过表达CYB5R3的长寿小鼠肝脏中线粒体、自噬和营养感知途径的适应是性别依赖的,涉及器官间反应。

IF 5.4 2区 医学 Q1 GERIATRICS & GERONTOLOGY
Luz Marina Sánchez-Mendoza,José A González-Reyes,Sandra Rodríguez-López,Cristina García-Caballero,Juan Antonio Moreno,Rafael de Cabo,M Isabel Burón,José M Villalba
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引用次数: 0

摘要

细胞色素b5还原酶3 (CYB5R3)的过度表达模拟了卡路里限制的几种代谢益处,具有性别和组织特异性效应。本研究旨在研究CYB5R3过表达如何影响年轻小鼠的肝脏代谢,重点关注线粒体生物发生、脂质代谢、自噬和营养感知途径,从而建立基线,允许随后与老年动物进行比较。CYB5R3多肽的积累表现出明显的性别二态性,因为它仅在雌性中通过转基因增加,主要靶向微粒体,而在雄性中主要位于线粒体中。然而,关键代谢标志物,包括TFAM(生物发生)、p62和LC3(自噬)、AKT和mTOR(营养感应)、SIRT1/SIRT3(酶调节和基因表达)和ACC1/ACAA2(脂质代谢),在转基因雄性中显著改变。野生型雄性比雌性表现出更高的线粒体复合物III和IV水平,这种差异通过转基因减弱。转基因小鼠的TFAM增加,表明线粒体生物发生增强。脂质代谢标志物的变化表明女性肝脏脂质积累减少,而男性则表现出ACC1和ACAA2的变化,影响脂质储存和氧化。自噬标记(p62, LC3I/II)在雄性中发生改变,而线粒体自噬标记(PINK1, PARKIN)在雌性中上调,表明线粒体更新有效。综上所述,CYB5R3的表达受转录后和翻译后机制的调控,并诱导性别依赖的肝脏代谢适应。雌性表现出CYB5R3蛋白的增加和相关的线粒体改善,而雄性则表现出明显的代谢重编程,尽管CYB5R3水平不变,这强调了两性二态性和系统调节机制在对长寿促进干预的反应中的相关性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Adaptations of mitochondrial, autophagy and nutrient sensing pathways in the liver from long-lived mice overexpressing CYB5R3 are sex-dependent and involve inter-organ responses.
Cytochrome b5 reductase 3 (CYB5R3) overexpression mimics several metabolic benefits of calorie restriction, with sex- and tissue-specific effects. This study aimed to investigate how CYB5R3 overexpression impacts hepatic metabolism in young mice, focusing on mitochondrial biogenesis, lipid metabolism, autophagy and nutrient sensing pathways thus establishing a baseline that allows for subsequent comparisons with older animals. The accrual of CYB5R3 polypeptide exhibited marked sexual dimorphism as it was increased by transgenesis only in females with predominant microsomal targeting but mainly located in the mitochondria in males. Nevertheless, key metabolic markers, including TFAM (biogenesis), p62 and LC3 (autophagy), AKT and mTOR (nutrient sensing), SIRT1/SIRT3 (enzymatic regulation and gene expression) and ACC1/ACAA2 (lipid metabolism), were significantly altered in transgenic males. Wild-type males exhibited higher levels of mitochondrial complexes III and IV than females, and these differences were attenuated by transgenesis. TFAM was increased in transgenic mice of both sexes, indicative of enhanced mitochondrial biogenesis. Changes of lipid metabolism markers indicated reduced hepatic lipid accumulation in females while males showed changes in ACC1 and ACAA2, affecting lipid storage and oxidation. Autophagy markers (p62, LC3I/II) were altered in males, whereas mitophagy markers (PINK1, PARKIN) were upregulated in females, suggesting efficient mitochondrial turnover. In conclusion, CYB5R3 expression is regulated by post-transcriptional and post-translational mechanisms and induces sex-dependent hepatic metabolic adaptations. While females exhibit increased CYB5R3 protein and associated mitochondrial improvements, males respond with distinct metabolic reprogramming despite unchanged CYB5R3 levels, underscoring the relevance of sexual dimorphism and systemic regulatory mechanisms in the response to longevity-promoting interventions.
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来源期刊
GeroScience
GeroScience Medicine-Complementary and Alternative Medicine
CiteScore
10.50
自引率
5.40%
发文量
182
期刊介绍: GeroScience is a bi-monthly, international, peer-reviewed journal that publishes articles related to research in the biology of aging and research on biomedical applications that impact aging. The scope of articles to be considered include evolutionary biology, biophysics, genetics, genomics, proteomics, molecular biology, cell biology, biochemistry, endocrinology, immunology, physiology, pharmacology, neuroscience, and psychology.
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