Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation

Abstract Fibroblast to myofibroblast differentiation is crucial for the initial healing response but excessive myofibroblast activation leads to pathological fibrosis. Therefore, it is imperative to understand the mechanisms underlying myofibroblast formation. Here we report that mitochondrial calcium (mCa2+) signaling is a regulatory mechanism in myofibroblast differentiation and fibrosis. We demonstrate that fibrotic signaling alters gating of the mitochondrial calcium uniporter (mtCU) in a MICU1-dependent fashion to reduce mCa2+ uptake and induce coordinated changes in metabolism, i.e., increased glycolysis feeding anabolic pathways and glutaminolysis yielding increased α-ketoglutarate (αKG) bioavailability. mCa2+-dependent metabolic reprogramming leads to the activation of αKG-dependent histone demethylases, enhancing chromatin accessibility in loci specific to the myofibroblast gene program, resulting in differentiation. Our results uncover an important role for the mtCU beyond metabolic regulation and cell death and demonstrate that mCa2+ signaling regulates the epigenome to influence cellular differentiation.

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Mitochondrial calcium uniporter regulates PGC-1α expression to mediate metabolic reprogramming in pulmonary fibrosis

Redox Biology ◽

10.1016/j.redox.2019.101307 ◽

2019 ◽

Vol 26 ◽

pp. 101307 ◽

Cited By ~ 7

Author(s):

Linlin Gu ◽

Jennifer L. Larson Casey ◽

Shaida A. Andrabi ◽

Jun Hee Lee ◽

Selene Meza-Perez ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Metabolic Reprogramming ◽

Mitochondrial Calcium ◽

Mitochondrial Calcium Uniporter ◽

Calcium Uniporter

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The Regulatory Mechanism and Biological Significance of Mitochondrial Calcium Uniporter in the Migration, Invasion, Angiogenesis and Growth of Gastric Cancer

OncoTargets and Therapy ◽

10.2147/ott.s262049 ◽

2020 ◽

Vol Volume 13 ◽

pp. 11781-11794 ◽

Cited By ~ 2

Author(s):

Xiaofei Wang ◽

Xudong Song ◽

Guang Cheng ◽

Jingwen Zhang ◽

Liru Dong ◽

...

Keyword(s):

Gastric Cancer ◽

Regulatory Mechanism ◽

Biological Significance ◽

Mitochondrial Calcium ◽

Mitochondrial Calcium Uniporter ◽

Calcium Uniporter

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Targeting Cpt1a-Bcl-2 interaction modulates apoptosis resistance and fibrotic remodeling

Cell Death and Differentiation ◽

10.1038/s41418-021-00840-w ◽

2021 ◽

Author(s):

Linlin Gu ◽

Ranu Surolia ◽

Jennifer L. Larson-Casey ◽

Chao He ◽

Dana Davis ◽

...

Keyword(s):

Fatty Acid ◽

Pulmonary Fibrosis ◽

B Cell Lymphoma ◽

Dominant Negative ◽

Metabolic Reprogramming ◽

Mitochondrial Calcium ◽

Apoptosis Resistance ◽

Mitochondrial Calcium Uniporter ◽

Lung Macrophages ◽

Calcium Uniporter

AbstractThe mitochondrial calcium uniporter (MCU) regulates metabolic reprogramming in lung macrophages and the progression of pulmonary fibrosis. Fibrosis progression is associated with apoptosis resistance in lung macrophages; however, the mechanism(s) by which apoptosis resistance occurs is poorly understood. Here, we found a marked increase in mitochondrial B-cell lymphoma-2 (Bcl-2) in lung macrophages from subjects with idiopathic pulmonary fibrosis (IPF). Similar findings were seen in bleomycin-injured wild-type (WT) mice, whereas Bcl-2 was markedly decreased in mice expressing a dominant-negative mitochondrial calcium uniporter (DN-MCU). Carnitine palmitoyltransferase 1a (Cpt1a), the rate-limiting enzyme for fatty acid β-oxidation, directly interacted with Bcl-2 by binding to its BH3 domain, which anchored Bcl-2 in the mitochondria to attenuate apoptosis. This interaction was dependent on Cpt1a activity. Lung macrophages from IPF subjects had a direct correlation between CPT1A and Bcl-2, whereas the absence of binding induced apoptosis. The deletion of Bcl-2 in macrophages protected mice from developing pulmonary fibrosis. Moreover, mice had resolution when Bcl-2 was deleted or was inhibited with ABT-199 after fibrosis was established. These observations implicate an interplay between macrophage fatty acid β-oxidation, apoptosis resistance, and dysregulated fibrotic remodeling.

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Restoring mitochondrial calcium uniporter expression in diabetic mouse heart improves mitochondrial calcium handling and cardiac function

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.002066 ◽

2018 ◽

Vol 293 (21) ◽

pp. 8182-8195 ◽

Cited By ~ 24

Author(s):

Jorge Suarez ◽

Federico Cividini ◽

Brian T. Scott ◽

Kim Lehmann ◽

Julieta Diaz-Juarez ◽

...

Keyword(s):

Cardiac Function ◽

Glucose Oxidation ◽

Cardiac Myocyte ◽

Diabetic Mouse ◽

Metabolic Reprogramming ◽

Mitochondrial Calcium ◽

Adeno Associated Virus ◽

Mitochondrial Calcium Uniporter ◽

Calcium Uniporter ◽

And Function

Diabetes mellitus is a growing health care problem, resulting in significant cardiovascular morbidity and mortality. Diabetes also increases the risk for heart failure (HF) and decreased cardiac myocyte function, which are linked to changes in cardiac mitochondrial energy metabolism. The free mitochondrial calcium level ([Ca2+]m) is fundamental in activating the mitochondrial respiratory chain complexes and ATP production and is also known to regulate pyruvate dehydrogenase complex (PDC) activity. The mitochondrial calcium uniporter (MCU) complex (MCUC) plays a major role in mediating mitochondrial Ca2+ import, and its expression and function therefore have a marked impact on cardiac myocyte metabolism and function. Here, we investigated MCU's role in mitochondrial Ca2+ handling, mitochondrial function, glucose oxidation, and cardiac function in the heart of diabetic mice. We found that diabetic mouse hearts exhibit altered expression of MCU and MCUC members and a resulting decrease in [Ca2+]m, mitochondrial Ca2+ uptake, mitochondrial energetic function, and cardiac function. Adeno-associated virus-based normalization of MCU levels in these hearts restored mitochondrial Ca2+ handling, reduced PDC phosphorylation levels, and increased PDC activity. These changes were associated with cardiac metabolic reprogramming toward normal physiological glucose oxidation. This reprogramming likely contributed to the restoration of both cardiac myocyte and heart function to nondiabetic levels without any observed detrimental effects. These findings support the hypothesis that abnormal mitochondrial Ca2+ handling and its negative consequences can be ameliorated in diabetes by restoring MCU levels via adeno-associated virus–based MCU transgene expression.

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Metabolic Regulation of the Senescence Program

Innovation in Aging ◽

10.1093/geroni/igaa057.437 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 133-133

Author(s):

Manali Potnis ◽

Timothy Nacarelli ◽

Eishi Noguchi ◽

Ashley Azar ◽

Christian Sell

Keyword(s):

Cell Fate ◽

Metabolic Regulation ◽

Human Fibroblasts ◽

Chromatin Accessibility ◽

Metabolic Reprogramming ◽

Metabolic Inhibitors ◽

Open Chromatin ◽

Age Related ◽

Methionine Restriction ◽

Senescence Program

Abstract Cellular senescence is a cell fate defined by an irreversible cell-cycle arrest and a pro-inflammatory secretory profile. It is a consequence of a shift in metabolism and rearrangement of chromatin. Accumulation of senescent cells is a universal hallmark of age-related pathologies suggesting these cells contribute to age-related susceptibility to disease. Here, we examine the interplay between two metabolic inhibitors of senescence: Rapamycin treatment and Methionine restriction (metR). We report that a combination of methionine restriction and rapamycin induces a metabolic reprogramming that prevents activation of the senescence program in human fibroblasts. The treated cells continue to divide at a slow rate at a high passage and lack senescence-associated markers and inflammatory cytokines. Genome-wide chromatin accessibility analysis reflects chromatin remodeling with distinctly increased accessibility of heterochromatic regions in treated cells. Further, Transcriptome-wide analysis reveals increased expression of specific methyltransferases which alter the trimethylation of H3, one of the strongest hallmarks of open chromatin. This may represent a mechanistic link between a major hallmark of senescence and nuclear events required for senescence.

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