bims-hafaim 2026-06-07 papers

Issue of 2026–06–07
five papers selected by
Kyle McCommis, Saint Louis University

Circ Res. 2026 Jun 05. 138(12): e327471

Cardiac Lipid Metabolism: Cells, Metabolites, and Rhythms.

Ira J Goldberg, Martin E Young, P Christian Schulze, Konstantinos Drosatos.

Although studied for decades, metabolic therapies that target cardiac lipid metabolism are underdeveloped, and most approaches have thus far failed as a heart failure treatment. In contrast, new therapies for diabetes and obesity are widely used for the prevention and treatment of heart failure. The heart depends heavily on lipid uptake and utilization for proper function. Too much or too little cardiac lipid catabolism becomes detrimental and causes heart failure, either due to lipotoxicity or energetic depletion. For this reason, cardiac lipid metabolism is carefully controlled and balanced. Moreover, cardiac fatty acid oxidation affects systemic energy metabolism, as evidenced by changes in circulating levels of fatty acids and lipoproteins. This review describes mechanisms of regulation of lipid uptake and metabolism by cardiomyocytes, how fatty acid and glucose use are coordinated, how mitochondrial fatty acid metabolism is regulated at the transcriptional and posttranslational levels, as well as how fed/fasting cycles and circadian clocks modulate heart metabolism during the day. We review studies that used cultured cells, animal models, human tissue, and nuclear tracing. Our objective is to present current knowledge on mechanisms that control cardiac lipid metabolism, thereby suggesting experimental directions that could lead to new metabolic therapies.

Keywords: fatty acids; glucose; heart failure; lipoproteins

DOI: https://doi.org/10.1161/CIRCRESAHA.126.327471

Am J Physiol Heart Circ Physiol. 2026 Jun 01.

Loss of SIRT2 in Cardiomyocytes Reduces Glycolytic Flux via Increased Acetylation of Glycolytic Enzymes.

Ezra B Ketema, Ruth Han, Muhammad Ahsan, Fariha Fairuz, Kaya L Persad, Qiuyu Sun, Liyan Zhang, Jason R B Dyck, Gary D Lopaschuk.

Cardiac glycolytic rates is altered under many pathological conditions, although the mechanism(s) responsible for these changes in glycolysis is not completely clear. Since cardiac hyperacetylation also occurs under many pathological conditions, we determined if glycolytic enzyme lysine acetylation can regulate cardiac glycolysis rates. The effects of modifying cardiac acetylation on glycolysis was examined in isolated working rat hearts and H9c2 cardiomyocytes using SIRT2 inhibition (AGK2 or siRNA knockdown), SIRT1 inhibition (EX-527), pan-sirtuin inhibition (NAM), or acetyltransferase inhibition (C646). Glycolysis rates were directly measured in hearts or cardiomyocytes perfused with 5 mM glucose and 0.8 mM palmitate, using radiolabeled [5-3H] glucose. SIRT2 inhibition significantly decreased glycolysis rates in isolated working rat hearts compared to controls (1844±153 vs 2753±236 nmol.g dry wt-1.min-1, p<0.05) with no significant effect on glucose oxidation rates. In H9c2 cardiomyocytes, both SIRT2 inhibition and knockdown reduced glycolysis rates compared to controls (524±108 vs 2631±372 and 745±31 vs 1659±168 nmol.mg protien-1.hr-1, p<0.05, respectively). This decrease in glycolysis was accompanied by increased acetylation of glycolytic enzymes, including glyceraldehyde phosphate dehydrogenase (GAPDH) and phosphoglycerate mutase (PGAM), without changes in global acetylation patterns. SIRT2 inhibition or knockdown did not affect the phosphorylation status of insulin signaling proteins. However, SIRT2 inhibition did attenuate the phenylephrine-mediated hypertrophic response in H9c2 cells. We conclude that SIRT2 inhibition increases the acetylation of cardiac glycolytic enzymes and decreases glycolysis rates, suggesting that post-translational acetylation is an important pathway regulating cardiac glycolysis.

Keywords: Cardiac metabolism; Glycolysis; Protein lysine acetylation; SIRT2

DOI: https://doi.org/10.1152/ajpheart.00145.2026

Ageing Res Rev. 2026 Jun 01. pii: S1568-1637(26)00184-4. [Epub ahead of print]120 103192

Intracellular mitochondrial-subcellular communication: A regulator of myocardial energy metabolic homeostasis in heart failure.

Yu-Xin Kang, Xi-Tong Sun, Ao-Lin Li, Ao Zhang, Xin-Biao Fan, Wen-Yu Shang, Yun-Feng Jia, Yi-Xuan Zhao, Miao-Miao Wei, Yu-Xiao Cao, Lei Wei, Tian-Qi Wang, Zheng Zhang, Bo-Yu Zhu, Yong-Chun Liang, Yue Hu, Jun-Ping Zhang.

Heart failure (HF) is characterized by a severe disruption of myocardial energy metabolism, with mitochondrial dysfunction standing as a central pathological feature. However, the upstream regulatory mechanisms that drive metabolic remodeling, particularly across distinct HF phenotypes, remain inadequately defined. Mounting evidence reveals that, beyond their metabolic role, mitochondria act as central signaling hubs. This review proposes that dysfunctional mitochondrial-organelle crosstalk is a critical upstream initiator of the metabolic dyshomeostasis observed in HF. We analyze how such inter-organelle crosstalk regulates cardiac metabolism in health and deteriorates with aging and disease. A key focus is elucidating the phenotype-specific metabolic reprogramming in HF with reduced and preserved ejection fraction, tracing their differential traits to distinct alterations in inter-organelle signaling. We further dissect this self-perpetuating vicious cycle: communication defects trigger metabolic dysfunction, which in turn erodes inter-organelle communication, thereby accelerating disease progression. We evaluate technologies and propose that restoring the mitochondrial-subcellular interface offers a novel therapeutic strategy to correct the core metabolic disturbance in HF.

Keywords: Energy metabolic remodelling; Heart failure; Lipotoxic substances; Mitochondrial communication; Mitochondrial dysfunction; Reactive oxygen species

DOI: https://doi.org/10.1016/j.arr.2026.103192

Metabolism. 2026 Jun 04. pii: S0026-0495(26)00179-4. [Epub ahead of print] 156669

MitoNEET in cardiac mitochondria: Linking mitochondrial function and cardiac disease.

Lechen Su, Yinru Huang, Hangfei Zhou, Zhangping Liao.

MitoNEET is a protein localized to the mitochondrial outer membrane and is recognized as an important regulator of mitochondrial activity, participating in redox signaling, iron-sulfur cluster trafficking, and trace element homeostasis. The heart is an organ with exceptionally high energy demands and relies critically on tightly coordinated mitochondrial processes to sustain continuous contractile activity. Accumulating evidence indicates that mitoNEET influences multiple aspects of cardiac mitochondrial biology, including mitochondrial dynamics, energy production, redox balance, ion homeostasis, and metabolic regulation of fatty acid and glucose utilization, all of which are essential for normal cardiac contraction and relaxation. Alterations in mitoNEET expression or activity are closely associated with mitochondrial dysfunction in cardiovascular diseases, including ischemic heart disease and heart failure, in which it regulates mitochondrial oxidative stress, ion homeostasis, and metabolic flexibility. In this review, we outline the molecular mechanisms through which mitoNEET affects cardiac mitochondrial function, providing a perspective on its therapeutic potential for the prevention and treatment of cardiovascular disease through modulation of mitochondrial function.

Keywords: Cardiovascular disease; Iron-sulfur clusters; MitoNEET; Mitochondrial dysfunction

DOI: https://doi.org/10.1016/j.metabol.2026.156669

J Lipid Res. 2026 May 29. pii: S0022-2275(26)00098-2. [Epub ahead of print] 101072

Plasma Acylcarnitine Profiling Reveals Heart Failure Specific Fatty Acid Oxidation Signature in Chronic Kidney Disease.

Farsad Afshinnia, Thekkelnaycke M Rajendiran, Jaeman Byun, Subramaniam Pennathur.

BACKGROUND: Acylcarnitines are key intermediates in fatty acid oxidation (FAO). Chronic kidney disease (CKD) and heart failure (HF) both alter FAO. However, it is unclear whether specific FAO changes are associated with CKD coupled with HF. Aim is to investigate alterations in various chain acylcarnitines (AC) in patients with CKD with and without HF and examine their independent associations.
METHODS: In a case-control study at the University of Michigan (2010-2022), 562 participants with HF and available plasma samples were selected and compared with 461 participants without HF, frequency matched by CKD stage. Plasma samples were retrieved for mass spectrometry-based AC quantification.
RESULTS: Mean age (± standard deviation) was 65±14 years in HF, and 54±14 years in those without HF. We observed a significant increase in short- (SCAC) and medium-chain acylcarnitines (MCAC) but a decrease in long-chain acylcarnitines (LCAC) due to the worsening stage of CKD in the absence of HF. In patients with HF, the slope of changes in SCAC and LCAC was mitigated, whereas the increase in MCAC due to worsening CKD stage was greater than that in the absence of HF. The mean SCAC, MCAC, and LCAC scores were significantly different at CKD stage 4 in HF versus those without HF (P≤0.002).
CONCLUSION: These findings suggest that CKD with HF is characterized by impaired β-oxidation of MCAC and LCAC and greater myocardial utilization of short-chain fatty acids. Inefficient β-oxidation coupled with the accumulation of MCAC and LCAC may in part explain the poorer outcomes in the HF-CKD complex.

Keywords: Acylcarnitines; chronic kidney disease; heart failure; mass spectrometry

DOI: https://doi.org/10.1016/j.jlr.2026.101072