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 chronic stress in neuronal mitochondria can have far-reaching effects, not only damaging the neurons themselves but also influencing other tissues and systemic metabolic functions.
A new study led by Dr. TIAN Ye's research team at the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences (CAS) 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 researchers 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 was published online in
Journal of Cell Biology on March 18th and it was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China,and the Strategic Priority Research Program of CAS, etc.
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)
