atp -柠檬酸解酶支持心功能和NAD+/NADH平衡，并在人类衰竭心肌中被抑制

IF 8.4 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

JACC: Basic to Translational Science Pub Date : 2025-06-10 DOI:10.1016/j.jacbts.2025.04.015

Mariam Meddeb MD , Navid Koleini MD, PhD , Mohammad Keykhaei MD , Ting Liu PhD , Marcus Rhodehamel BA , Lorena Mandarano BS , Farnaz Farshidfar MD , Liang Zhao PhD , Seoyoung Kwon BS , Gizem Keceli PhD , Ismayil Ahmet PhD , Nazareno Paolocci MD, PhD , Virginia Hahn MD , Kavita Sharma MD , Erika L. Pearce PhD , David A. Kass MD

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引用次数: 0

摘要

atp -柠檬酸裂解酶（ACLY）调节脂肪生成和细胞增殖，并形成影响NADH的胞质tca旁路回路。我们发现心肌细胞急性和慢性ACLY抑制通过增加线粒体NADH来降低NAD+/NADH比率。急性抑制引起剂量依赖性细胞毒性，但在低剂量下增加有氧呼吸而不妨碍肌细胞功能。ACLY在人类衰竭心肌中降低，心肌或肌细胞ACLY敲低的小鼠表现出轻度功能抑制，特别是在压力过载和运动受限后。NAD+增强可改善ACLY抑制引起的功能障碍/毒性。这些结果表明ACLY内在调节心脏NAD+/NADH平衡和呼吸，从而影响心脏的休息和储备功能。

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ATP-Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance and Is Depressed in Human Failing Myocardium

ATP-citrate lyase (ACLY) regulates lipogenesis and cell proliferation, and forms a cytosolic TCA-bypass circuit impacting NADH. We show that acute and chronic ACLY inhibition in cardiomyocytes depresses the NAD⁺/NADH ratio by increasing mitochondrial NADH. Acute suppression causes dose-dependent cytotoxicity, but at low doses augments aerobic respiration without impeding myocyte function. ACLY is reduced in human failing myocardium, and mice with myocardial or myocyte ACLY knockdown display mildly depressed function, particularly after pressure-overload, and exertional limitations. NAD+ enhancement ameliorates dysfunction/toxicity from ACLY inhibition. These results reveal that ACLY intrinsically regulates cardiac NAD⁺/NADH balance and respiration, which can affect rest and reserve heart function.

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来源期刊

JACC: Basic to Translational Science CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

14.20

自引率

1.00%

发文量

161

审稿时长

16 weeks

期刊介绍： JACC: Basic to Translational Science is an open access journal that is part of the renowned Journal of the American College of Cardiology (JACC). It focuses on advancing the field of Translational Cardiovascular Medicine and aims to accelerate the translation of new scientific discoveries into therapies that improve outcomes for patients with or at risk for Cardiovascular Disease. The journal covers thematic areas such as pre-clinical research, clinical trials, personalized medicine, novel drugs, devices, and biologics, proteomics, genomics, and metabolomics, as well as early phase clinical trial methodology.