Mitochondria, often referred to as the "powerhouse of the cell", play a crucial role in maintaining energy balance and cellular health. Recent studies have shown that when neuronal mitochondria experience chronic stress, they not only affect the neurons themselves but also transmit signals to other tissues, regulating systemic metabolic functions.
A recent study led by Dr. Ye Tian’s research team at the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, reveals that chronic mitochondrial stress in neurons promotes serotonin release via TMBIM-2-dependent calcium (Ca²⁺) oscillations, which in turn activates the mitochondrial unfolded protein response (UPRmt) in the intestine.
The study found that TMBIM-2 works in coordination with the plasma membrane calcium pump MCA-3 (a PMCA homolog) to regulate synaptic Ca²⁺ balance, sustaining persistent calcium signaling oscillations at neuronal synaptic sites. Further investigation showed that TMBIM-2 expression declines with age. In Caenorhabditis elegans, overexpression of TMBIM-2 significantly improved cognitive decline and extended lifespan in aged worms. Notably, TMBIM-2 is highly conserved in humans and mice, and its expression similarly decreases with age in neural tissues, underscoring its broad biological significance in aging regulation.
In summary, this study highlights the critical role of neuronal calcium oscillations in cross-tissue signaling and lifespan regulation, providing new theoretical insights and potential therapeutic targets for aging intervention and metabolic health.
This study entitled “TMBIM-2 orchestrates systemic mitochondrial stress response via facilitating Ca2+ oscillations” was published online in Journal of Cell Biology (https://doi.org/10.1083/jcb.202408050) on March 18th, 2025.
Figure: Model of chronic mitochondrial stress leads to tmbim-2-dependent spatiotemporal Ca2+ waves to coordinate neuronal-to-intestinal UPRmt activation and aging (Image by IGDB)
The research was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, the CAS Project for Young Scientists in Basic Research and the New Cornerstone Science Foundation through the XPLORER PRIZE, etc.
Contact:
Dr. TIAN Ye
Institute of Genetics and Developmental Biology, the Chinese Academy of Sciences
Email: ytian@genetics.ac.cn
CAS
中文
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Figure: Model of chronic mitochondrial stress leads to tmbim-2-dependent spatiotemporal Ca2+ waves to coordinate neuronal-to-intestinal UPRmt activation and aging (Image by IGDB)The research was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, the CAS Project for Young Scientists in Basic Research and the New Cornerstone Science Foundation through the XPLORER PRIZE, etc.Contact:Dr. TIAN YeInstitute of Genetics and Developmental Biology, the Chinese Academy of SciencesEmail: ytian@genetics.ac.cn