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Citrin mediated metabolic rewiring in response to altered basal subcellular Ca²⁺ homeostasis.

ABSTRACT: In contrast to long-term metabolic reprogramming, metabolic rewiring represents an instant and reversible cellular adaptation to physiological or pathological stress. Ca²⁺ signals of distinct spatio-temporal patterns control a plethora of signaling processes and can determine basal cellular metabolic setting, however, Ca²⁺ signals that define metabolic rewiring have not been conclusively identified and characterized. Here, we reveal the existence of a basal Ca²⁺ flux originating from extracellular space and delivered to mitochondria by Ca²⁺ leakage from inositol triphosphate receptors in mitochondria-associated membranes. This Ca²⁺ flux primes mitochondrial metabolism by maintaining glycolysis and keeping mitochondria energized for ATP production. We identified citrin, a well-defined Ca²⁺-binding component of malate-aspartate shuttle in the mitochondrial intermembrane space, as predominant target of this basal Ca²⁺ regulation. Our data emphasize that any manipulation of this ubiquitous Ca²⁺ system has the potency to initiate metabolic rewiring as an instant and reversible cellular adaptation to physiological or pathological stress.

SUBMITTER: Koshenov Z

PROVIDER: S-EPMC8776887 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Citrin mediated metabolic rewiring in response to altered basal subcellular Ca2+ homeostasis.

Koshenov Zhanat Z Oflaz Furkan E FE Hirtl Martin M Gottschalk Benjamin B Rost Rene R Malli Roland R Graier Wolfgang F WF

Communications biology 20220120 1

In contrast to long-term metabolic reprogramming, metabolic rewiring represents an instant and reversible cellular adaptation to physiological or pathological stress. Ca2+ signals of distinct spatio-temporal patterns control a plethora of signaling processes and can determine basal cellular metabolic setting, however, Ca2+ signals that define metabolic rewiring have not been conclusively identified and characterized. Here, we reveal the existence of a basal Ca2+ ...[more]

PMID: 35058562

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Project description:AimsHeart failure with preserved ejection fraction (HFpEF) is frequently (30%) associated with right ventricular (RV) dysfunction, which increases morbidity and mortality in these patients. Yet cellular mechanisms of RV remodelling and RV dysfunction in HFpEF are not well understood. Here, we evaluated RV cardiomyocyte function in a rat model of metabolically induced HFpEF.Methods and resultsHeart failure with preserved ejection fraction-prone animals (ZSF-1 obese) and control rats (Wistar Kyoto) were fed a high-caloric diet for 13 weeks. Haemodynamic characterization by echocardiography and invasive catheterization was performed at 22 and 23 weeks of age, respectively. After sacrifice, organ morphometry, RV histology, isolated RV cardiomyocyte function, and calcium (Ca2+ ) transients were assessed. ZSF-1 obese rats showed a HFpEF phenotype with left ventricular (LV) hypertrophy, LV diastolic dysfunction (including increased LV end-diastolic pressures and E/e' ratio), and preserved LV ejection fraction. ZSF-1 obese animals developed RV dilatation (50% increased end-diastolic area) and mildly impaired RV ejection fraction (42%) with evidence of RV hypertrophy. In isolated RV cardiomyocytes from ZSF-1 obese rats, cell shortening amplitude was preserved, but cytosolic Ca2+ transient amplitude was reduced. In addition, augmentation of cytosolic Ca2+ release with increased stimulation frequency was lost in ZSF-1 obese rats. Myofilament sensitivity was increased, while contractile kinetics were largely unaffected in intact isolated RV cardiomyocytes from ZSF-1 obese rats. Western blot analysis revealed significantly increased phosphorylation of cardiac myosin-binding protein C (Ser282 cMyBP-C) but no change in phosphorylation of troponin I (Ser23, 24 TnI) in RV myocardium from ZSF-1 obese rats.ConclusionsRight ventricular dysfunction in obese ZSF-1 rats with HFpEF is associated with intrinsic RV cardiomyocyte remodelling including reduced cytosolic Ca2+ amplitudes, loss of frequency-dependent augmentation of Ca2+ release, and increased myofilament Ca2+ sensitivity.

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Citrin mediated metabolic rewiring in response to altered basal subcellular Ca²⁺ homeostasis.

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Citrin mediated metabolic rewiring in response to altered basal subcellular Ca<sup>2+</sup> homeostasis.

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Citrin mediated metabolic rewiring in response to altered basal subcellular Ca2+ homeostasis.

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Citrin mediated metabolic rewiring in response to altered basal subcellular Ca&lt;sup&gt;2+&lt;/sup&gt; homeostasis.

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OmicsDI is part of the ELIXIR infrastructure

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Citrin mediated metabolic rewiring in response to altered basal subcellular Ca²⁺ homeostasis.

Citrin mediated metabolic rewiring in response to altered basal subcellular Ca<sup>2+</sup> homeostasis.