Autophagy/mitophagy, a cellular catabolic process necessary for sustaining normal cellular function, has emerged as a potential therapeutic strategy against numerous obstinate diseases. In this regard, endurance exercise (EXE)-induced autophagy/mitophagy (EIAM) has been considered as a potential health-enriching factor in various tissues including the brain; however, underlying mechanisms of EIAM in the brain has not been fully defined yet. This study investigated the molecular signaling nexus of EIAM pathways in the cortex of the brain. C57BL/6 young male mice were randomly assigned to a control group (CON, n = 12) and an endurance exercise group (EXE, n = 12). Our data demonstrated that exercise-induced autophagy coincided with an enhanced anabolic state (p-AKT, p-mTOR, and p-p70S6K); furthermore, mitophagy concurred with enhanced mitochondrial turnover: increases in both fission (DRP1, BNIP3, and PINK1) and fusion (OPA1 and MFN2) proteins. In addition, neither oxidative stress nor sirtuins (SIRT) 1 and 3 were associated with EIAM; instead, the activation of AMPK as well as a JNK-BCL2 axis was linked to EIAM promotion. Collectively, our results demonstrated that EXE-induced anabolic enrichment did not hinder autophagy/mitophagy and that the concurrent augmentation of mitochondrial fusion and fusion process contributed to sustaining mitophagy in the cortex of the brain. Our findings suggest that the EXE-induced concomitant potentiation of the catabolic and anabolic state is a unique molecular mechanism that simultaneously contributes to recycling and rebuilding the cellular structure, leading to upholding healthy cellular environment. Thus, the current study provides a novel autophagy/mitophagy mechanism, from which groundbreaking pharmacological strategies of autophagy can be developed.

自噬/线粒体自噬是维持正常细胞功能所必需的细胞分解代谢过程，已成为对抗多种顽固疾病的潜在治疗策略。在这方面，耐力运动 (EXE) 诱导的自噬/线粒体自噬 (EIAM) 已被认为是包括大脑在内的各种组织中潜在的有益健康的因素。然而，EIAM 在大脑中的潜在机制尚未完全确定。这项研究调查了大脑皮层中 EIAM 通路的分子信号传导关系。C57BL/6 年轻雄性小鼠被随机分配到对照组（CON，n  = 12）和耐力运动组（EXE，n = 12）。我们的数据表明，运动诱导的自噬与增强的合成代谢状态（p-AKT、p-mTOR 和 p-p70S6K）同时发生；此外，线粒体自噬与线粒体周转增强一致：裂变（DRP1、BNIP3 和 PINK1）和融合（OPA1 和 MFN2）蛋白均增加。此外，氧化应激和 Sirtuins (SIRT) 1 和 3 均与 EIAM 无关；相反，AMPK 的激活以及 JNK-BCL2 轴与 EIAM 的促进有关。总的来说，我们的结果表明 EXE 诱导的合成代谢富集不会阻碍自噬/线粒体自噬，并且线粒体融合和融合过程的同时增强有助于维持大脑皮层中的线粒体自噬。我们的研究结果表明，EXE 诱导的分解代谢和合成代谢状态的伴随增强是一种独特的分子机制，它同时有助于回收和重建细胞结构，从而维持健康的细胞环境。因此，目前的研究提供了一种新的自噬/线粒体自噬机制，从中可以开发出开创性的自噬药理学策略。