Hypoxia as a therapy for mitochondrial disease

Jain, Isha H.; Zazzeron, L.; Goli, Rahul; Alexa, Kristen; Schatzman-Bone, Stephanie; Dhillon, Harveen; Goldberger, Olga; Peng, Jun; Shalem, Ophir; Sanjana, Neville E.; Zhang, Feng; Goessling, Wolfram; Zapol, Warren M.; Mootha, Vamsi K.

doi:10.1126/science.aad9642

Cited by 346 publications

(358 citation statements)

References 45 publications

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“…On the other hand, several studies have demonstrated a beneficial effect of reduced mitochondrial activity. For example, in a recent study, the cellular hypoxia response was activated in cell lines, in zebrafish, and in mice via pharmacological and genetic manipulations or via exposure to low oxygen levels (33). The hypoxia response caused a shift to glycolytic energy metabolism and provided neuroprotection in a mouse model of Leigh syndrome, a genetic defect of respiratory chain function.…”

Section: Discussionmentioning

confidence: 99%

Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect

Bas‐Orth

Tan²,

Lau

et al. 2017

Journal of Biological Chemistry

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Edited by F. Anne StephensonSynaptic activity drives changes in gene expression to promote long lasting adaptations of neuronal structure and function. One example of such an adaptive response is the buildup of acquired neuroprotection, a synaptic activity-and gene transcription-mediated increase in the resistance of neurons against harmful conditions. A hallmark of acquired neuroprotection is the stabilization of mitochondrial structure and function. We therefore re-examined previously identified sets of synaptic activity-regulated genes to identify genes that are directly linked to mitochondrial function. In mouse and rat primary hippocampal cultures, synaptic activity caused an up-regulation of glycolytic genes and a concomitant down-regulation of genes required for oxidative phosphorylation, mitochondrial biogenesis, and maintenance. Changes in metabolic gene expression were induced by action potential bursting, but not by glutamate bath application activating extrasynaptic NMDA receptors. The specific and coordinate pattern of gene expression changes suggested that synaptic activity promotes a shift of neuronal energy metabolism from oxidative phosphorylation toward aerobic glycolysis, also known as the Warburg effect. The ability of neurons to up-regulate glycolysis has, however, been debated. We therefore used FACS sorting to show that, in mixed neuron glia co-cultures, activity-dependent regulation of metabolic gene expression occurred in neurons. Changes in gene expression were accompanied by changes in the phosphorylation-dependent regulation of the key metabolic enzyme, pyruvate dehydrogenase. Finally, increased synaptic activity caused an increase in the ratio of L-lactate production to oxygen consumption in primary hippocampal cultures. Based on these data we suggest the existence of a synaptic activity-mediated neuronal Warburg effect that may promote mitochondrial homeostasis and neuroprotection.Synaptic activity can drive changes in gene expression to promote long lasting adaptations of neuronal structure and function (1, 2). Examples of such gene transcription-dependent adaptive responses are the formation of long term memories, activity-dependent dendritic remodeling, and the buildup of acquired neuroprotection. The latter is defined as a synaptic activity-and gene transcription-mediated increase in the resistance of neurons against harmful conditions (3). We have previously identified a number of so-called activity-regulated inhibitor of death genes that are able to confer such neuroprotection (4, 5). Although the exact mechanisms through which those genes confer neuroprotection are not yet fully understood, the functional changes mediated by activity-regulated inhibitor of death genes all seem to result in the protection of mitochondria (5-7). In the present study, we re-examined the synaptic activity-regulated gene pool to search for additional genes that are more directly linked to mitochondrial function. We found activity-dependent changes in the expression of several genes that encode for...

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Section: Discussionmentioning

confidence: 99%

Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect

Bas‐Orth

Tan²,

Lau

et al. 2017

Journal of Biological Chemistry

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“…Genetic or small-molecule activation of the hypoxia response is, therefore, protective against mitochondrial toxicity (150).…”

Section: Perspectivesmentioning

confidence: 99%

Redox Control of Skeletal Muscle Regeneration

Moal

Pialoux

Juban

et al. 2017

Antioxidants & Redox Signaling

137

109

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Skeletal muscle shows high plasticity in response to external demand. Moreover, adult skeletal muscle is capable of complete regeneration after injury, due to the properties of muscle stem cells (MuSCs), the satellite cells, which follow a tightly regulated myogenic program to generate both new myofibers and new MuSCs for further needs. Although reactive oxygen species (ROS) and reactive nitrogen species (RNS) have long been associated with skeletal muscle physiology, their implication in the cell and molecular processes at work during muscle regeneration is more recent. This review focuses on redox regulation during skeletal muscle regeneration. An overview of the basics of ROS/RNS and antioxidant chemistry and biology occurring in skeletal muscle is first provided. Then, the comprehensive knowledge on redox regulation of MuSCs and their surrounding cell partners (macrophages, endothelial cells) during skeletal muscle regeneration is presented in normal muscle and in specific physiological (exercise-induced muscle damage, aging) and pathological (muscular dystrophies) contexts. Recent advances in the comprehension of these processes has led to the development of therapeutic assays using antioxidant supplementation, which result in inconsistent efficiency, underlying the need for new tools that are aimed at precisely deciphering and targeting ROS networks. This review should provide an overall insight of the redox regulation of skeletal muscle regeneration while highlighting the limits of the use of nonspecific antioxidants to improve muscle function. Antioxid. Redox Signal. 27, 276-310.

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“…Although our ability to obtain a genetic diagnosis has vastly improved (see below), there remains little in the way of effective treatment. Several treatment approaches have been successful in animal models (11,23,46,47,104), but there is little evidence that this has progressed to effective clinical trials in humans. The lack of effective treatment highlights the importance of developing methods to prevent transmission of mitochondrial disease.…”

Section: Mitochondrial Diseasementioning

confidence: 99%

Recent Advances in Mitochondrial Disease

Craven

Alston

Taylor

et al. 2017

Annu. Rev. Genom. Hum. Genet.

220

168

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Mitochondrial disease is a challenging area of genetics because two distinct genomes can contribute to disease pathogenesis. It is also challenging clinically because of the myriad of different symptoms and, until recently, a lack of a genetic diagnosis in many patients. The last five years has brought remarkable progress in this area. We provide a brief overview of mitochondrial origin, function, and biology, which are key to understanding the genetic basis of mitochondrial disease. However, the primary purpose of this review is to describe the recent advances related to the diagnosis, genetic basis, and prevention of mitochondrial disease, highlighting the newly described disease genes and the evolving methodologies aimed at preventing mitochondrial DNA disease transmission.

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Hypoxia as a therapy for mitochondrial disease

Cited by 346 publications

References 45 publications

Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect

Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect

Redox Control of Skeletal Muscle Regeneration

Recent Advances in Mitochondrial Disease

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