Ketone Catabolism is Essential for Maintaining Normal Heart Function During Aging DOI Open Access
Mariko Aoyagi Keller, Michinari Nakamura

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 19, 2025

The heart utilizes various nutrient sources for energy production, primarily favoring fatty acid oxidation. While ketones can be fuel substrates, ketolysis has been shown to dispensable development and function in mice. However, the long-term consequences of downregulation remain unknown. Here we demonstrate that ketone catabolism is essential preserving cardiac during aging. expression succinyl-CoA:3-ketoacid CoA transferase (SCOT), a rate-limiting enzyme ketolysis, decreases with aging female SCOT cardiomyocyte-specific knockout (cKO) mice exhibit normal at 10 weeks age but progressively develop dysfunction remodeling as they age, without overt hypertrophy both sexes. Notably, supplementation via ketogenic diet partially rescues contractile cKO mice, suggesting oxidation-independent mechanisms contribute cardiomyopathy caused by downregulation. These findings indicate crucial maintaining aging, confer cardioprotection independently

Язык: Английский

KAT6A acetylation drives metabolic adaptation to mediate cellular growth and mitochondrial metabolism through AMPK interaction DOI Open Access
Mariko Aoyagi Keller, Andreas S. Ivessa, Tong Liu

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 14, 2025

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 KAT6A acetylation is crucial for mitochondrial function cell growth. Proteomic analysis revealed acetylated at (K)816 in hearts of mice fed under hypertension, which enhances its interaction AMPK regulatory subunits. RNA-sequencing acetylation-mimetic mutant stimulates signaling cardiomyocytes. Moreover, mitigated phenylephrine-induced dysfunction cardiomyocyte hypertrophy via activation. However, KAT6A-K816R acetylation-resistant knock-in unexpectedly exhibited smaller enhanced activity, conferring protection against neurohumoral stress-induced remodeling. These findings indicate regulates cellular growth by interacting modulating activity K816-acetylation type-specific manner.

Язык: Английский

Процитировано

1
Ketone Catabolism is Essential for Maintaining Normal Heart Function During Aging DOI Open Access
Mariko Aoyagi Keller, Michinari Nakamura

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 19, 2025

The heart utilizes various nutrient sources for energy production, primarily favoring fatty acid oxidation. While ketones can be fuel substrates, ketolysis has been shown to dispensable development and function in mice. However, the long-term consequences of downregulation remain unknown. Here we demonstrate that ketone catabolism is essential preserving cardiac during aging. expression succinyl-CoA:3-ketoacid CoA transferase (SCOT), a rate-limiting enzyme ketolysis, decreases with aging female SCOT cardiomyocyte-specific knockout (cKO) mice exhibit normal at 10 weeks age but progressively develop dysfunction remodeling as they age, without overt hypertrophy both sexes. Notably, supplementation via ketogenic diet partially rescues contractile cKO mice, suggesting oxidation-independent mechanisms contribute cardiomyopathy caused by downregulation. These findings indicate crucial maintaining aging, confer cardioprotection independently

Язык: Английский

Процитировано

0