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Mitochondrial calcium and its regulation in neurodegeneration induced by oxidative stress.

ABSTRACT: A proposed mechanism of neuronal death associated with a variety of neurodegenerative diseases is the response of neurons to oxidative stress and consequent cytosolic Ca(2+) overload. One hypothesis is that cytosolic Ca(2+) overload leads to mitochondrial Ca(2+) overload and prolonged opening of the permeability transition pore (PTP), resulting in mitochondrial dysfunction. Elimination of cyclophilin D (CyPD), a key regulator of the PTP, results in neuroprotection in a number of murine models of neurodegeneration in which oxidative stress and high cytosolic Ca(2+) have been implicated. However, the effects of oxidative stress on the interplay between cytosolic and mitochondrial Ca(2+) in adult neurons and the role of the CyPD-dependent PTP in these dynamic processes have not been examined. Here, using primary cultured cerebral cortical neurons from adult wild-type (WT) mice and mice missing cyclophilin D (CyPD-KO), we directly assess cytosolic and mitochondrial Ca(2+) , as well as ATP levels, during oxidative stress. Our data demonstrate that during acute oxidative stress mitochondria contribute to neuronal Ca(2+) overload by release of their Ca(2+) stores. This result contrasts with the prevailing view of mitochondria as a buffer of cytosolic Ca(2+) under stress conditions. In addition, we show that CyPD deficiency reverses the release of mitochondrial Ca(2+) , leading to lower of cytosolic Ca(2+) levels, attenuation of the decrease in cytosolic and mitochondrial ATP, and a significantly higher viability of adult CyPD-knockout neurons following exposure of neurons oxidative stress. The study offers a first insight into the mechanism underlying CyPD-dependent neuroprotection during oxidative stress.

SUBMITTER: Barsukova AG

PROVIDER: S-EPMC3221651 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Mitochondrial calcium and its regulation in neurodegeneration induced by oxidative stress.

Barsukova Anna G AG Bourdette Dennis D Forte Michael M

The European journal of neuroscience 20110704 3

A proposed mechanism of neuronal death associated with a variety of neurodegenerative diseases is the response of neurons to oxidative stress and consequent cytosolic Ca(2+) overload. One hypothesis is that cytosolic Ca(2+) overload leads to mitochondrial Ca(2+) overload and prolonged opening of the permeability transition pore (PTP), resulting in mitochondrial dysfunction. Elimination of cyclophilin D (CyPD), a key regulator of the PTP, results in neuroprotection in a number of murine models of ...[more]

PMID: 21722208

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Project description:In neuroinflammatory and neurodegenerative disorders such as multiple sclerosis, mitochondrial damage caused by oxidative stress is believed to contribute to neuroaxonal damage. Previously, we demonstrated that exposure to hydrogen peroxide (H2O2) alters mitochondrial morphology and motility in myelinated axons and that these changes initiate at the nodes of Ranvier, where numerous sodium channels are located. Therefore, we suggested that mitochondrial damage may lead to ATP deficit, thereby affecting the efficiency of the sodium-potassium ATPase and eventually leading to sodium overload in axons. The increased intra-axonal sodium may revert the axonal sodium-calcium exchangers and thus may lead to a pathological calcium overload in the axoplasm and mitochondria. Here, we used the explanted murine ventral spinal roots to investigate whether modulation of sodium or calcium influx may prevent mitochondrial alterations in myelinated axons during exogenous application of H2O2 inducing oxidative stress. For that, tetrodotoxin, an inhibitor of voltage-gated sodium ion channels, and ruthenium 360, an inhibitor of the mitochondrial calcium uniporter, were applied simultaneously with hydrogen peroxide to axons. Mitochondrial shape and motility were analyzed. We showed that inhibition of axonal sodium influx prevented oxidative stress-induced morphological changes (i.e., increase in circularity and area and decrease in length) and preserved mitochondrial membrane potential, which is crucial for ATP production. Blocking mitochondrial calcium uptake prevented decrease in mitochondrial motility and also preserved membrane potential. Our findings indicate that alterations of both mitochondrial morphology and motility in the contexts of oxidative stress can be counterbalanced by modulating intramitochondrial ion concentrations pharmacologically. Moreover, motile mitochondria show preserved membrane potentials, pointing to a close association between mitochondrial motility and functionality.

Project description:Oxidative stress is one of the main causes of osteoblast apoptosis induced by post-menopausal osteoporosis. The authors previously found that metformin can reverse the loss of bone mass in post-menopausal osteoporosis. The present study aimed to further clarify the effects and mechanisms of action of metformin in post-menopausal osteoporosis under conditions of oxidative stress. Combined with an in-depth investigation using the transcriptome database, the association between oxidative stress and mitochondrial dysfunction in post-menopausal osteoporosis was confirmed. A pre-osteoblast model of oxidative stress was constructed, and the apoptotic rate following the addition of hydrogen peroxide and metformin was detected using CCK-8 assay and Annexin V-FITC/PI staining. Mitochondrial membrane potential was detected using the JC-1 dye, the intracellular calcium concentration was detected using Fluo-4 AM, the intracellular reactive oxygen species (ROS) level was observed using DCFH-DA, and the mitochondrial superoxide level was observed using MitoSOX Red. Bay K8644 was used to increase the level of intracellular calcium. siRNA was used to interfere with the expression of glycogen synthase kinase (GSK)-3β. Western blot analysis was used to detect the expression of mitochondrial dysfunction-related proteins. The results revealed that oxidative stress decreased mitochondrial membrane potential and increased intracellular ROS, mitochondrial superoxide and cytoplasmic calcium levels in pre-osteoblasts; however, metformin improved mitochondrial dysfunction and reversed oxidative stress-induced injury. Metformin inhibited mitochondrial permeability transition pore opening, suppressed the cytoplasmic calcium influx and reversed pre-osteoblast apoptosis by promoting GSK-3β phosphorylation. Moreover, it was found that EGFR was the cell membrane receptor of metformin in pre-osteoblasts, and the EGFR/GSK-3β/calcium axis played a key role in metformin reversing the oxidative stress response of pre-osteoblasts in post-menopausal osteoporosis. On the whole, these findings provide a pharmacological basis for the use of metformin for the treatment of post-menopausal osteoporosis.

Dataset Information

Mitochondrial calcium and its regulation in neurodegeneration induced by oxidative stress.

Publications

Mitochondrial calcium and its regulation in neurodegeneration induced by oxidative stress.

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