The mitochondrial division inhibitor mdivi-1 attenuates spinal cord ischemia–reperfusion injury both in vitro and in vivo: Involvement of BK channels

Liu, Jianmin; Zhi, Yi; Liu, Shizhang; Chang, Juntao; Dang, Xingbo; Li, Quanyi; Zhang, Yuelin

doi:10.1016/j.brainres.2015.03.033

Cited by 34 publications

(32 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Earlier studies using mdivi‐1 at a concentration of 10 μmol/L reported no toxic effects in cultured neurons 34, 35. Therefore, we treated the NRCs with different concentrations of mdivi‐1 (1, 5, and 10 μmol/L) or the same volume of vehicle (dimethyl sulfoxide) to determine whether mitochondrial fission inhibition by mdivi‐1 affects mitochondrial respiration and cellular toxicity.…”

Section: Resultsmentioning

confidence: 99%

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

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

View full text Add to dashboard Cite

show abstract

“…These effects correlated with improved locomotor function in the treated group. Similarly, Liu et al (2015) observed neuroprotective effects of Mdivi-1, both in cultured spinal cord neurons exposed to glutamate and after ischemic/reperfusion SCI in rats. Mdivi-1 treatment resulted in increased endogenous antioxidant activity, decreased ROS, and decreased cytochrome c release in vitro, as well as improved locomotor function in vivo (Liu et al, 2015).…”

Section: Mitochondrial-based Treatmentmentioning

confidence: 67%

“…Similarly, Liu et al (2015) observed neuroprotective effects of Mdivi-1, both in cultured spinal cord neurons exposed to glutamate and after ischemic/reperfusion SCI in rats. Mdivi-1 treatment resulted in increased endogenous antioxidant activity, decreased ROS, and decreased cytochrome c release in vitro, as well as improved locomotor function in vivo (Liu et al, 2015). Although these data are promising, one study used a pretreatment method, whereas the other began treatment at the initiation of injury; therefore, additional work is necessary to assess the therapeutic efficacy of Mdivi-1 after SCI.…”

Section: Mitochondrial-based Treatmentmentioning

confidence: 67%

“…2), a selective Drp1 inhibitor, has proven beneficial in in vivo models of various CNS and non-CNS pathologies, including TBI (Wu et al, 2016), amyotrophic lateral sclerosis (Luo et al, 2013), stroke (Zhang et al, 2013;Cui et al, 2016), acute kidney injury (Tang et al, 2013), and myocardial infarction (Ding et al, 2017). Despite these data, only two studies thus far have investigated the effect of Mdivi-1 on SCI Liu et al, 2015). observed that treatment with Mdivi-1 prior to SCI in rats increased ATP and mitochondrial membrane potential, and decreased caspase-3 release and the number of apoptotic cells by 72 hours postinjury.…”

Section: Mitochondrial-based Treatmentmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial-Based Therapeutics for the Treatment of Spinal Cord Injury: Mitochondrial Biogenesis as a Potential Pharmacological Target

Scholpa

Schnellmann

2017

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Spinal cord injury (SCI) is characterized by an initial trauma followed by a progressive cascade of damage referred to as secondary injury. A hallmark of secondary injury is vascular disruption leading to vasoconstriction and decreased oxygen delivery, which directly reduces the ability of mitochondria to maintain homeostasis and leads to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity, and oxidative stress, further exacerbating injury. Restoration of mitochondria dysfunction during the acute phases of secondary injury after SCI represents a potentially effective therapeutic strategy. This review discusses the past and present pharmacological options for the treatment of SCI as well as current research on mitochondria-targeted approaches. Increased antioxidant activity, inhibition of the mitochondrial permeability transition, alternate energy sources, and manipulation of mitochondrial morphology are among the strategies under investigation. Unfortunately, many of these tactics address single aspects of mitochondrial dysfunction, ultimately proving largely ineffective. Therefore, this review also examines the unexplored therapeutic efficacy of pharmacological enhancement of mitochondrial biogenesis, which has the potential to more comprehensively improve mitochondrial function after SCI.

show abstract

“…In cultured neurons Drp1 ablation leads to a super-elongation of the mitochondrial network and has been shown to be neuroprotective [11]. Accordingly, several studies reported neuroprotective effects of Drp1 inhibitors in animal models of brain ischemia [12][13][14][15], retinal ganglion cell ischemia [16], spinal cord ischemia and injury [17,18], traumatic brain injury [19], status epilepticus [20][21][22], as well as Huntington's [23] and Parkinson's disease (PD) [24]. However, seemingly contradictory in vitro studies of Drp1 ablation in cultured neurons have also reported the formation of spherically enlarged mitochondria that aggregate in the perikarya.…”

Section: Commentarymentioning

confidence: 99%

Lessons Learned from Transgenic Mouse Models for the Therapeutic Use of Drp1 Inhibitors

Licci¹,

Björn²

2016

Single Cell Biol

View full text Add to dashboard Cite

Pharmacological inhibition of dynamin-related protein 1 (Drp1) the main mammalian promoter of mitochondrial fission -has emerged as a promising therapeutic target for the treatment of neuronal injuries. Genetic studies, however, have revealed that inhibiting Drp1 during development leads to defects especially in neuronal differentiation. Bypassing this neurodevelopmental impairment, a number of recent studies have genetically ablated Drp1 in different adult neuronal subpopulations. This has led to new insights into the importance of mitochondrial fission in differentiated neurons and has highlighted potentially severe side effects of this new therapeutic strategy.

show abstract

The mitochondrial division inhibitor mdivi-1 attenuates spinal cord ischemia–reperfusion injury both in vitro and in vivo: Involvement of BK channels

Cited by 34 publications

References 57 publications

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

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

Mitochondrial-Based Therapeutics for the Treatment of Spinal Cord Injury: Mitochondrial Biogenesis as a Potential Pharmacological Target

Lessons Learned from Transgenic Mouse Models for the Therapeutic Use of Drp1 Inhibitors

Contact Info

Product

Resources

About