bims-hafaim 2024-10-13 papers

Issue of 2024‒10‒13
four papers selected by
Kyle McCommis, Saint Louis University

Cell Rep. 2024 Oct 10. pii: S2211-1247(24)01190-2. [Epub ahead of print]43(10): 114839

Mitochondrial MOF regulates energy metabolism in heart failure via ATP5B hyperacetylation.

Yuehuai Hu, Yongjia Zheng, Cui Liu, Yuyu You, Ying Wu, Panxia Wang, Yiyang Wu, Hongjun Ba, Jing Lu, Yanqiu Yuan, Peiqing Liu, Yang Mao.

Lysine acetylation is a conserved post-translational modification involved in energy metabolism in mitochondria and heart function. This study investigates the role of mitochondria-localized lysine acetyltransferase MOF (males absent on the first) in heart failure (HF). We find that MOF is upregulated in mitochondria during HF, and overexpression of mitochondria-targeted MOF (mtMOF) in mouse models results in mitochondria dysfunction, cardiac remodeling, and HF. Furthermore, sirtuin 3 (SIRT3) knockout aggravates mtMOF-induced damages, underscoring the role of MOF-catalyzed hyperacetylation in HF. Quantitative lysine acetylome analysis identifies ATP5B as a substrate of MOF. We demonstrate that the acetylation of ATP5B at K201, co-regulated by MOF and SIRT3, impairs mitochondrial respiration and energy metabolism both in vitro and in vivo. These findings suggest that the role of MOF in HF could be attributed to its regulation of ATP5B acetylation. Overall, our results highlight the disruptive impact of mitochondrial MOF on cardiac function and emphasize the significance of enzyme-catalyzed acetylation in mitochondria.

Keywords: ATP5B; CP: Metabolism; CP: Molecular biology; KAT8; MOF; SIRT3; acetylation; heart failure; mitochondria

DOI: https://doi.org/10.1016/j.celrep.2024.114839

Mol Cell Biochem. 2024 Oct 05.

Gene expression profiles, potential targets and treatments of cardiac remodeling.

Dong Fan, Han Feng, Mengyu Song, Penglin Tan.

Hypertensive and ischemic heart diseases have high morbidity all over the world, and they primarily contribute to heart failure associated with high mortality. Cardiac remodeling, as a basic pathological process in heart diseases, is mainly comprised of cardiac hypertrophy and fibrosis, as well as cell death which occurs especially in the ischemic cardiomyopathy. Myocardial remodeling has been widely investigated by a variety of animal models, including pressure overload, angiotensin II stimulation, and myocardial infarction. Pressure overload can cause compensatory cardiac hypertrophy at the early stage, followed by decompensatory hypertrophy and heart failure at the end. Recently, RNA sequencing and differentially expressed gene (DEG) analyses have been extensively employed to elucidate the molecular mechanisms of cardiac remodeling and related heart failure, which also provide potential targets for high-throughput drug screenings. In this review, we summarize recent advancements in gene expression profiling, related gene functions, and signaling pathways pertinent to myocardial remodeling induced by pressure overload at distinct stages, ischemia-reperfusion, myocardial infarction, and diabetes. We also discuss the effects of sex differences and inflammation on DEGs and their transcriptional regulatory mechanisms in cardiac remodeling. Additionally, we summarize emerging therapeutic agents and strategies aimed at modulating gene expression profiles during myocardial remodeling.

Keywords: Cardiac remodeling; Differentially expressed gene; Heart failure; Pressure overload; RNA sequencing

DOI: https://doi.org/10.1007/s11010-024-05126-6

Circ J. 2024 Oct 05.

Mitochondrial Structural Abnormalities and Cardiac Reverse Remodeling in Patients With Systolic Dysfunction.

Koji Nakano, Masayoshi Yamamoto, Yu Yamada, Tomofumi Nakatsukasa, Naoto Kawamatsu, Kimi Sato, Tomoko Machino-Ohtsuka, Nobuyuki Murakoshi, Tomoko Ishizu.

BACKGROUND: Mitochondrial dysfunction in the heart is associated with the development of heart failure (HF). However, the clinical consequences of mitochondrial structural abnormalities in patients with HF remain unexplored.METHODS AND RESULTS: Ninety-one patients with left ventricular (LV) systolic dysfunction who underwent endomyocardial biopsy (EMB) were enrolled in the study. Myocardial specimens were obtained from the right ventricular septum. Specimens were characterized using electron microscopy to assess mitochondrial size, outer membrane disruption, and cristae disorganization. The primary endpoint was a composite of cardiovascular death and unplanned hospitalization for HF. Patients were classified into LV reverse remodeling (LVRR)-positive (n=52; 57.1%) and LVRR-negative (n=39; 42.9%) groups. Cristae disorganization was observed in 21 (23.1%) patients: 6 (11.5%) in the LVRR-positive group and 15 (38.5%) in the LVRR-negative group (P=0.005). During the 1-year post-EMB observation period, 16 patients (17.6%) met the primary endpoint, with 2 (2.2%) cardiovascular deaths and 14 (15.4%) HF hospitalizations. Cristae disorganization (P=0.002) was significantly associated with the endpoints, independent of age (P=0.115), systolic blood pressure (P=0.004), B-type natriuretic peptide level (P=0.042), and mitral regurgitation (P=0.003).
CONCLUSIONS: We classified mitochondrial structural abnormalities and showed that cristae disorganization was associated with LVRR and worse prognosis. These findings may affect the management of patients with HF and systolic dysfunction who undergo EMB.

Keywords: Cristae disorganization; Heart failure; Mitochondrial dysfunction

DOI: https://doi.org/10.1253/circj.CJ-24-0451

Int J Cardiol. 2024 Oct 09. pii: S0167-5273(24)01233-6. [Epub ahead of print] 132611

Glucagon-like peptide-1 receptor agonists improve outcomes in individuals with type 2 diabetes with and without heart failure.

Yu Horiuchi, Nicholas Wettersten, Masahiko Asami, Kazuyuki Yahagi, Kota Komiyama, Hitomi Yuzawa, Jun Tanaka, Jiro Aoki, Kengo Tanabe.

BACKGROUND: The effectiveness of glucagon-like peptide-1 receptor agonists (GLP1Ras) for prevention of heart failure (HF) in patients with type 2 diabetes (T2DM) without HF and for risk of death in patients with T2DM with HF has not been fully elucidated in routine clinical practice.METHODS: Using the real-world global electronic medical record TriNetX database, individuals with T2DM and with or without HF who initiated either GLP1Ras or sitagliptin from 2017 to 2020 were retrospectively analyzed. In individuals with T2DM without HF, the primary outcome was a composite of all-cause mortality and a new diagnosis of HF within three years. In individuals with T2DM with HF, the primary outcome was all-cause mortality within three years. Propensity-score (PS) matching was used to adjust for over 100 baseline characteristics.
RESULTS: A total of 65,598 individuals with T2DM without HF starting a GLP1Ras were PS matched with 65,598 starting sitagliptin. GLP1Ras were associated with a lower incidence of the composite endpoint (10.5 % versus 11.8 %, hazard ratio [HR] 0.82, [0.80-0.85], p < 0.001), mortality (HR 0.66 [0.63-0.69]) and new diagnosis of HF (HR 0.92 [0.88-0.96]). There were 6002 individuals in each group matched for T2DM and HF. Mortality was lower in the GLP1Ras group (17.6 % versus 22.8 %, HR 0.70 [0.65-0.76], p < 0.001). Results were consistent across subgroups.
CONCLUSIONS: In this global real-world data analysis, GLP1Ra use was associated with a lower risk of death and HF in individuals with T2DM without HF, and lower risk of death in those with HF.

Keywords: Glucagon-like peptide-1 receptor agonists; Heart failure; Prognosis; Type 2 diabetes mellitus

DOI: https://doi.org/10.1016/j.ijcard.2024.132611