bims-raghud 2025-09-14 papers

Issue of 2025–09–14
four papers selected by
Irene Sambri, TIGEM

Aging Cell. 2025 Sep 08. e70216

An mTOR-Tfeb-Fabp7a Axis Ameliorates bag3 Cardiomyopathy via Decelerating Cardiac Aging.

Yonghe Ding, Xueling Ma, Feixiang Yan, Baul Yoon, Wei Wei, Yuji Zhang, Xueying Lin, Xiaolei Xu.

While BAG3 has been identified as a causative gene for dilated cardiomyopathy, the major pathological events in BAG3-related cardiomyopathy that could be targeted for therapeutic benefit remain to be discovered. Here, we aim to uncover novel pathological events through genetic studies in a zebrafish bag3 cardiomyopathy model. Given the known cardioprotective effects of mtor inhibition and the fact that transcription factor EB (tfeb) encodes a direct downstream phosphorylation target of mTOR signaling, we generated a cardiomyocyte-specific transgenic line overexpressing tfeb (Tg[cmlc2:tfeb]). This overexpression was sufficient to restore defective proteostasis and rescue cardiac dysfunction in the bag3 cardiomyopathy model. Importantly, we detected accelerated cardiac senescence in the bag3 cardiomyopathy model, which can be mitigated by Tg(cmlc2:tfeb). We compared cardiac transcriptomes between the Tg(cmlc2:tfeb) transgenic fish and the mtorxu015/+ mutant and found that inhibition of the fatty acid binding protein a (fabp7a) gene exerts therapeutic effects. Consistent with this genetic evidence, we detected elevated fabp7a expression in the bag3 cardiomyopathy model, whereas cardiomyocyte-specific overexpression of fabp7a induced dysregulated proteostasis, accelerated cardiac senescence, and cardiac dysfunction. To elucidate the functions of Fabp7a in normative cardiac aging, we turned to the African Turquoise Killifish. We noted elevated Fabp7a expression in the hearts of aged killifish, and pharmacological inhibition of Fabp7a mitigated the cardiac aging process. Together, this study uncovered accelerated cardiac senescence as a key pathological event in bag3 cardiomyopathy and reveals that manipulating the mTOR-Tfeb-Fabp7a axis can mitigate this pathology and confer cardioprotective effects.

DOI: https://doi.org/10.1111/acel.70216

Trends Mol Med. 2025 Sep 05. pii: S1471-4914(25)00192-3. [Epub ahead of print]

Human cardiac organoids for disease modeling and drug discovery.

Sean Escopete, Madelyn Arzt, Maedeh Mozneb, Jemima Moses, Arun Sharma.

Cardiac organoids are 3D self-assembling structures that recapitulate some of the functional, structural, and cellular aspects of the developing heart. Cardiac organoid modeling has overcome many of the limitations of current cardiac modeling systems by providing a human-relevant, multicellular, spatially advanced model that can replicate early key developmental stages of human cardiogenesis. Recent advancements in cardiac organoid modeling have enabled further understanding of cardiogenesis, cardiovascular disease, and drug-induced cardiotoxicity. Emerging tools to effectively characterize cardiac organoid models to understand their morphology, function, and cellular phenotype will enable further understanding of cardiac development, cardiovascular disease, and preclinical drug discovery.

Keywords: cardiovascular; disease modeling; drug screening; organoid; stem cell

DOI: https://doi.org/10.1016/j.molmed.2025.08.004

G Ital Nefrol. 2025 Aug 29. pii: 2025-vol4. [Epub ahead of print]42(4):

[SGLT2i: Exploring Multiple Pathways in Cardiorenal Protection. Insights Into Nutrient Deprivation].

Fabio Mazza, Francesca Apponi, Angela Cicciarelli, Filomena Rubino, Ernesto Anselmo Cioffi, Roberto Simonelli.

SGLT-2 inhibitors are a relatively new class of antidiabetic drugs. They activate a transcriptional response similar to calorie restriction characterized by the up-regulation of sensors involved in nutrient deprivation, such as SIRT1 and AMPK, and the down-regulation of mTOR, a molecule involved in nutritional excess signaling. The purpose of this review is to illustrate the main pathways of nutrient deprivation: a complex mechanistic framework partly responsible for the cardio-renal benefits that makes these drugs unique.

Keywords: AMPK; ROS; SGLT2i; autophagy; mTORC1; mitophagy

DOI: https://doi.org/10.69097/42-04-2025-05

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