《生命科学》 2026, 38(1): 99-108
mTOR核心通路在线粒体自噬过程中的调控作用
摘 要：
线粒体自噬（mitochondrial autophagy，mitophagy）是细胞内高度保守的质量控制机制，通过选择性清除受损或功能障碍的线粒体，维持线粒体功能完整性及细胞内稳态。哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）复合体（mTORC1/2）是细胞生长和代谢的核心调控枢纽，不仅参与细胞增殖调控，更通过整合多种信号通路和多种关键小分子蛋白，在介导线粒体自噬中发挥关键作用。研究表明，mTORC1/2通过双向调控mTOR-AMPK和PI3K-AKT-mTOR信号通路，促进作用域UNC-51样激酶1（ULK1） 复合体、转录因子EB（TFEB）等关键效应分子的激活，从而精细调控线粒体自噬的启动、包裹、溶酶体融合及降解等关键环节。值得注意的是，相较于mTORC1的深入研究，mTORC2在线粒体自噬中的调控机制仍存在显著认知空白。本综述系统阐释mTORC2影响线粒体自噬的最新进展，同时探讨其与mTORC1的功能协同性及在代谢应激条件下的双向调控特性，为深入解析mTOR信号网络在线粒体质量控制中的多维调控机制提供新视角。
通讯作者：沈佳琪 , Email:shenjiaqi0606@163.com 仵敏娟 , Email:minjuanwu@163.com
Abstract:
As a selective autophagy process, mitophagy is crucial for clearing dysfunctional mitochondria and maintaining cellular energy homeostasis and survival. Its core mechanisms are primarily categorized into ubiquitin-dependent pathways, such as the classic PINK1/Parkin pathway, and ubiquitin-independent pathways involving receptors like BNIP3. mTOR, a central kinase that senses nutrients, energy, and growth factors within the cell, forms two functionally distinct complexes, mTORC1 and mTORC2. These complexes work in concert to bidirectionally regulate each stage of mitophagy—from initiation and phagophore formation to final fusion with lysosomes for degradation. The article is primarily divided into two main sections, respectively discussing the topic from the perspectives of core mTOR-related signaling pathways and small molecular proteins. Among these, two representative mTOR-associated pathways are highlighted: the mTOR-AMPKULK1 pathway and the PI3K-AKT-mTOR pathway. The former is involved in autophagy initiation and serves as a key mechanism through which cells sense energy status and regulate the onset of autophagy. Under energy-sufficient conditions, it inhibits the formation of the initiation complex, thereby suppressing autophagy. The latter primarily responds to growth factor signals and generally functions to inhibit autophagy, playing an indispensable role in maintaining basal mitochondrial quality. Beyond these classic pathways, mTOR also precisely regulates specific stages of mitophagy by influencing a series of particular proteins. Proteins involved in regulating autophagosome formation and maturation include p300, WIPI2, UVRAG, and Pacer. Primarily under nutrient-rich conditions, these proteins enhance mTORC1 activity, thereby activating the expression of downstream cytokines to inhibit autophagosome formation. Additionally, TFEB, the master regulator of autophagy-lysosome gene expression, is a core protein governing lysosome biogenesis, and its activity is tightly controlled by mTORC1. Studies have shown that activating TFEB can promote mitophagy and exhibits therapeutic potential in disease models such as cancer. Based on the current research on mTOR, the following recommendations can be proposed: First, as an integrative hub within the mitochondrial quality control network, mTOR serves as a dynamic, multi-tiered regulatory nexus capable of achieving spatiotemporally precise regulation of mitophagy initiation, progression, and lysosomal degradation capacity. Future studies should place greater emphasis on the synergistic and antagonistic interplay between mTORC1 and mTORC2 in specific physiological and pathological contexts, as well as their crosstalk with stress signals from other organelles. Second, targeting the mTOR regulatory network represents a potential strategy for treating diseases associated with mitochondrial dysfunction. Given that the mTOR pathway is dysregulated and impacts mitophagy in a variety of disorders—including neurodegenerative diseases, metabolic disorders, and cancers—drug development aimed at precisely modulating this network holds considerable promise. Lastly, efforts should be strengthened to bridge the gap between fundamental mTOR-related mechanisms and clinical research, thereby offering more novel insights for clinical diseases. For example, delving deeper into atypical mitophagy pathways mediated by factors such as OPTN and ZDHHC13, and elucidating how these novel mechanisms interact with mTOR signaling, will deepen our understanding of the plasticity of mitochondrial quality control. This review systematically elucidates recent advances regarding the impact of mTORC2 on mitophagy, while exploring its functional synergy with mTORC1 and its bidirectional regulatory properties under metabolic stress conditions. It aims to provide novel perspectives for an in-depth analysis of the multifaceted regulatory mechanisms of the mTOR signaling network in mitochondrial quality control. Furthermore, it seeks to offer critical theoretical foundations and identify new drug targets for developing precision medicine strategies aimed at restoring mitochondrial quality.
Communication Author：SHEN Jia-Qi , Email:shenjiaqi0606@163.com WU Min-Juan , Email:minjuanwu@163.com
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