Energy Failure

Pathak, Divya; Berthet, Amandine; Nakamura, Ken

doi:10.1002/ana.24014

Cited by 125 publications

(69 citation statements)

References 131 publications

(160 reference statements)

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“…In our studies, we showed that both mitochondrial impairment and ER stress (Ren et al, 2017) are involved in leflunomide’s toxicity and that mitochondrial impairment seems closely related to ER stress. ATP depletion, a result of impaired cellular bioenergetic, primarily leads to imbalanced mitochondrial dynamics and membrane depolarization (Pathak et al, 2013; Valero, 2014) and impacts other cellular functions such as the functions of the ER, including protein folding and calcium level regulation since they are ATP dependent. One of the plausible explanations is that the effect of bioenergetic failure and mitochondrial damage caused by leflunomide exposure could disrupt normal ER function and result in ER stress.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction induced by leflunomide and its active metabolite

et al. 2018

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Leflunomide, an anti-inflammatory drug used for the treatment of rheumatoid arthritis, has been marked with a black box warning regarding an increased risk of liver injury. The active metabolite of leflunomide, A771726, which also carries a boxed warning about potential hepatotoxicity, has been marketed as teriflunomide for the treatment of relapsing multiple sclerosis. Thus far, however, the mechanism of liver injury associated with the two drugs has remained elusive. In this study, cytotoxicity assays showed that ATP depletion and subsequent LDH release were induced in a time- and concentration-dependent manner by leflunomide in HepG2 cells, and to a lesser extent, by A77 1726. The decline of cellular ATP levels caused by leflunomide was dramatically exacerbated when galactose was substituted for glucose as the sugar source, indicating a potential mitochondrial liability of leflunomide. By measuring the activities of immuno-captured mitochondrial oxidative phosphorylation (OXPHOS) complexes, we found that leflunomide and A77 1726 preferentially targeted complex V (F1FO ATP synthase), with IC50 values of 35.0 and 63.7 μM, respectively. Bongkrekic acid, a mitochondrial permeability transition pore blocker that targets adenine nucleotide translocase, profoundly attenuated mitochondrial membrane depolarization, ATP depletion, and LDH leakage induced by leflunomide and A77 1726. Substantial alterations of mitochondrial function at the transcript level were observed in leflunomide-treated HepG2 cells, whereas the effects of A77 1726 on the cellular transcriptome were much less profound. Our results suggest that mitochondrial dysfunction may be implicated in the hepatotoxicity associated with leflunomide and A77 1726, with the former exhibiting higher toxicity potency.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction induced by leflunomide and its active metabolite

et al. 2018

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“…Together, our findings illustrate a neuroprotective mechanism whereby RPC via neuronal Sirt1 promotes glycolytic efficiency to combat energetic stress. These results have far-reaching implications, as dysregulation of glycolysis plays a role in the pathogenesis and/or manifestation of Huntingtin’s disease, Alzheimer’s disease and Parkinson’s disease, in all of which Sirt1 has a neuroprotective role 40, 41 .…”

Section: Discussionmentioning

confidence: 99%

Neuronal SIRT1 (Silent Information Regulator 2 Homologue 1) Regulates Glycolysis and Mediates Resveratrol-Induced Ischemic Tolerance

Koronowski

Khoury

Saul

et al. 2017

Stroke

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BACKGROUND AND PURPOSE Resveratrol, at least in part via Sirt1 activation, protects against cerebral ischemia when administered 2 days prior to injury. However, it remains unclear if Sirt1 activation must occur, and in which brain cell types, for the induction of neuroprotection. We hypothesized that neuronal Sirt1 is essential for resveratrol-induced ischemic tolerance and sought to characterize the metabolic pathways regulated by neuronal Sirt1 at the cellular level in the brain. METHODS We assessed infarct size and functional outcome following transient 60 minute middle cerebral artery occlusion in control and inducible, neuronal-specific Sirt1 knockout mice. Non-targeted primary metabolomics analysis identified putative Sirt1-regulated pathways in brain. Glycolytic function was evaluated in acute brain slices from adult mice and primary neuronal-enriched cultures under ischemic penumbra-like conditions. RESULTS Resveratrol-induced neuroprotection from stroke was lost in neuronal Sirt1 knockout mice. Metabolomics analysis revealed alterations in glucose metabolism upon deletion of neuronal Sirt1, accompanied by transcriptional changes in glucose metabolism machinery. Furthermore, glycolytic ATP production was impaired in acute brain slices from neuronal Sirt1 knockout mice. Conversely, resveratrol increased glycolytic rate in a Sirt1-dependent manner and under ischemic penumbra-like conditions in vitro. CONCLUSIONS Our data demonstrate that resveratrol requires neuronal Sirt1 to elicit ischemic tolerance and identify a novel role for Sirt1 in the regulation of glycolytic function in brain. Identification of robust neuroprotective mechanisms that underlie ischemia tolerance and the metabolic adaptations mediated by Sirt1 in brain are crucial for the translation of therapies in cerebral ischemia and other neurological disorders.

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“…A role for mitochondrial dysfunction has emerged as a common mechanism underlying many neurological disorders [8, 12, 41–43] including ASD [15, 18, 44] with specific detrimental outcomes, such as lower ATP production, increases in mitochondrial ROS, and/or metabolite-inhibition of critical steps within mitochondrial pathways [45]. In this study, we tested for bioenergetics in fibroblasts from carriers of the premutation before a significant clinical involvement was observed.…”

Section: Discussionmentioning

confidence: 99%

Altered Bioenergetics in Primary Dermal Fibroblasts from Adult Carriers of the FMR1 Premutation Before the Onset of the Neurodegenerative Disease Fragile X-Associated Tremor/Ataxia Syndrome

et al. 2016

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder, characterized by tremors, ataxia, impaired coordination, and cognitive decline. While all FXTAS individuals are carriers of a 55–200 CGG expansion at the 5′ UTR of the fragile X mental retardation gene (FMR1), also known as premutation, not all carriers develop FXTAS symptoms and some display other types of psychological/emotional disorders (e.g., autism, anxiety). The goal of this study was to investigate whether the mitochondrial dysfunction previously observed in fibroblasts from older premutation individuals (>60 y) was already present in younger (17–48 y), non-FXTAS affected carriers and to identify the type and severity of the bioenergetci deficit. Since FXTAS affects mostly males, while females account for a small part of the FXTAS-affected population displaying less severe symptoms, only fibroblasts from males were evaluated in this study. Based on polarographic and enzymatic measurements, a generalized OXPHOS deficit was noted accompanied by increases in the matrix biomarker citrate synthase, oxidative stress (as increased mtDNA copy number and deletions), and mitochondrial network disruption/disorganization. Some of the outcomes (ATP-linked oxygen uptake, coupling, citrate synthase activity and mitochondrial network organization) strongly correlated with the extent of the CGG expansion, with more severe deficits observed in cell lines carrying higher CGG number. Furthermore, mitochondrial outcomes can identify endophenotypes among carriers and are robust predictors of the premutation diagnosis before the onset of FXTAS, with the potential to be used as markers of prognosis and/or as readouts of pharmacological interventions.

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Energy Failure

Cited by 125 publications

References 131 publications

Mitochondrial dysfunction induced by leflunomide and its active metabolite

Mitochondrial dysfunction induced by leflunomide and its active metabolite

Neuronal SIRT1 (Silent Information Regulator 2 Homologue 1) Regulates Glycolysis and Mediates Resveratrol-Induced Ischemic Tolerance

Altered Bioenergetics in Primary Dermal Fibroblasts from Adult Carriers of the FMR1 Premutation Before the Onset of the Neurodegenerative Disease Fragile X-Associated Tremor/Ataxia Syndrome

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