Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via regulation of pyruvate dehydrogenase phosphorylation

Ikizawa, Takeshi; Ikeda, Kazutaka; Arita, Makoto; Kitajima, Shojiro; Soga, Tomoyoshi; Ichijo, Hidenori; Naguro, Isao

doi:10.1016/j.jbc.2022.102837

Cited by 5 publications

(2 citation statements)

References 52 publications

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“…In inflammation, whatever its cause, there is increased secretion of lactate, resulting in increased serum and urine levels of lactate [103,104]. It has been shown that in response to osmotic stress, cells display acute metabolic remodeling through the control of pyruvate dehydrogenase phosphorylation through direct osmosensing in mitochondria [105]. The correlations between inflammation, hyperosmolarity, and metabolic changes in AMD are shown in Figure 1. .…”

Section: Metabolic Shift Because Of Increased Pressurementioning

confidence: 99%

Metabolic Shift and Increased Osmotic Pressure Underlie Age-Related Macular Degeneration: A Review

Schwartz,

Hnery

et al. 2024

Preprint

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In our previous papers, we demonstrated that inflammation and aging are the common roots of cancer and Alzheimer’s disease (AD). In both diseases, there is an inhibition of the mitochondria. In cancer, the alkaline intracellular pH (pHi) is associated with cell proliferation; acidic pHi causes apoptosis in AD. This difference is because cancer feeds on chemically neutral glucose, while neurons feed on acidic lactic acid. Increased uptake of lactic acid is responsible for acidic pH and cell death. Similarly, to AD, inflammation is responsible for metabolic shifts in age-related macular degeneration (AMD). In AD, there is hyperosmolarity responsible for increased lactic secretion by glial cells. Increased lactic secretion will cause neo-angiogenesis and neural cell death. Drugs increasing hyperosmolarity (Polyethylene Glycol) cause neo-angiogenesis and drusen-like structures in rodents. The link between AMD and inflammation is reinforced by the fact that treatments aiming at restoring mitochondrial activity, such as lipoic acid and/or methylene blue, have been experimentally shown to be effective in each set of diseases. The role of osmolarity has been demonstrated in the pathologies of the anterior segment of the eye, such as dry eye, corneal ulceration, cataracts, and glaucoma. The role of increased osmolarity in age-related macular degeneration (AMD) has been largely overlooked. We herein suggest that metabolic shift, inflammation, and hyperosmolarity are key players in the pathogenesis of AMD.

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Section: Metabolic Shift Because Of Increased Pressurementioning

confidence: 99%

Metabolic Shift and Increased Osmotic Pressure Underlie Age-Related Macular Degeneration: A Review

Schwartz,

Hnery

et al. 2024

Preprint

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“…RTG pathway activation leads to a reconfiguration in the expression of a subset of nuclear genes that rewires metabolism to bypass the block in the tricarboxylic acid (TCA) cycle and promote cell survival [ 13 , 14 ]. Metabolic adjustment is a cytoprotective strategy in stress response and it has been recently shown that mitochondria can support the survival of cancer cells upon a hyperosmotic environment [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Lack of Mitochondrial DNA Provides Metabolic Advantage in Yeast Osmoadaptation

Di Noia,

Ocheja,

Scarcia

et al. 2024

Biomolecules

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Alterations in mitochondrial function have been linked to a variety of cellular and organismal stress responses including apoptosis, aging, neurodegeneration and tumorigenesis. However, adaptation to mitochondrial dysfunction can occur through the activation of survival pathways, whose mechanisms are still poorly understood. The yeast Saccharomyces cerevisiae is an invaluable model organism for studying how mitochondrial dysfunction can affect stress response and adaptation processes. In this study, we analyzed and compared in the absence and in the presence of osmostress wild-type cells with two models of cells lacking mitochondrial DNA: ethidium bromide-treated cells (ρ0) and cells lacking the mitochondrial pyrimidine nucleotide transporter RIM2 (ΔRIM2). Our results revealed that the lack of mitochondrial DNA provides an advantage in the kinetics of stress response. Additionally, wild-type cells exhibited higher osmosensitivity in the presence of respiratory metabolism. Mitochondrial mutants showed increased glycerol levels, required in the short-term response of yeast osmoadaptation, and prolonged oxidative stress. The involvement of the mitochondrial retrograde signaling in osmoadaptation has been previously demonstrated. The expression of CIT2, encoding the peroxisomal isoform of citrate synthase and whose up-regulation is prototypical of RTG pathway activation, appeared to be increased in the mutants. Interestingly, selected TCA cycle genes, CIT1 and ACO1, whose expression depends on RTG signaling upon stress, showed a different regulation in ρ0 and ΔRIM2 cells. These data suggest that osmoadaptation can occur through different mechanisms in the presence of mitochondrial defects and will allow us to gain insight into the relationships among metabolism, mitochondria-mediated stress response, and cell adaptation.

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Water Versus Electrolyte Rehydration on Vocal Fold Osmotic and Oxidative Stress Gene Expression

Bailey,

Venkatraman,

Cannes do Nascimento

et al. 2024

The Laryngoscope

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ObjectivesSystemic dehydration may induce osmotic and oxidative stress in the vocal folds, but our knowledge of the biology and mitigation with rehydration is limited. The purpose of this experiment was to evaluate whether systemic dehydration induces vocal fold oxidative and osmotic stress and to compare the impact of rehydration by water intake versus electrolyte intake on osmotic and oxidative stress‐related gene expression.MethodsFour‐month‐old male Sprague–Dawley rats (N = 32) underwent water restriction. Rehydration was achieved with ad libitum access to water or electrolytes for 24 hours. Rats were divided into four groups: euhydration control, dehydration‐only, dehydration followed by either water or electrolyte rehydration (n = 8/group). Gene expression was assessed via RT2 Gene Expression Profiler arrays.ResultsWith respect to oxidative stress, 10 genes were upregulated and 2 were downregulated after vocal fold dehydration compared with the euhydrated control. Concerning osmotic stress, six genes were upregulated with dehydration only, six genes were upregulated following rehydration with water, whereas a single gene was upregulated with electrolyte rehydration. All genes with significantly different expression between the rehydration groups showed lower expression with electrolytes compared with water.ConclusionsThe results support a potential role of oxidative and osmotic stresses in vocal folds related to systemic dehydration. The differences in stress‐related gene expression in vocal fold tissue between rehydration with electrolytes or water, albeit modest, suggest that both rehydration options offer clinical utility to subjects experiencing vocal fold dehydration with preliminary evidence that electrolytes may be more effective than water in resolving osmotic stress.Levels of EvidenceNA (prospective animal study) Laryngoscope, 2024

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Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via regulation of pyruvate dehydrogenase phosphorylation

Cited by 5 publications

References 52 publications

Metabolic Shift and Increased Osmotic Pressure Underlie Age-Related Macular Degeneration: A Review

Metabolic Shift and Increased Osmotic Pressure Underlie Age-Related Macular Degeneration: A Review

Lack of Mitochondrial DNA Provides Metabolic Advantage in Yeast Osmoadaptation

Water Versus Electrolyte Rehydration on Vocal Fold Osmotic and Oxidative Stress Gene Expression

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