Tang Min, Outissint Ikram, Chen Yijing, Gong Xun
School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China.
Department of Rehabilitation, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
J Cell Biochem. 2025 Jul;126(7):e70056. doi: 10.1002/jcb.70056.
Mitophagy, a selective autophagic process, is critical for maintaining mitochondrial quality and cellular homeostasis. It plays a dual role, facilitating cell survival by removing damaged mitochondria or contributing to programmed cell death in certain conditions. Dysregulation of mitophagy is implicated in various diseases, including neurodegenerative disorders, metabolic syndromes, cardiovascular diseases, and cancers. This review examines the key regulatory mechanisms of mitophagy, focusing on pathways such as the PINK1-Parkin, BNIP3/NIX, and FUNDC1 pathways, alongside emerging modulators. Notably, mitophagy is frequently associated with various cell death pathways, such as apoptosis, necroptosis, ferroptosis, and pyroptosis. Primarily, mitophagy functions as a protective mechanism rather than a direct trigger of cell death. It may be connected to cell death when its capacity is overwhelmed rather than actively promoting the process. For instance, impaired mitophagy exacerbates neurodegeneration in Parkinson's and Alzheimer's diseases, while its activation protects against ischemic injury in cardiovascular diseases. In cancer, mitophagy is paradoxical, as it either inhibits tumor growth or promotes survival under stress. Therapeutic interventions targeting mitophagy, including small-molecule modulators, show promise in preclinical studies; however, they require further clinical validation. Advancements in imaging techniques, single-cell omics, and high-throughput screenings are anticipated to deepen our understanding of mitophagy dynamics and therapeutic potential. This review highlights mitophagy as a pivotal target for treating diseases associated with mitochondrial dysfunction, providing insights into innovative therapeutic strategies.
线粒体自噬是一种选择性自噬过程，对于维持线粒体质量和细胞稳态至关重要。它具有双重作用，通过清除受损线粒体促进细胞存活，或在某些情况下促成程序性细胞死亡。线粒体自噬失调与多种疾病有关，包括神经退行性疾病、代谢综合征、心血管疾病和癌症。本综述探讨了线粒体自噬的关键调控机制，重点关注PINK1-Parkin、BNIP3/NIX和FUNDC1等途径以及新出现的调节因子。值得注意的是，线粒体自噬经常与各种细胞死亡途径相关，如凋亡、坏死性凋亡、铁死亡和焦亡。主要地，线粒体自噬作为一种保护机制，而非细胞死亡的直接触发因素。当它的能力不堪重负时，可能与细胞死亡有关，而不是积极促进这一过程。例如，线粒体自噬受损会加剧帕金森病和阿尔茨海默病中的神经退行性变，而其激活则可预防心血管疾病中的缺血性损伤。在癌症中，线粒体自噬是矛盾的，因为它要么抑制肿瘤生长，要么在应激状态下促进存活。针对线粒体自噬的治疗干预措施，包括小分子调节剂，在临床前研究中显示出前景；然而，它们需要进一步的临床验证。预计成像技术、单细胞组学和高通量筛选方面的进展将加深我们对线粒体自噬动态和治疗潜力的理解。本综述强调线粒体自噬是治疗与线粒体功能障碍相关疾病的关键靶点，为创新治疗策略提供了见解。
