KAT6A acetylation regulates AMPK function and hypertrophic remodeling in the heart

IF 6.6 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Mariko Aoyagi Keller , Andreas Ivessa , Tong Liu , Hong Li , Peter J. Romanienko , Michinari Nakamura
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引用次数: 0

Abstract

Diets influence metabolism and disease susceptibility, with lysine acetyltransferases (KATs) serving as key regulators through acetyl-CoA. We have previously demonstrated that a ketogenic diet alleviates cardiac pathology, though the underlying mechanisms remain largely unknown. Here we show that KAT6A acetylation is crucial for mitochondrial function and cell growth. Proteomic analysis revealed that KAT6A is acetylated at lysine (K)816 in the hearts of mice fed a ketogenic diet under hypertension, which enhances its interaction with AMPK regulatory subunits. RNA-sequencing analysis demonstrated that the KAT6A acetylation-mimetic mutant stimulates AMPK signaling in cardiomyocytes. Moreover, the acetylation-mimetic mutant mitigated phenylephrine-induced mitochondrial dysfunction and cardiomyocyte hypertrophy via AMPK activation. However, KAT6A-K816R acetylation-resistant knock-in mice unexpectedly exhibited smaller hearts with enhanced AMPK activity, conferring protection against neurohumoral stress-induced cardiac hypertrophy and remodeling. These findings indicate that KAT6A regulates metabolism and cellular growth by interacting with and modulating AMPK activity through K816-acetylation in a cell type-specific manner.
KAT6A乙酰化调节AMPK功能和心脏肥厚重塑。
饮食影响代谢和疾病易感性,赖氨酸乙酰转移酶(KATs)通过乙酰辅酶a发挥关键调节作用。我们之前已经证明生酮饮食可以减轻心脏病理,尽管其潜在的机制仍然很大程度上未知。我们发现KAT6A乙酰化对线粒体功能和细胞生长至关重要。蛋白质组学分析显示,在高血压小鼠的生酮饮食中,KAT6A在赖氨酸(K)816位点被乙酰化,这增强了它与AMPK调节亚基的相互作用。rna测序分析表明,KAT6A乙酰化模拟突变体刺激心肌细胞中的AMPK信号传导。此外,乙酰化模拟突变体通过激活AMPK减轻了苯肾上腺素诱导的线粒体功能障碍和心肌细胞肥大。然而,KAT6A-K816R乙酰化抵抗敲入小鼠出乎意料地表现出更小的心脏和增强的AMPK活性,赋予对神经体液应激诱导的心脏肥大和重塑的保护。这些发现表明,KAT6A通过细胞类型特异性的k816乙酰化与AMPK活性相互作用并调节AMPK活性,从而调节代谢和细胞生长。
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来源期刊
Molecular Metabolism
Molecular Metabolism ENDOCRINOLOGY & METABOLISM-
CiteScore
14.50
自引率
2.50%
发文量
219
审稿时长
43 days
期刊介绍: Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.
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