bims-hafaim 2026-03-01 papers

Issue of 2026–03–01
five papers selected by
Kyle McCommis, Saint Louis University

bioRxiv. 2026 Feb 10. pii: 2026.02.06.704519. [Epub ahead of print]

Metabolic Perturbation Exacerbates Sinoatrial Node Dysfunction in Heart Failure.

Lu Ren, Yu Liu, Hao Zhang, Daphne A Diloretto, Yang Zheng, Arianne Caudal, Mengjie Xie, Wenshu Zeng, Ryan L Woltz, Hye Sook Shin, Richard Q Ngo, Guy A Perkins, Gabriela Grigorean, Ebenezer N Yamoah, Joseph C Wu, Nipavan Chiamvimonvat, Phung N Thai.

Heart failure (HF) affects approximately 6.2 million people in the United States, with a 5-year mortality exceeding 50%. Bradyarrhythmia, a known complication in HF due to sinoatrial node (SAN) dysfunction (SAND), increases the morbidity and mortality of HF patients. Insights into the mechanistic underpinnings of SAND in HF could therefore uncover vital therapeutic targets to improve clinical outcomes. The SAN cells are endowed with a dense mitochondrial network crucial for sustaining their pacemaking function on a beat-to-beat basis. We have previously demonstrated significant disruptions in the mitochondrial-sarcoplasmic reticulum connectomics, resulting in abnormal mitochondrial Ca 2+ handling and impaired mitochondrial function in HF. Here, we hypothesize that the metabolic perturbation is one of the critical mechanisms underlying SAND. To this end, we took advantage of a multi-omics approach combined with ultra-resolution imaging and functional analyses to decipher the metabolic shift that transpires in the HF SAN. Our findings revealed significant metabolic remodeling within the SAN mitochondria in HF, with a diminished reliance on fatty acid β-oxidation, enhanced utilization of ketone bodies, and heightened dependence on carbohydrate catabolism. Notably, metabolomics analyses identified the pronounced increase of glucosylceramides and ceramides as one of the mechanisms leading to mitochondrial dysfunction. We directly test this hypothesis and demonstrate that ceramides induce a dose-dependent metabolic shift from oxidative phosphorylation to glycolysis. Importantly, these alterations lead to a significant impairment in SAN automaticity in a dose-dependent manner. Collectively, the findings support the notion that ceramides are not only markers of metabolic derangement, but also active mediators of mitochondrial and metabolic dysfunction in the SAN. Overall, the study provides evidence that ceramides may be a potential therapeutic target for mitigating SAND in HF.

DOI: https://doi.org/10.64898/2026.02.06.704519

Circulation. 2026 Feb 24. 153(8): 564-566

Inhibiting Fatty Acid Oxidation With a Mitotrope in Heart Failure With Preserved Ejection Fraction.

Craig R Malloy, Daniel Cheeran.

Keywords: Editorials; congestive heart failure; fatty acids; glycolysis; metabolism; mitochondria; trimetazidine

DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.078151

J Transl Med. 2026 Feb 21.

PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes.

Silvia Radenkovic, Graeme Preston, Rohit Budhraja, Irena Muffels, Anna Ligezka, Nathan P Staff, Ron Hrstka, Bijina Balakrishnan, Rameen Shah, Sanne Verberkmoes, Ibrahim Shammas, Inez Bosnyak, Kyle M Stiers, Kent Lai, Lesa J Beamer, Akhilesh Pandey, Eva Morava, Tamas Kozicz.

BACKGROUND: PGM1-congenital disorder of glycosylation (PGM1-CDG) is frequently associated with cardiomyopathy. Although galactose therapy corrects glycosylation defects, cardiac dysfunction typically persists, suggesting a glycosylation-independent mechanism. Recent evidence of mitochondrial abnormalities in PGM1-deficient human and murine heart, together with the association of PGM1 with the Z-disk protein LDB3 (ZASP/Cypher), suggests a critical role for PGM1 in cardiomyocyte structural and energetic homeostasis. We hypothesized that PGM1-related cardiomyopathy arises from a glycosylation-independent disruption of Z-disk-mitochondrial coupling driven by loss of PGM1-LDB3 interactions, resulting in mitochondrial energy failure and impaired contractile function.
METHODS: Induced pluripotent stem cell-derived cardiomyocytes (iCMs) were generated from PGM1-deficient patient fibroblasts. Multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and pathway analysis were performed to assess functional and molecular changes. Key findings were validated using tracer metabolomics and mitochondrial respiration assays.
RESULTS: PGM1-deficient iCMs exhibited reduced beating frequency, impaired contractility, and prolonged contraction kinetics. Proteomic analyses revealed depletion of Z-disk components, including LDB3. AlphaFold3 structural modeling predicted a direct interaction between PGM1 and LDB3, implicating PGM1 in Z-disk integrity, which was confirmed in vitro. In addition, mitochondrial proteins were severely depleted, prompting us to investigate mitochondrial function. Functional validation confirmed extensive metabolic rewiring, energy depletion, and severely impaired mitochondrial respiration. Finally, the in silico drug repurposing identified possible therapeutic options that could target PGM1-deficient cardiomyopathy.
CONCLUSION: Our data suggests PGM1 is key regulator of cardiomyocyte function, linking sarcomeric Z-disk integrity with mitochondrial metabolism. These mechanistic insights offer a foundation for developing targeted therapies for PGM1-CDG and potentially other cardiomyopathies involving Z-disk dysfunction.

Keywords: Cardiac dysfunction; Mitochondrial dysfunction; PGM1-CDG; Phosphoglucomutase-1; Z-disk

DOI: https://doi.org/10.1186/s12967-026-07808-9

Exp Physiol. 2026 Feb 22.

Mitochondrial respiration and hydrogen peroxide production rate in right atrial tissues from obese diabetic patients.

Toan Pham, Sarbjot Kaur, Anthony Hickey, Marie-Louise Ward, Kenneth Tran.

Type 2 diabetes (T2D) is a global epidemic, with heart failure being the leading cause of premature death. Mitochondrial dysfunction, characterized by impaired energy metabolism, weakened energy transport system and increased oxidative stress, has been proposed as a key contributor to the impairment of contractile function in T2D hearts. However, direct evidence from human T2D hearts remains limited. We assessed the mitochondrial function of right atrial tissues obtained from consenting patients undergoing coronary bypass surgery, comparing T2D and non-diabetic groups. We used high-resolution respirometry and fluorometry techniques to assess mitochondrial O2 flux and H2O2 production in permeabilized cardiac fibres in simulated physiological conditions supported by ATP substrate. Our findings showed that O2 flux during oxidative phosphorylation and ATP-stimulated respiration states was similar between groups. T2D fibres exhibited a lower H2O2 production rate during the leak state, both per tissue mass and per O2 consumed, but no group difference was observed in the oxidative phosphorylation respiratory state. These findings suggest that T2D, in the context of other comorbidities, such as coronary artery disease and obesity, might not contribute significantly to mitochondrial dysfunction in the human heart.

Keywords: diabetic human heart; hydrogen peroxide production; mitochondrial respiration

DOI: https://doi.org/10.1113/EP093121

Genes (Basel). 2026 Feb 11. pii: 225. [Epub ahead of print]17(2):

Redox Imbalance and Genetic Mutations in Heart Failure: Synergistic Mechanisms and Therapeutic Strategies.

Vinod Kumar Balakrishnan, Abinayaa Rajkumar, Monisha K G Ganesh, Harilalith Reddy Kovvuri, Durgadevi Selvam, Preetam Krishnamurthy, Sandhya Sundaram, Kalaiselvi Periandavan, Sankaran Ramesh, Muralidharan Thoddi Ramamurthy, Namakkal S Rajasekaran.

Heart failure (HF) is a significant global health challenge, with rising prevalence and a complex, multifactorial pathophysiology. Emerging evidence suggests that disruptions in redox signaling pathways and genetic mutations play critical, synergistic roles in the development and progression of HF. This comprehensive review synthesizes current knowledge on how redox imbalance and genetic alterations interact to drive cardiac dysfunction and critically evaluates the therapeutic strategies targeting these mechanisms. We begin by introducing the basic concepts of redox biology and its role in maintaining cardiac homeostasis. Next, we examine the specific redox signaling pathways and genetic mutations implicated in HF pathogenesis, highlighting the latest mechanistic insights and findings from human studies. The complex interplay between redox dysregulation and genetic factors is explored, including their synergistic effects, compensatory mechanisms, and illustrative case studies. We also review current therapeutic strategies aimed at restoring redox balance and correcting underlying genetic mutations, discussing their progress and limitations. Finally, we present the latest research advances, identify critical knowledge gaps, and propose future directions for both basic and translational research. Understanding the redox-genetic axis is key to developing novel, targeted therapies to address the growing HF epidemic.

Keywords: cardiomyopathy; genetic mutations; heart failure; mitochondrial dysfunction; oxidative stress; redox imbalance; redox signaling

DOI: https://doi.org/10.3390/genes17020225