bims-lypmec 2025-08-24 papers

PLoS Genet. 2025 Aug;21(8): e1011818

High-fat diet impairs intermediate-term memory by autophagic-lysosomal dysfunction in Drosophila.

Tong Yue, Minrui Jiang, Kotomi Onuki, Motoyuki Itoh, Ayako Tonoki.

High-fat diet (HFD) is considered a risk factor for age-related memory impairments such as Alzheimer's disease. However, how HFD affects memory formation remains unclear. In this study, we established a model of memory defects caused by HFD in Drosophila. Our results revealed that the HFD impaired intermediate-term memory (ITM), but not short-term memory (STM), produced by classical aversive olfactory conditioning, and decreased autophagic activity in the heads of the HFD-fed flies. Transient reduction in autophagic activity also impaired ITM, but not STM. Genetic enhancement of autophagic activity in neurons effectively restored ITM performance in the HFD-fed flies. Mechanistically, HFD impairs lysosomal function by downregulating the expression of lysosome-related genes, leading to impaired fusion of autophagosomes with lysosomes. These findings suggest that HFD impairs ITM by reducing autophagic activity and lysosomal dysfunction in the neurons.

DOI: https://doi.org/10.1371/journal.pgen.1011818

Diabetes Metab Res Rev. 2025 Sep;41(6): e70081

Established and Emerging Roles of Epigenetic Regulation in Diabetic Cardiomyopathy.

Adam Russell-Hallinan, Narainrit Karuna, Frank Lezoualc'h, Giuseppe Matullo, Hana Baker, Monique Bernard, Yvan Devaux, Lina Badimon, Gemma Vilahur, Jennifer Rieusset, Geneviève A Derumeaux, Chris J Watson.

An increasing number of individuals are at high risk of type 2 diabetes (T2DM) and its cardiovascular (CV) complications, which challenges healthcare systems with an increased risk of developing CV diseases. Patients with T2DM exhibit a unique cardiac phenotype termed diabetic cardiomyopathy (DCM). DCM usually involves complex and multifactorial pathogenic drivers, including myocardial inflammation, fibrosis, hypertrophy, and early diastolic dysfunction, which potentially evolve into systolic dysfunction and heart failure. There is a lack of effective treatments for DCM on the basis of the complexity of the disease per se and poor understanding of the mechanisms behind disease development and progression. Despite the considerable research attention on the onset of DCM development and progression, understanding of the full spectrum of pathogenic mechanisms has not yet been fully deciphered. Epigenetic alterations, including DNA methylation, histone modifications, bromodomain extra-terminal (BET)-containing reader proteins, and RNA-based mechanisms (e.g., miRs, lncRNAs, circRNA), are significantly associated with the initiation and evolution of DCM, particularly in the early stage. In this review, we provide insights into the evidence of epigenetic alterations related to DCM development and progression characteristics. Furthermore, the uniqueness of epigenetic changes in DCM in specific cell types within diabetic hearts is discussed. We also review epigenetic cooperation in the context of DCM development and epigenetic biomarkers related to DCM progression. With recent advancements in technology, epitranscriptomics-related to DCM has been uniquely discussed. Finally, this review may provide new avenues for potential implications for future research and the discovery of novel treatment targets for preventing the onset and progression of DCM.

Keywords: BET proteins; DNA methylation; circRNAs; diabetic cardiomyopathy; epigenetics; epitranscriptomics; histone modifications; lncRNA; miRNA

DOI: https://doi.org/10.1002/dmrr.70081

Nat Cardiovasc Res. 2025 Aug 19.

Excessive HIF-1α driven by phospholipid metabolism causes septic cardiomyopathy through cytopathic hypoxia.

Masatsugu Watanabe, Masataka Ikeda, Ko Abe, Shun Furusawa, Kosei Ishimaru, Takuya Kanamura, Satoshi Fujita, Hiroko Deguchi Miyamoto, Eisho Kozakura, Yoko Shojima Isayama, Yuki Ikeda, Takashi Kai, Toru Hashimoto, Shouji Matsushima, Tomomi Ide, Ken-Ichi Yamada, Hiroyuki Tsutsui, Ken Yamaura, Kohtaro Abe.

Septic cardiomyopathy, one manifestation of multiple organ dysfunction syndrome, is a challenging complication in sepsis, and cytopathic hypoxia has been proposed to have a key role in the pathophysiology of multiple organ dysfunction syndrome. However, the underlying mechanisms remain unknown. Here, we show that upregulation of hypoxia-inducible factor-1α (HIF-1α) in cardiomyocytes following lipopolysaccharide (LPS) treatment suppresses mitochondrial respiration via inducible nitric oxide synthase-dependent nitric oxide, leading to cytopathic hypoxia. Cardiac-specific heterozygous deletion of HIF-1α ameliorates mitochondrial and contractile dysfunction in a mouse model of septic cardiomyopathy. Mechanistically, nuclear factor-κB (NF-κB)-mediated upregulation of cyclooxygenase 2 (COX2) and secretory phospholipases A2 (sPLA2) enhances HIF-1α expression following LPS exposure, whereas their inhibition prevents LPS-induced HIF-1α upregulation, cytopathic hypoxia and contractile dysfunction. In addition, phospholipid metabolites (prostaglandins and lysophospholipids/free fatty acids, respectively) stabilize HIF-1α via protein kinase A activation. These findings highlight a crucial role of excessive HIF-1α, driven by LPS-enhanced phospholipid metabolism, in septic cardiomyopathy through induction of cytopathic hypoxia.

DOI: https://doi.org/10.1038/s44161-025-00687-1

Biophys J. 2025 Aug 18. pii: S0006-3495(25)00529-6. [Epub ahead of print]

Vesicle tension in porous membranes: aspiration, spreading, and tube extraction.

Grégory Beaune, Françoise Brochard-Wyart.

We review recent theoretical and experimental advances in understanding the mechanical tension of porous vesicles. Focusing on three key deformation processes, aspiration, spreading, and tube extrusion, we show how membrane porosity introduces novel timescales and feedback mechanisms that alter vesicle behavior. In particular, we highlight how tube extrusion from porous membranes demonstrates the vesicle's ability to regulate internal volume and dynamically modulate membrane tension. This regulation enables the sustained elongation of membrane tubes under milder mechanical conditions than those required for non-porous vesicles. These findings provide new insight into biologically relevant processes such as organelle shaping, intracellular transport, and mechanosensitive remodeling, emphasizing the crucial role of membrane permeability in cellular morphodynamics.

DOI: https://doi.org/10.1016/j.bpj.2025.08.017

Biochim Biophys Acta Mol Cell Res. 2025 Aug 15. pii: S0167-4889(25)00151-X. [Epub ahead of print] 120046

Calcium-dependent regulation of physiological vs pathological cardiomyocyte hypertrophy.

Joshua Chung, Nathan Isles, Stuart Johnston, David J Collins, Julie R McMullen, H Llewelyn Roderick, Vijay Rajagopal.

Cardiomyocyte hypertrophic growth contributes to the adaptative response of the heart to meet sustained increases in hemodynamic demand. While hypertrophic responses to physiological cues maintains or enhances cardiac function, when triggered by pathological cues, this response is maladaptive, associated with compromised heart function, although initially, this response maybe adaptive with preserved function. Since cues and activated pathways associated with both forms of hypertrophy overlap, the question arises as to the mechanism that determines these different outcomes. Here we evaluate the hypothesis that cardiomyocyte Ca2+ signalling - a regulator of pathological hypertrophy - also signals physiological hypertrophy. We discuss how different Ca2+ profiles, in distinct subcellular organelles/microdomains, and interacting with other signalling pathways, provide a mechanism for Ca2+ to be decoded to induce distinct hypertrophic phenotypes. We discuss how integration of computational with rich structural and functional cellular measurements can be used to decipher the role of Ca2+ in hypertrophic gene programming.

Keywords: Ca(2+) signalling; Cardiac hypertrophy; Cardiomyocyte; Computational modelling; IP(3) signalling

DOI: https://doi.org/10.1016/j.bbamcr.2025.120046