bims-lypmec 2025-07-20 papers

Biochem J. 2025 May 21. 482(10): 499-518

Cardiac substrate metabolism in type 2 diabetes.

Jordan S F Chan, Tanin Shafaati, John R Ussher.

As the most metabolically demanding organ on a per gram basis, substrate metabolism in the heart is intricately linked to cardiac function. Virtually all major cardiovascular pathologies are associated with perturbations in cardiac substrate metabolism, and increasing evidence supports that these perturbations in substrate metabolism can directly contribute to cardiac dysfunction. Furthermore, type 2 diabetes (T2D) is a major risk factor for increased cardiovascular disease burden, while also being characterized by a very distinct metabolic profile in the heart. This includes increases in cardiac fatty oxidation rates and a robust reduction in cardiac glucose oxidation rates. Herein, we will describe the primary mechanisms responsible for the increase in cardiac fatty acid oxidation and decrease in cardiac glucose oxidation during T2D, while also detailing perturbations in cardiac ketone and amino acid metabolism. In addition, we will interrogate preclinical studies that have addressed whether correcting perturbations in cardiac substrate metabolism may have clinical utility against ischemic heart disease, diabetic cardiomyopathy, or heart failure associated with T2D. Lastly, we will consider the translational potential of such an approach to manage cardiovascular disease in people living with T2D.

Keywords: cardiac substrate metabolism; diabetes; diabetic cardiomyopathy; diastolic dysfunction

DOI: https://doi.org/10.1042/BCJ20240189

Nat Struct Mol Biol. 2025 Jul 11.

A heterotrimeric protein complex assembles the metazoan V-ATPase upon dissipation of proton gradients.

Christopher Nardone, Julian Mintseris, Dingwei He, Justine C Rutter, Benjamin L Ebert, Steven P Gygi, Tom Rapoport.

Organelles such as lysosomes and synaptic vesicles are acidified by V-ATPases, which consist of a cytosolically oriented V1 complex that hydrolyzes ATP and a membrane-embedded VO complex that pumps protons. In yeast, V1-VO association is facilitated by the RAVE (regulator of H+-ATPase of the vacuolar and endosomal membrane) complex, but how higher eukaryotes assemble V-ATPases remains unclear. Here we identify a metazoan RAVE complex (mRAVE) whose structure and composition are notably divergent from the ancestral counterpart. mRAVE consists of DMXL1 or DMXL2, WDR7 and the central linker ROGDI. DMXL1 and DMXL2 interact with subunits A and D of the inactive, isolated V1. On dissipation of proton gradients, mRAVE binds to V1 and VO, forming a supercomplex on the membrane. mRAVE then catalyzes V1-VO assembly, enabling lysosomal acidification, neurotransmitter loading into vesicles and ATG16L1 recruitment for LC3/ATG8 conjugation onto single membranes. Our findings provide a molecular basis for neurological disorders caused by mRAVE mutations.

DOI: https://doi.org/10.1038/s41594-025-01610-9

Curr Diab Rep. 2025 Jul 15. 25(1): 42

From Type 2 Diabetes Mellitus To Diabetic Cardiomyopathy - A Systematic Review On The Role Of MicroRNA.

Anna Żarek-Starzewska, Dominika Klimczak-Tomaniak, Amelia Mądrecka, Grażyna Sygitowicz, Maciej Janiszewski, Marek Kuch.

PURPOSE OF REVIEW: Diabetes mellitus (DM) is a growing global health concern, and diabetic cardiomyopathy (DCM) affects up to 12% of individuals with diabetes, leading to myocardial hypertrophy, ventricular remodeling, and contractile dysfunction, ultimately progressing to heart failure (HF). This review explores the role of microRNAs (miRNAs) in DCM development and their potential as diagnostic and therapeutic biomarkers.
RECENT FINDINGS: MicroRNAs, short single-stranded non-coding RNAs, are key regulators of various pathophysiological processes in DCM. By modulating gene expression, they influence critical signaling pathways involved in inflammation, apoptosis, pyroptosis, oxidative stress, and fibrosis, all of which contribute to DCM progression. Emerging research suggests that miRNAs could serve as early-stage biomarkers for asymptomatic DCM and may offer novel therapeutic targets. This systematic review compiles current findings from both animal and human studies on the role of miRNAs in DCM. It highlights their potential in the early diagnosis and treatment of DCM, underscoring the need for further research to translate these insights into clinical applications.

Keywords: Diabetes; Diabetic cardiomyopathy; Heart failure; MiRNA; MicroRNA

DOI: https://doi.org/10.1007/s11892-025-01590-6

Front Physiol. 2025 ;16 1602271

Mitochondria-derived peptide MOTS-c restores mitochondrial respiration in type 2 diabetic heart.

Toan Pham, Andrew Taberner, Anthony Hickey, June-Chiew Han.

Introduction: Type 2 diabetes (T2D) is a global epidemic, and heart failure is the primary cause of premature death among T2D patients. Mitochondrial dysfunction has been linked to decreased contractile performance in diabetic heart, partly due to a disturbance in the mitochondrial capacity to supply adequate metabolic energy to contractile proteins. MOTS-c, a newly discovered mitochondrial-derived peptide, has shown promise as a therapeutic for restoring energy homeostasis and muscle function in metabolic diseases. However, whether MOTS-c therapy improves T2D heart function by increasing mitochondrial bioenergetic function remains unknown.
Methods: Here we studied the mitochondrial bioenergetic function of heart tissues isolated from a rat model mimicking type 2 diabetes induced by a high-fat diet and low-dose streptozotocin. Treated diabetic group received MOTS-c (15 mg/kg) daily injection for 3 weeks. We employed high-resolution respirometric and fluorometric techniques to simultaneously assess mitochondrial ATP production and hydrolysis capacity, reactive oxygen species (ROS) production, and oxygen flux in cardiac tissue homogenates.
Results: We found that untreated T2D rats had hyperglycemia, poor glucose control, and left ventricular hypertrophy relative to controls. T2D mitochondria showed decreased oxygen flux at the oxidative phosphorylation (OXP) while ROS production, ATP production and hydrolysis rates remained unchanged. Diabetic rats treated with MOTS-c showed decreased fasting glucose levels, improved glucose homeostasis, and decreased degree of cardiac hypertrophy. At the subcellular level, MOTS-c treated mitochondria showed increased OXPHOS respiration and ROS levels and decreased ATP hydrolysis rate during anoxic conditions.
Discussion: These findings demonstrate beneficial effects of MOTS-c treatment on glucose homeostasis and suggest a useful therapeutic option for diabetic-related cardiomyopathy and mitochondrial dysfunction.

Keywords: ATP; MOTS-c; diabetic heart; mitochondrial respiration; reactive oxygen species

DOI: https://doi.org/10.3389/fphys.2025.1602271