Mitochondrial membrane permeabilization in neuronal injury

Galluzzi, Lorenzo; Blomgren, Klas; Kroemer, Guido

doi:10.1038/nrn2665

Cited by 368 publications

(294 citation statements)

References 180 publications

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“…In support of this hypothesis, we find that NMNAT3 overexpression following neonatal H‐I decreased the activity of calpain and caspase‐3 (Fig. 4), two proteases that are well known to be triggered by the cellular events that lead to the permeabilization and altered function of mitochondria in ischemic neurons 48, 49. Furthermore, we also observed that NMNAT3 upregulation was associated with a significant decrease in the degradation of calpastatin (Fig.…”

Section: Discussionsupporting

confidence: 73%

NMNAT3 is protective against the effects of neonatal cerebral hypoxia‐ischemia

Galindo

Greenberg

Araki

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo determine whether the NAD+ biosynthetic protein, nicotinamide mononucleotide adenylyltransferase‐3 (NMNAT3), is a neuroprotective inducible enzyme capable of decreasing cerebral injury after neonatal hypoxia‐ischemia (H‐I) and reducing glutamate receptor‐mediated excitotoxic neurodegeneration of immature neurons.MethodsUsing NMNAT3‐overexpressing mice we investigated whether increases in brain NMNAT3 reduced cerebral tissue loss following H‐I. We then employed biochemical methods from injured neonatal brains to examine the inducibility of NMNAT3 and the mechanism of NMNAT3‐dependent neuroprotection. Using AAV8‐mediated vectors for in vitro neuronal NMNAT3 knockdown, we then examine the endogenous role of this protein on immature neuronal survival prior and following NMDA receptor‐mediated excitotoxicity.ResultsNMNAT3 mRNA and protein levels increased after neonatal H‐I. In addition, NMNAT3 overexpression decreased cortical and hippocampal tissue loss 7 days following injury. We further show that the NMNAT3 neuroprotective mechanism involves a decrease in calpastatin degradation, and a decrease in caspase‐3 activity and calpain‐mediated cleavage. Conversely, NMNAT3 knockdown of cortical and hippocampal neurons in vitro caused neuronal degeneration and increased excitotoxic cell death. The neurodegenerative effects of NMNAT3 knockdown were counteracted by exogenous upregulation of NMNAT3.ConclusionsOur observations provide new insights into the neuroprotective mechanisms of NMNATs in the injured developing brain, adding NMNAT3 as an important neuroprotective enzyme in neonatal H‐I via inhibition of apoptotic and necrotic neurodegeneration. Interestingly, we find that endogenous NMNAT3 is an inducible protein important for maintaining the survival of immature neurons. Future studies aimed at uncovering the mechanisms of NMNAT3 upregulation and neuroprotection may offer new therapies against the effects of hypoxic‐ischemic encephalopathy.

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Section: Discussionsupporting

confidence: 73%

NMNAT3 is protective against the effects of neonatal cerebral hypoxia‐ischemia

Galindo

Greenberg

Araki

et al. 2017

Ann Clin Transl Neurol

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“…Reduction of GSK3 correlated strongly with caspase-3 activation, this observation is consistent with the previous study by Petit-Paitel et al 38 , which demonstrated that the phosphorylation of tyr216 was involved in mitochondria dependent neuronal cell death and that inactivation of GSK3 has been proposed to be important for the neuroprotection afforded by IGF-1 and hexarelin 27,39 . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 During acute neuronal injury, cytochrome c causes the activation and release of apoptotic protease-activating factor-1 (Apaf-1) into apoptosome, which activates caspase-9 and subsequently caspase-3 40,41 . An up-regulation of Bcl-2 suppresses this pathway 42 and therefore protects the neurons against apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Mediates Neuroprotection Conferred by Argon in Combination with Hypothermia in Neonatal Hypoxia–Ischemia Brain Injury

et al. 2016

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Background Hypoxic–ischemic encephalopathy is a major cause of mortality and disability in the newborn. The authors investigated the protective effects of argon combined with hypothermia on neonatal rat hypoxic–ischemic brain injury. Methods In in vitro studies, rat cortical neuronal cell cultures were challenged by oxygen and glucose deprivation for 90 min and exposed to 70% Ar or N2 with 5% CO2 balanced with O2, at 33°C for 2 h. Neuronal phospho-Akt, heme oxygenase-1 and phospho-glycogen synthase kinase-3β expression, and cell death were assessed. In in vivo studies, neonatal rats were subjected to unilateral common carotid artery ligation followed by hypoxia (8% O2 balanced with N2 and CO2) for 90 min. They were exposed to 70% Ar or N2 balanced with oxygen at 33°, 35°, and 37°C for 2 h. Brain injury was assessed at 24 h or 4 weeks after treatment. Results In in vitro studies, argon–hypothermia treatment increased phospho-Akt and heme oxygenase-1 expression and significantly reduced the phospho-glycogen synthase kinase-3β Tyr-216 expression, cytochrome C release, and cell death in oxygen–glucose deprivation–exposed cortical neurons. In in vivo studies, argon–hypothermia treatment decreased hypoxia/ischemia-induced brain infarct size (n = 10) and both caspase-3 and nuclear factor-κB activation in the cortex and hippocampus. It also reduced hippocampal astrocyte activation and proliferation. Inhibition of phosphoinositide-3-kinase (PI3K)/Akt pathway through LY294002 attenuated cerebral protection conferred by argon–hypothermia treatment (n = 8). Conclusion Argon combined with hypothermia provides neuroprotection against cerebral hypoxia–ischemia damage in neonatal rats, which could serve as a new therapeutic strategy against hypoxic–ischemic encephalopathy.

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“…9 Owing to its central role in cell death regulation, MOMP is involved in the pathophysiology of human diseases as diverse as cancer, ischemia and viral infections. 10,11 MOMP can either be initiated at the outer mitochondrial membrane, owing to the pore-forming activity of the proapoptotic BCL-2 family members BAX and BAK, 12 or ensue the so-called "mitochondrial permeability transition" (MPT), an abrupt increase in the permeability of the inner mitochondrial Here, we reveal the important finding that the c subunit of the F O ATP synthase is required for MPT-driven mitochondrial fragmentation and cell death triggered by cytosolic calcium overload and oxidative stress.…”

Section: Introductionmentioning

confidence: 99%