Li Jiasheng, Cui Jimeng, Li Xinyu, Zhu Di, Chen Zhenhua, Huang Xiahe, Wang Yingchun, Wu Qingfeng, Tian Ye
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences , Beijing, China.
J Cell Biol. 2025 May 5;224(5). doi: 10.1083/jcb.202408050. Epub 2025 Mar 18.
Neuronal mitochondrial function is critical for orchestrating inter-tissue communication essential for overall fitness. Despite its significance, the molecular mechanism underlying the impact of prolonged mitochondrial stresses on neuronal activity and how they orchestrate metabolism and aging remains elusive. Here, we identified the evolutionarily conserved transmembrane protein XBX-6/TMBIM-2 as a key mediator in the neuronal-to-intestinal mitochondrial unfolded protein response (UPRmt). Our investigations reveal that intrinsic neuronal mitochondrial stress triggers spatiotemporal Ca2+ oscillations in a TMBIM-2-dependent manner through the Ca2+ efflux pump MCA-3. Notably, persistent Ca2+ oscillations at synapses of ADF neurons are critical for facilitating serotonin release and the subsequent activation of the neuronal-to-intestinal UPRmt. TMBIM2 expression diminishes with age; however, its overexpression counteracts the age-related decline in aversive learning behavior and extends the lifespan of Caenorhabditis elegans. These findings underscore the intricate integration of chronic neuronal mitochondrial stress into neurotransmission processes via TMBIM-2-dependent Ca2+ equilibrium, driving metabolic adaptation and behavioral changes for the regulation of aging.
神经元线粒体功能对于协调组织间通讯至关重要，而这种通讯对整体健康状况至关重要。尽管其具有重要意义，但长期线粒体应激对神经元活动的影响及其如何协调代谢和衰老的分子机制仍不清楚。在这里，我们确定了进化上保守的跨膜蛋白XBX-6/TMBIM-2是神经元到肠道线粒体未折叠蛋白反应（UPRmt）中的关键介质。我们的研究表明，内在的神经元线粒体应激通过Ca2+外流泵MCA-3以TMBIM-2依赖的方式触发时空Ca2+振荡。值得注意的是，ADF神经元突触处持续的Ca2+振荡对于促进血清素释放和随后激活神经元到肠道的UPRmt至关重要。TMBIM2的表达随年龄增长而减少；然而，其过表达可抵消厌恶学习行为中与年龄相关的下降，并延长秀丽隐杆线虫的寿命。这些发现强调了慢性神经元线粒体应激通过TMBIM-2依赖的Ca2+平衡复杂地整合到神经传递过程中，驱动代谢适应和行为变化以调节衰老。
