Sánchez-Mendoza Luz Marina, González-Reyes José A, Rodríguez-López Sandra, García-Caballero Cristina, Moreno Juan Antonio, de Cabo Rafael, Burón M Isabel, Villalba José M
Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario, ceiA3, 14014, Córdoba, Spain.
Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain.
Geroscience. 2025 Jun 28. doi: 10.1007/s11357-025-01761-z.
Cytochrome b 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.
细胞色素b还原酶3（CYB5R3）的过表达模拟了卡路里限制的多种代谢益处，具有性别和组织特异性效应。本研究旨在探讨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、自噬和营养感应途径，从而建立一个基线，以便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，因为转基因仅在具有主要微粒体靶向的雌性小鼠中增加，而在雄性小鼠中主要位于线粒体中。尽管如此，转基因雄性小鼠的关键代谢标志物，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）以及ACC1/ACAA2（脂质代谢），均发生了显著改变。野生型雄性小鼠的线粒体复合物III和IV水平高于雌性小鼠，而转基因减弱了这些差异。TFAM在两性转基因小鼠中均增加，表明线粒体生物发生增强。脂质代谢标志物的变化表明雌性小鼠肝脏脂质积累减少，而雄性小鼠的ACC1和ACAA2发生变化，影响脂质储存和氧化。雄性小鼠的自噬标志物（p62、LC3I/II）发生改变，而雌性小鼠的线粒体自噬标志物（PINK1、PARKIN）上调，表明线粒体周转效率高。总之，CYB5R3的表达受转录后和翻译后机制调控，并诱导性别依赖性的肝脏代谢适应。虽然雌性小鼠CYB5R3蛋白增加且相关线粒体功能改善，但雄性小鼠尽管CYB5R3水平不变却出现了明显的代谢重编程，这突出了性别二态性和全身调节机制在对促进长寿干预的反应中的相关性。
