bims-miptne 2025-09-14 papers

Int J Mol Sci. 2025 Aug 31. pii: 8475. [Epub ahead of print]26(17):

Mitochondrial Transport Proteins in Cardiovascular Diseases: Metabolic Gatekeepers, Pathogenic Mediators and Therapeutic Targets.

Yue Pei, Sitong Wan, Jingyi Qi, Xueyao Xi, Yinhua Zhu, Peng An, Junjie Luo, Yongting Luo.

Mitochondria, as the metabolic hubs of cells, play a pivotal role in maintaining cardiovascular homeostasis through dynamic regulation of energy metabolism, redox balance, and calcium signaling. Cardiovascular diseases (CVDs), including heart failure, ischemic heart disease, cardiomyopathies, and myocardial infarction, remain the leading cause of global mortality, with mitochondrial dysfunction emerging as a unifying pathological mechanism across these conditions. Emerging evidence suggests that impaired mitochondrial transport systems-critical gatekeepers of metabolite flux, ion exchange, and organelle communication-drive disease progression by disrupting bioenergetic efficiency and exacerbating oxidative stress. This review synthesizes current knowledge on mitochondrial transport proteins, such as the voltage-dependent anion channels, transient receptor potential channels, mitochondrial calcium uniporter, and adenine nucleotide translocator, focusing on their structural-functional relationships and dysregulation in CVD pathogenesis. We highlight how aberrant activity of these transporters contributes to hallmark features of cardiac pathology, including metabolic inflexibility, mitochondrial permeability transition pore destabilization, and programmed cell death. Furthermore, we critically evaluate preclinical advances in targeting mitochondrial transport systems through pharmacological modulation, gene editing, and nanoparticle-based delivery strategies. By elucidating the mechanistic interplay between transport protein dysfunction and cardiac metabolic reprogramming, we address a critical knowledge gap in cardiovascular biology and provide a roadmap for developing precision therapies. Our insights underscore the translational potential of mitochondrial transport machinery as both diagnostic biomarkers and therapeutic targets, offering new avenues to combat the growing burden of CVDs in aging populations.

Keywords: cardiovascular diseases (CVDs); metabolic reprogramming; mitochondrial dysfunction; mitochondrial transport proteins; therapeutic targets

DOI: https://doi.org/10.3390/ijms26178475

Cell Biol Int. 2025 Sep 12.

The Effect of Malonate as a Succinate Dehydrogenase Inhibitor on Myocardial Ischemia/Reperfusion Injury.

Amir Modarresi Chahardehi, Reza Arefnezhad, Sajjad Rafei, Alireza Arzhangzadeh, Reza Nasiri, Fatemeh Rezaei-Tazangi, Marziye Ranjbar Tavakoli.

Myocardial ischemia-reperfusion injury (MIRI) continues to provide a serious therapeutic challenge, substantially influencing myocardial infarct size and negative cardiovascular outcomes. Recent research underscores the critical significance of succinate accumulation and its rapid oxidation during reperfusion, initiating the generation of reactive oxygen species (ROS) and mitochondrial impairment. Malonate, a competitive inhibitor of succinate dehydrogenase (SDH), has attracted interest as a cardioprotective drug by reducing ROS production and cellular damage during the first reperfusion. Malonate preferentially accumulates in ischemic tissues via monocarboxylate transporter 1 (MCT1), driven by the acidic conditions of ischemia. This specific dosing prevents SDH, which in turn reduces succinate oxidation and ROS production, protecting mitochondrial integrity and heart function. The effects of malonate on infarct size reduction, left ventricular ejection fraction enhancement, and pro-inflammatory and fibrotic marker mitigation have been demonstrated in preclinical research conducted on animal models. Additionally, acidified malonate formulations improve therapeutic selectivity, providing significant cardioprotection at lower dosages. Notwithstanding encouraging experimental results, clinical validation is crucial to ascertain malonate's translational potential for the treatment of acute myocardial infarction (MI) and post-reperfusion heart failure. This review discusses the pathophysiology of MIRI, the function of SDH, and the mechanism of action of malonate, highlighting its potential as a targeted intervention for MIRI.

Keywords: ROS production; infract size; malonate; myocardial ischemia‐reperfusion injury; reperfusion therapy; succinate accumulation; succinate dehydrogenase; targeted therapy

DOI: https://doi.org/10.1002/cbin.70079

Biochim Biophys Acta Bioenerg. 2025 Sep 04. pii: S0005-2728(25)00037-4. [Epub ahead of print] 149571

Mechanism of Na+ ions contribution to the generation and maintenance of a high inner membrane potential in mitochondria.

Victor V Lemeshko.

A recent revision of the chemiosmotic theory was reported by Hernansanz-Agustín and coauthors as a discovery that a Na+ gradient across the mitochondrial inner membrane equates with the H+ gradient and contributes up to half of the inner membrane potential, without an explanation of the possible underlying mechanism. Based on the experimental data of these and other authors, and performed biophysical estimations, I propose a mechanism by which both the reported fast-acting Na+/H+ exchanger, associated with the complex I of the respiratory chain, and Na+ electrodiffusion in the intracristae space and the matrix allow maintenance of a high membrane potential.

Keywords: Chemiosmotic theory; Energy coupling; Inner membrane potential; Mitochondria; Na(+)/H(+) antiport

DOI: https://doi.org/10.1016/j.bbabio.2025.149571