bims-hafaim 2025-11-30 papers

Issue of 2025–11–30
four papers selected by
Kyle McCommis, Saint Louis University

Front Physiol. 2025 ;16 1700313

Mechanisms of metabolic transition in hypertrophic cardiomyopathy.

Conghao Tan, Zhexuan Guo, Junjie Zhou, Wei Yuan.

Hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiovascular disease that affects individuals worldwide. While current treatments have improved the prognosis for many patients, HCM continues to impose a significant burden on global healthcare systems. Understanding its underlying mechanisms, particularly the role of metabolic transition, is crucial for enhancing diagnosis and treatment strategies. One of the most promising areas of research in HCM is the study of metabolic transition. This process, which involves significant changes in energy production and consumption within cardiac cells, has become increasingly recognized as a key factor in the disease's progression. In HCM, glucose metabolism is markedly altered. The heart increasingly relies on glycolysis for energy production, while the aerobic oxidation of glucose is impaired. These changes are accompanied by alterations in the activity of glucose transporter proteins and key enzymes involved in glycolysis. Such abnormalities are closely associated with myocardial ischemia, fibrosis, and an increased risk of acidosis in cardiomyocytes, which in turn affects calcium cycling and cardiac diastolic function. Lipid metabolism is significantly altered in HCM. There is a defect in fatty acid β-oxidation, leading to the accumulation of ceramides and sphingomyelins in cardiomyocytes. Additionally, changes in ketone body metabolism occur as an adaptive response to energy deficiency, which may further affect cardiac function. Amino acid metabolism is also altered in HCM. Elevated levels of branched-chain amino acids have been observed, and these metabolites are strongly associated with cardiac remodeling and the development of insulin resistance. These changes further contribute to the maladaptive processes in HCM. A comprehensive understanding of the metabolic transition process in HCM is essential for unraveling the disease's pathogenesis. Such insights could pave the way for novel therapeutic strategies, ultimately improving patient outcomes and quality of life.

Keywords: glucose metabolism; hypertrophic cardiomyopathy; lipid metabolism; metabolic transition; mitochondrial dysfunction

DOI: https://doi.org/10.3389/fphys.2025.1700313

Curr Heart Fail Rep. 2025 Nov 29. 22(1): 42

Metabolic-Electrophysiological Coupling in Heart Failure: from Bidirectional Decoupling to Therapeutic Recoupling.

Hong Yu, Shi-Yao Chang, Xin Tian, Hui Xiao, Jia-Jia Xu, Cai-Li Zhu, Lin Li, Li-Li Xu.

PURPOSE OF REVIEW: Heart failure (HF) is a complex clinical syndrome of progressive cardiac dysfunction, posing a major global burden on public health. The coupling between cardiomyocyte electrophysiology and energy metabolism is critical for sustaining cardiac electromechanical function. This review aims to elucidate the role of disrupted metabolic-electrophysiological coupling in disease progression and summarize emerging therapeutic targets.
RECENT FINDINGS: Currently, drugs that correct electrical or metabolic issues are proving effective in patients, while theoretical research and preliminary experiments have corroborated electro-metabolic coupling and its regulatory crosstalk among metabolic signaling, electrical activity, and energy utilization. These foundational studies have established a viable basis for multi-target interventions in HF. Restoring the disrupted integration between metabolism and electrophysiology emerges as a promising strategic direction in HF therapy. Interventions targeting this integration, such as metabolic modulators and mitochondrially targeted agents, may suppress arrhythmias, reverse adverse remodeling, and improve contractile function. This integrated approach may ultimately lead to more effective treatments that improve clinical outcomes for HF patients.

Keywords: Cardiomyocytes; Electrophysiology; Energy metabolism; Heart failure; Metabolic flexibility; Mitochondrial dysfunction

DOI: https://doi.org/10.1007/s11897-025-00731-y

Biomolecules. 2025 Nov 09. pii: 1572. [Epub ahead of print]15(11):

Mitochondrial Dysfunction in Cardiomyopathy and Heart Failure: From Energetic Collapse to Therapeutic Opportunity.

Nikola Pavlović, Petar Todorović, Mirko Maglica, Marko Kumrić, Katarina Vukojević, Zenon Pogorelić, Joško Božić.

The heart's relentless contractile activity depends critically on mitochondrial function to meet its extraordinary bioenergetic demands. Mitochondria, through oxidative phosphorylation, not only supply ATP but also regulate metabolism, calcium homeostasis, and apoptotic signaling, ensuring cardiomyocyte viability and cardiac function. Mitochondrial dysfunction is a hallmark of cardiomyopathies and heart failure, characterized by impaired oxidative phosphorylation, excessive production of reactive oxygen species (ROS), dysregulated calcium handling, and disturbances in mitochondrial dynamics and mitophagy. These defects culminate in energetic insufficiency, cellular injury, and cardiomyocyte death, driving heart disease progression. Diverse cardiomyopathy phenotypes exhibit distinct mitochondrial pathologies, from acute ischemia-induced mitochondrial collapse to chronic remodeling seen in dilated, hypertrophic, restrictive, and primary mitochondrial cardiomyopathies. Mitochondria also orchestrate cell death and inflammatory pathways that worsen cardiac dysfunction. Therapeutic strategies targeting mitochondrial dysfunction, including antioxidants, modulators of mitochondrial biogenesis, metabolic therapies, and innovative approaches such as mitochondrial transplantation, show promise but face challenges in clinical translation. Advances in biomarker discovery and personalized medicine approaches hold promise for optimizing mitochondrial-targeted therapies. Unlike previous reviews that examined these pathways or interventions individually, this work summarizes insights into mechanisms with emerging therapeutic strategies, such as SGLT2 inhibition in HFpEF, NAD+ repletion, mitochondrial transplantation, and biomarker-driven precision medicine, into a unified synthesis. This framework underscores the novel contribution of linking basic mitochondrial biology to translational and clinical opportunities in cardiomyopathy and heart failure. This review synthesizes the current understanding of mitochondrial biology in cardiac health and disease, delineates the molecular mechanisms underpinning mitochondrial dysfunction in cardiomyopathy and heart failure, and explores emerging therapeutic avenues aimed at restoring mitochondrial integrity and improving clinical outcomes in cardiac patients.

Keywords: bioenergetics; cardiomyopathy; heart failure; mitochondrial dynamics; mitochondrial dysfunction

DOI: https://doi.org/10.3390/biom15111572

Sci Rep. 2025 Nov 28. 15(1): 42770

Astragalus membranaceus injection activates mitophagy and protects mitochondrial function in chronic heart failure via inhibiting AKT/mTOR pathway.

Sinai Li, Juju Shang, Wenlong Xing, Mingxue Zhou, Shenglei Qiu, Weihong Liu, Lei Zhang, Haoyue Shi, Huanning Niu, Songtao Kuang, Tong Wu, Mengting Liu, Hongxu Liu.

To investigate the effects and mechanisms of Astragalus Membranaceus Injection (AMI) on mitophagy and mitochondrial function in chronic heart failure (CHF) based on phosphoproteomic and network pharmacology analysis. Primary neonatal mouse cardiomyocytes were isolated and hypertrophy cardiomyocyte model was induced by phenylephrine (PE) stimulation. AMI's effects on cell size, apoptosis, mitophagy, and mitochondrial function in hypertrophic cardiomyocytes were assessed. A pressure-overload CHF model was established via transverse aortic constriction (TAC) surgery in C57BL/6N mice. Echocardiography and histopathology were employed to evaluate AMI's effects on cardiac function and structural remodeling. Transmission electron microscope (TEM) and immunofluorescence were used to detect the distribution of autophagosomes and mitochondria. Phosphorylation-antibody microarray and network pharmacology were employed to explore AMI's cardioprotective mechanisms. The AKT/mTOR pathway's involvement was verified through Western blotting of AKTSer473 and mTORSer2481 phosphorylation and pharmacological validation using SC79 (AKT/mTOR activator) and GSK-690693 (AKT/mTOR inhibitor) in gain/loss-of-function experiments. In vitro, AMI dose-dependently suppressed pathological hypertrophy, attenuated apoptosis, restored mitochondrial function, and enhanced mitophagic flux. In vivo, AMI treatment significantly improved left ventricular ejection fraction while attenuated cardiac hypertrophy and interstitial fibrosis in TAC-induced CHF mice. Besides, AMI treatment increased the number of mitochondria and elevated autophagy in TAC mice. Phosphoproteomic screening and network pharmacology analysis identified the PI3K/AKT/mTOR axis as the primary regulatory pathway mediating AMI's cardioprotection. Pharmacological activation of AKT/mTOR signaling using SC79 significantly suppressed mitophagic flux, whereas AMI treatment mirrored the effects of the AKT/mTOR inhibitor GSK-690693, effectively restoring mitophagy and mitochondrial homeostasis. AMI exerts its cardioprotective effects through inhibition of the AKT/mTOR pathway, thereby ameliorating maladaptive remodeling and mitochondrial dysfunction in CHF.

Keywords: AKT/mTOR pathway; Astragalus membranaceus; Chronic heart failure; Mitochondrial dysfunction; Mitophagy

DOI: https://doi.org/10.1038/s41598-025-27065-y