A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats

Xie, Ning; Wang, Cui; Lian, Yajun; Zhang, Haifeng; Wu, Chuanjie; Zhang, Qian

doi:10.1016/j.neulet.2013.04.026

Cited by 51 publications

(32 citation statements)

References 21 publications

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“…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%

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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“…Several groups have screened chemical libraries and uncovered three novel molecules: Mdivi-1 (Cassidy-Stone et al, 2008), Dynasore (Macia et al, 2006), and P110 (Qi et al, 2013). Among these, Mdivi-1 has been extensively investigated in experimental rodent models of epilepsy Xie et al, 2013), ischemia (Park et al, 2011;Zhang et al, 2013), oxygen-glucose deprivation (Wappler et al, 2013), rhabdomyolysis (Tang et al, 2013), and conditions involving endosome aggregation and vesicle fusion during exocytosis (Chlystun et al, 2013). In all of these states, Mdivi-1 exhibited beneficial effects on cells and tissues by restricting mitochondrial fission and maintaining normal fission-fusion balance and cell function.…”

Section: Targeting Mitochondrial Dynamics and Mitophagymentioning

confidence: 99%

Mitochondrial Quality Control as a Therapeutic Target

2015

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“…Several groups have independently screened chemical libraries and have found three different molecules: Mdivi [37], Dynasore [38] and P110 [39]. Among these, the Mdivi molecule has been extensively investigated with experimental rodent models for epilepsy and/or seizures [40,41], ischemia [42,43], oxygen glucose deprivation [44], rhabdomyolysis [45] and conditions such as aggregation of endosomes and vesicle fusion during exocytosis [46]. In all of these diseased states, Mdivi exhibited beneficial effects on affected tissues and cells by reducing excessive mitochondrial fission, and maintaining the fission–fusion balance and the normal functioning of cells.…”

Section: Inhibitors Of Excessive Mitochondrial Fission As Therapeuticmentioning

confidence: 99%

Increased mitochondrial fission and neuronal dysfunction in Huntington's disease: implications for molecular inhibitors of excessive mitochondrial fission

Reddy

2014

Drug Discovery Today

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Huntington’s disease (HD) is a fatal, progressive neurodegenerative disease with an autosomal dominant inheritance, characterized by chorea, involuntary movements of the limbs and cognitive impairments. Since identification of the HD gene in 1993, tremendous progress has been made in identifying underlying mechanisms involved in HD pathogenesis and progression, and in developing and testing molecular therapeutic targets, using cell and animal models of HD. Recent studies have found that mutant Huntingtin (mHtt) interacts with Dynamin-related protein 1 (Drp1), causing excessive fragmentation of mitochondria, leading to abnormal mitochondrial dynamics and neuronal damage in HD-affected neurons. Some progress has been made in developing molecules that can reduce excessive mitochondrial fission while maintaining both the normal balance between mitochondrial fusion and fission, and normal mitochondrial function in diseases in which excessive mitochondrial fission has been implicated. In this article, we highlight investigations that are determining the involvement of excessive mitochondrial fission in HD pathogenesis, and that are developing inhibitors of excessive mitochondrial fission for potential therapeutic applications.

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A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats

Cited by 51 publications

References 21 publications

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

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

Mitochondrial Quality Control as a Therapeutic Target

Increased mitochondrial fission and neuronal dysfunction in Huntington's disease: implications for molecular inhibitors of excessive mitochondrial fission

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