Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane Permeabilization

Cassidy-Stone, Ann; Chipuk, Jerry E.; Ingerman, Elena; Song, Cheng; Yoo, Choong Leol; Kuwana, Tomomi; Kurth, Mark J.; Shaw, Jared T.; Hinshaw, Jenny E.; Green, Douglas R.; Nunnari, Jodi

doi:10.1016/j.devcel.2007.11.019

Cited by 972 publications

(926 citation statements)

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“…To test whether aberrant mitochondrial fission in the D7‐Des Tg hearts is responsible for mitochondrial dysfunction and cellular toxicity, we used the mitochondrial fission inhibitor, mdivi‐133, in NRCs. Earlier studies using mdivi‐1 at a concentration of 10 μmol/L reported no toxic effects in cultured neurons 34, 35.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we used the mitochondrial division inhibitor mdivi‐1, which is known to selectively inhibit mitochondrial fission by Drp1 (18). Mdivi‐1 was reported to inhibit the activity of the mitochondrial fission regulator Drp1 and also impedes apoptosis early in the intrinsic pathway by blocking Bax/Bak‐dependent mitochondrial outer membrane permeabilization 33. Moreover, studies also showed that mdivi‐1 also blocks pro‐apoptotic Bax‐dependent cytochrome C release from isolated mitochondria33 and attenuates neural cell death in vitro and in vivo 56, 57.…”

Section: Discussionmentioning

confidence: 99%

“…Mdivi‐1 was reported to inhibit the activity of the mitochondrial fission regulator Drp1 and also impedes apoptosis early in the intrinsic pathway by blocking Bax/Bak‐dependent mitochondrial outer membrane permeabilization 33. Moreover, studies also showed that mdivi‐1 also blocks pro‐apoptotic Bax‐dependent cytochrome C release from isolated mitochondria33 and attenuates neural cell death in vitro and in vivo 56, 57. In the current study, we found that mdivi‐1 inhibited Drp1‐mediated mitochondrial fission, decreased Bax expression, and significantly improved mitochondrial respiration, resulting in decreased cell death induced by D7‐Des in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

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“…47 Interestingly, this compound has been proposed as a potential new drug for neurodegenerative diseases. 48,49 To this aim, it is relevant that TG2 has been shown to play a role in the pathogenesis of neurodegenerative diseases characterized by mitochondria impairment, such as Parkinson's disease and Huntington's disease. 17,50 Thus, future studies should clarify by which mechanism Mdivi-1 inhibits TG2 transamidating activity and whether this might represent a possibility to treat neurodegenerative disease.…”

Section: Discussionmentioning

confidence: 99%

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

et al. 2014

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Macroautophagy selectively degrades dysfunctional mitochondria by a process known as mitophagy. Here we demonstrate the involvement of transglutaminase 2 (TG2) in the turnover and degradation of damaged mitochondria. In TG2-ablated cells we observed the presence of a large number of fragmented mitochondria that display decreased membrane potential, downregulation of IF1 along with increased Drp1 and PINK1 levels, two key proteins regulating the mitochondrial fission. Of note, we demonstrate that in healthy mitochondria, TG2 interacts with the dynamic proteins Drp1 and Fis1; interestingly, their interaction is largely reduced upon induction of the fission process by carbonyl cyanide m-chlorophenyl hydrazine (CCCP). In keeping with these findings, mitochondria lacking TG2 are more susceptible to CCCP treatment. As a consequence of accumulation of damaged mitochondria, cells lacking TG2 increased their aerobic glycolysis and became sensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). In contrast, TG2-proficient cells are more resistant to 2-DG-induced apoptosis as the caspase 3 is inactivated through the enzyme's crosslinking activity. The data presented in this study show that TG2 plays a key role in cellular dynamics and consequently influences the energetic metabolism.

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“…In addition, mitochondria fragment during apoptosis under the control of Drp-1 and Fis1 (35,45). Strong evidence suggests that Drp-1 is critical for mitochondrial outer-membrane permeabilization and release of cytochrome c. In particular during apoptosis Bax translocates to mitochondria and coalesces with Drp-1 and Mitofusin 2 (Mfn-2) at mitochondria fission sites (46), Bax is required to stabilize Drp1 localization on the mitochondria (47) and inhibition of Drp-1 inhibits Bax-mediated cytochrome c release and apoptosis (35,48). We had also found evidence of mitochondrial structural alterations in response to Bcl-x L overexpression (49).…”

Section: Discussionmentioning

confidence: 99%

Detection of mitochondrial fission with orientation‐dependent optical Fourier filters

2011

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We utilize a recently developed optical imaging method based on Fourier processing with Gabor-like filters to detect changes in light scattering resulting from alterations in mitochondrial structure in endothelial cells undergoing apoptosis. Imaging based on Gabor filters shows a significant decrease in the orientation of subcellular organelles at 60 to 100 minutes following apoptosis induction and concomitant with mitochondrial fragmentation observed by fluorescence. The optical scatter changes can be detected at low resolution at the whole cell level. At high resolution, we combine fluorescence imaging of the mitochondria with optical Fourier-based imaging to demonstrate that the dynamic decrease in organelle orientation measured by optical Gabor filtering is spatially associated with fluorescent mitochondria and remains largely absent from nonfluorescent subcellular regions. These results provide strong evidence that the optical Gabor responses track mitochondrial fission during apoptosis and can be used to provide label-free, rapid monitoring of this morphological process within single cells. '

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Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane Permeabilization

Cited by 972 publications

References 61 publications

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

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

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

Detection of mitochondrial fission with orientation‐dependent optical Fourier filters

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