ATF4 Protects the Heart From Failure by Antagonizing Oxidative Stress

Circulation Research, Journal Year: 2022, Volume and Issue: 131(1), P. 91 - 105

Published: May 16, 2022

Background: Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced activation antioxidative pathways. Disruption balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox the exposed hemodynamic however, remains be fully elucidated. Methods: Pressure overload was triggered transverse aortic constriction mice. Transcriptomic and metabolomic regulations were evaluated RNA-sequencing metabolomics, respectively. Stable isotope tracer labeling experiments conducted determine metabolic flux vitro. Neonatal rat ventricular myocytes H9c2 cells used examine molecular mechanisms. Results: We show that production cardiomyocyte NADPH, key factor regulation, decreased pressure overload-induced As consequence, level reduced glutathione downregulated, change associated with fibrosis cardiomyopathy. report pentose phosphate pathway mitochondrial serine/glycine/folate signaling, 2 NADPH-generating pathways cytosol mitochondria, respectively, are induced constriction. identify ATF4 (activating transcription 4) as an upstream controlling expression multiple enzymes these Consistently, joint analysis transcriptomic data reveal preferably controls stress redox-related Overexpression neonatal increases NADPH-producing enzymes‚ whereas silencing decreases their expression. Further, stable overexpression augments within In vivo, cardiomyocyte-specific deletion exacerbates cardiomyopathy setting accelerates failure development, attributable, at least part, inability increase enzymes. Conclusions: Our findings plays critical role under conditions governing both cytosolic NADPH.

Language: Английский

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Sepsis: a failing starvation response

Trends in Endocrinology and Metabolism, Journal Year: 2022, Volume and Issue: 33(4), P. 292 - 304

Published: Feb. 15, 2022

Language: Английский

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The E3 Ligase TRIM16 Is a Key Suppressor of Pathological Cardiac Hypertrophy

Circulation Research, Journal Year: 2022, Volume and Issue: 130(10), P. 1586 - 1600

Published: April 19, 2022

Background: Pathological cardiac hypertrophy is one of the leading causes heart failure with highly complicated pathogeneses. The E3 ligase TRIM16 (tripartite motif–containing protein 16) has been recognized as a pivotal regulator to control cell survival, immune response, and oxidativestress. However, role Trim16 in unknown. Methods: We generated cardiac-specific knockout mice adeno-associated virus serotype 9–Trim16 evaluate function pathological myocardial hypertrophy. direct effect on cardiomyocyte enlargement was examined using an adenovirus system. Furthermore, we combined RNA-sequencing interactome analysis that followed by multiple molecular biological methodologies identify target corresponding events contributing function. Results: found intimate correlation expression hypertrophy-related both human mouse. Our functional investigations unbiased transcriptomic analyses clearly demonstrated deficiency markedly exacerbated vitro transverse aortic constriction–induced mouse model, whereas overexpression attenuated remodeling. Mechanistically, Prdx1 (peroxiredoxin 1) essential interacts inhibits its phosphorylation, robust enhancement downstream Nrf2 (nuclear factor–erythroid 2–related factor 2) pathway block Trim16-blocked phosphorylation largely dependent interaction between Src resultant ubiquitinational degradation. Notably, knockdown abolished anti-hypertrophic effects overexpression. Conclusions: findings provide first evidence supporting novel suppressor indicate targeting Trim16-Prdx1 axis represents promising therapeutic strategy for failure.

Language: Английский

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Mitochondrial heterogeneity in diseases

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 23, 2023

Abstract As key organelles involved in cellular metabolism, mitochondria frequently undergo adaptive changes morphology, components and functions response to various environmental stresses demands. Previous studies of research have gradually evolved, from focusing on morphological change analysis systematic multiomics, thereby revealing the mitochondrial variation between cells or within population a single cell. The phenomenon features is defined as heterogeneity. Moreover, heterogeneity has been reported influence variety physiological processes, including tissue homeostasis, repair, immunoregulation, tumor progression. Here, we comprehensively review different tissues under pathological states, involving variant DNA, RNA, protein lipid components. Then, mechanisms that contribute are also summarized, such mutation genome import proteins result DNA Additionally, multiple perspectives investigated better comprehend mysteries cells. Finally, summarize prospective heterogeneity-targeting therapies terms alleviating oxidative damage, reducing carbon stress enhancing biogenesis relieve conditions. possibility recent technological advances targeted gene editing discussed.

Language: Английский

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The pyruvate dehydrogenase complex: Life’s essential, vulnerable and druggable energy homeostat

Mitochondrion, Journal Year: 2023, Volume and Issue: 70, P. 59 - 102

Published: March 1, 2023

Language: Английский

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