression of mitochondrial fission regulatory proteins. Mitochondria isolated from D7‐Des Tg hearts showed decreased mitochondrial respiration and increased apoptotic cell death. Overexpression of mutant desmin by adenoviral infection in cultured cardiomyocytes led to increased mitochondrial fission, inhibition of mitochondrial respiration, and activation of cellular toxicity. Inhibition of mitochondrial fission by mitochondrial division inhibitor mdivi‐1 significantly improved mitochondrial respiration and inhibited cellular toxicity associated with D7‐Des overexpression in cardiomyocytes.ConclusionsAberrant mitochondrial fission results in mitochondrial respiratory defects and apoptotic cell death in D7‐Des Tg hearts. Inhibition of aberrant mitochondrial fission using mitochondrial division inhibitor significantly preserved mitochondrial function and decreased apoptotic cell death. Taken together, our study shows that maladaptive aberrant mitochondrial fission causes desminopathy‐associated cellular dysfunction.

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Section: Discussionmentioning

confidence: 99%

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

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“…This conclusion is confirmed by results showing that Bid induces the oligomerization and insertion of Bax in the MOM, 33 and Bax was also found to co-localize with Drp1 at fission sites. 28,37 Further, very recent findings demonstrated Drp1 recruitment to cardiolipin-rich membrane sites as a prerequisite for the formation of membrane hemifusion/fission structures and Bax oligomerization. 11,28 Notably, Drp1-induced Bax oligomerization at mitochondrial fission sites also required the presence of tBid, which further supports the conclusion that both, Drp1 and Bid concomitantly contribute to mitochondrial death pathways.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Drp1 provides neuroprotection in vitro and in vivo

et al. 2012

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Impaired regulation of mitochondrial dynamics, which shifts the balance towards fission, is associated with neuronal death in age-related neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. A role for mitochondrial dynamics in acute brain injury, however, has not been elucidated to date. Here, we investigated the role of dynamin-related protein 1 (Drp1), one of the key regulators of mitochondrial fission, in neuronal cell death induced by glutamate toxicity or oxygen-glucose deprivation (OGD) in vitro, and after ischemic brain damage in vivo. Drp1 siRNA and small molecule inhibitors of Drp1 prevented mitochondrial fission, loss of mitochondrial membrane potential (MMP), and cell death induced by glutamate or tBid overexpression in immortalized hippocampal HT-22 neuronal cells. Further, Drp1 inhibitors protected primary neurons against glutamate excitotoxicity and OGD, and reduced the infarct volume in a mouse model of transient focal ischemia. Our data indicate that Drp1 translocation and associated mitochondrial fission are key features preceding the loss of MMP and neuronal cell death. Thus, inhibition of Drp1 is proposed as an efficient strategy of neuroprotection against glutamate toxicity and OGD in vitro and ischemic brain damage in vivo. Mitochondria play crucial roles in energy metabolism, regulation of free radical formation and calcium storage, thereby determining essential metabolic functions and cell survival. 1 Further, mitochondria are highly dynamic organelles that undergo constant fission and fusion and these morphological changes are required for efficient ATP production, calcium buffering, regulation of signal transduction and apoptosis. 2 In neurons, mitochondrial fission is also essential for axonal transport of the organelles into areas of high metabolic demand, 3 whereas mitochondrial fusion supports substitution and regeneration of mitochondrial proteins, mtDNA repair and functional recovery. 2,4 Consistent with the critical roles of mitochondrial dynamics in neurons, defects in mitochondrial fission and fusion proteins are associated with a wide array of inherited or acquired neurodegenerative diseases such as Charcot-Marie-Tooth disease or Alzheimer's disease, respectively. 2 Fission and fusion defects may limit mitochondrial motility, decrease energy production, promote oxidative stress and lead to accumulating of mtDNA defects, thereby promoting neuronal dysfunction and cell death. 1 Recently, enhanced mitochondrial fragmentation was associated with induction of neuronal death triggered by oxidative stress. 5 These data imply that during neuronal cell death, the tubular mitochondrial network is fragmented into smaller and functionally impaired organelles. 5 It is, however, a matter of ongoing controversy, whether mitochondrial fragmentation is cause or consequence in programmed cell death.Current knowledge of the mechanisms regulating mitochondrial dynamics indicates that fission and fusion of mitochondria are under control of highly conserved dynamin-relate...

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“…Another study has indicated that Drp1 accumulates on mitochondria during apoptosis due to Bax/Bak-dependent sumolylation of Drp1, which results in stable membrane association of Drp1 with mitochondria and thus increased fission (Wasiak et al, 2007;Zunino et al, 2007). There is also evidence to suggest that mitochondrial fusion is blocked upon activation of apoptosis indicating that the fragmented phenotype may occur due to a combination of increased fission and decreased fusion (Karbowski et al, 2004).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Mitochondrial fission/fusion dynamics and apoptosis

2010

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Mitochondria play an important role in the progression of apoptosis through the release of pro-apoptotic factors, such as cytochrome c, from the mitochondrial intermembrane space.During this process, mitochondrial networks are dramatically reorganised from long filamentous interconnected tubules into small punctate spheres. Whether remodelling of mitochondrial networks is necessary for apoptosis-associated cytochrome c release, or merely an accompanying process, has been a subject of debate. Here we discuss evidence for and against the role of mitochondrial fragmentation in the progression of apoptosis and highlight recent advances which indicate that mitochondrial fission is not a critical requirement for apoptosis-associated cytochrome c release. We also discuss an emerging role for Bcl-2 family members as regulators of mitochondrial fission and fusion dynamics, independent of the role of this family in the regulation of apoptosis.

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Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death

Cited by 483 publications

References 70 publications

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

Inhibition of Drp1 provides neuroprotection in vitro and in vivo

Mitochondrial fission/fusion dynamics and apoptosis

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