The therapeutic potential of mitochondrial channels in cancer, ischemia–reperfusion injury, and neurodegeneration

Peixoto, Pablo M.; Dejean, Laurent M.; Kinnally, Kathleen W.

doi:10.1016/j.mito.2011.03.003

Cited by 26 publications

(19 citation statements)

References 160 publications

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“…VDAC is located in the outer mitochondrial membrane, which provides transport pathways for respiratory chain substrates required for oxidative phosphorylation (21,25,33,44). Our results are supported by results from other studies (33,44). Furthermore, we found that protein levels of complex V subunit-␣, located on the inner mitochondrial membrane, were significantly increased after ischemia-reperfusion in ipsilateral MCAs compared with control and contralateral MCAs.…”

Section: Discussionsupporting

confidence: 90%

“…First, the expression level of highly conserved VDAC, one of the major proteins in mitochondria-mediated apoptosis, was increased in ipsilateral MCAs compared with contralateral and control MCAs. VDAC is located in the outer mitochondrial membrane, which provides transport pathways for respiratory chain substrates required for oxidative phosphorylation (21,25,33,44). Our results are supported by results from other studies (33,44).…”

Section: Discussionsupporting

confidence: 89%

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Sustained mitochondrial functioning in cerebral arteries after transient ischemic stress in the rat: a potential target for therapies

Rutkai

Katakam

Dutta

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Rutkai I, Katakam PV, Dutta S, Busija DW. Sustained mitochondrial functioning in cerebral arteries after transient ischemic stress in the rat: a potential target for therapies. Am J Physiol Heart Circ Physiol 307: H958 -H966, 2014. First published July 25, 2014; doi:10.1152/ajpheart.00405.2014.-The objective of the present study was to determine whether mitochondrial function in the cerebral vasculature is maintained after transient middle cerebral artery (MCA) occlusion (tMCAO) in rats. Sprague-Dawley rats were exposed to 90 min of tMCAO followed by 4 or 48 h of reperfusion. MCAs from ischemic (ipsilateral) and nonischemic (contralateral) sides were compared with control MCAs from sham-operated rats. We determined 1) vasoreactivity to diazoxide (DZ; a mitochondrial ATP-activated K ϩ channel opener), ACh, bradykinin (BK), serotonin, and sodium nitroprusside; 2) levels of mitochondrial and nonmitochondrial proteins and mitochondrial DNA; and 3) vascular levels of tetramethylrhodamine ethyl ester (an indicator of mitochondrial membrane potential). All dilator responses, including those with DZ, were intact 4 h post-tMCAO. Dilator responses to ACh, BK, and sodium nitroprusside were reduced in ipsilateral MCAs at 48 h compared with contralateral MCAs, but DZ responses were comparable with control MCAs. Surprisingly, contralateral responses to ACh, BK, and serotonin were reduced compared with control MCAs at 48 h. Ipsilateral vasodilation to DZ at 48 h was eliminated by endothelial denudation and endothelial nitric oxide synthase (eNOS) inhibition but was only reduced in control MCAs. Mitochondrial proteins, phosphorylated eNOS, mitochondrial DNA, and mitochondrial membrane potential were higher in ipsilateral compared with contralateral MCAs. In conclusion, contrary to conventional wisdom, mitochondria remain functional for at least 48 h after severe ischemic stress in MCAs, and DZ-induced dilation is preserved due to maintained mitochondrial mass, probably in the endothelium, and eNOS signaling. Our findings support the concept that functioning vascular mitochondria are an unexpected target for novel stroke therapies.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 89%

Sustained mitochondrial functioning in cerebral arteries after transient ischemic stress in the rat: a potential target for therapies

Rutkai

Katakam

Dutta

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…Thus, conductance of VDAC in living cell needs to be studied in details in order to better understand VDAC function in vivo and effect of VDAC modulators in therapy, including the isoform specificity. However, as mentioned by [76], it is still not clear whether VDAC is intrinsically open in living cells as suggested by the low permeability barrier of the mitochondrial outer membrane or is closed. Therefore, answering the question appears to be important for development of new therapeutic interventions based on VDAC modulators.…”

Section: Vdac As a Versatile Proteinmentioning

confidence: 99%

VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

Karachitos¹,

Grobys²

2015

Pharmaceut Reg Affairs

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It is becoming increasingly evident that mitochondria dysfunction plays an important role in pathogenesis of Huntington's disease (HD). However, the underlying mechanism is still needs to be explained. The crucial aspect of the explanation is to indicate the upstream events in mitochondria dysfunction that could contribute to HD. In the review we propose the defect of voltage-dependent anion-selective channel (VDAC), as a causative event in HDrelated mitochondria dysfunction. Thus, we propose to consider VDAC as a crucial element in HD etiology and consequently as a reasonable target for therapeutic interventions in HD, based on developing novel therapeutic strategies eliminating mitochondria dysfunction.Keywords: Huntington's disease; VDAC; Mitochondria; Therapy Huntington's DiseaseHuntington's disease (HD) is a progressive and fatal neurodegenerative disease with a prevalence of about 5-10/100 000. Clinically, the disease is characterized by progressive chorea (involuntary dance-like movements), rigidity, weight loss, dementia, seizures and psychiatric disturbances such as depression, withdrawal and irritability. These symptoms including cognitive deterioration, psychiatric disturbances, and movement disorders result from a selective and continuous loss of neurons from the striatum and deep layers of the cerebral cortex although other brain regions such as thalamus and subthalamic nucleus are also affected [1][2][3]. Current treatments for HD relieve merely the symptoms and address the control of behavioral symptoms, motor sedatives, cognitive enhancers, and neuroprotective agents [4,5] but are not able to restore neuronal function nor to stop the insidious loss of neurons. As summarized by Kumar et al. [6], although there is an intensive research concerning development of neuroprotective strategies such as fetal neural transplantation, RNA interference (RNAi) and transglutaminase inhibitors (TGaseI), effective therapeutic strategies may not be developed until the next few decades. Thus, a new therapeutic approach involving new potential targets and to start before the symptomatic stage could contribute to HD treatment to be more specific and effective. This, in turn, requires further studies concerning molecular mechanisms underlying HD.The genetic hallmark of HD is an expansion of an unstable trinucleotide CAG repeat region within the first exon of the gene encoding the protein Huntington (Htt). This results in synthesis of its mutant form (mHtt) containing more than 36 glutamine residues at N terminus although the possible contribution of mHtt encoding mRNA, i.e. toxic mRNA in HD etiology has also been suggested [7]. HD inheritance is autosomal dominant and consequently the prevailing view is that mHtt mediated symptoms result from a toxic gain-offunction mechanism although loss-of-function mechanisms for mHtt and Htt are also proposed [8,9]. Htt is conserved among vertebrates [10], is localized mainly in cytoplasm and exhibits anti-apopptotic properties [11,12]. Importantly, Htt expression in diffe...

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“…Mitochondrial channels also control cell survival and death. These channels mainly include mPTP, mitochondrial porin or voltage-dependent anion-selective channel (VDAC), adenine nucleotide translocase (ANT), and protein import translocases (TOM, TIM23, and TIM22) in outer and inner membranes (Peixoto et al, 2012). A fully open VDAC allows the flux of metabolites, including ATP, ADP, Ca 2+ , K + , and Na + , across the outer membrane (Colombini, 2012).…”

Section: Function Of Mitochondrial Channels In Mitochondrion-dependenmentioning

confidence: 99%

Molecular pathways of mitochondrial dysfunctions: Possible cause of cell death in anesthesia-induced developmental neurotoxicity

2015

Brain Research Bulletin

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The therapeutic potential of mitochondrial channels in cancer, ischemia–reperfusion injury, and neurodegeneration

Cited by 26 publications

References 160 publications

Sustained mitochondrial functioning in cerebral arteries after transient ischemic stress in the rat: a potential target for therapies

Sustained mitochondrial functioning in cerebral arteries after transient ischemic stress in the rat: a potential target for therapies

VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

Molecular pathways of mitochondrial dysfunctions: Possible cause of cell death in anesthesia-induced developmental neurotoxicity

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