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.
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March 18 2025
TMBIM-2 orchestrates systemic mitochondrial stress response via facilitating Ca2+ oscillations
Jiasheng Li
,
Jiasheng Li
(Conceptualization, Data curation, Formal analysis, Methodology, Validation, Writing - original draft)
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
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Jimeng Cui
,
Jimeng Cui
(Investigation)
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
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Xinyu Li
,
Xinyu Li
(Data curation, Formal analysis, Investigation, Validation, Visualization)
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
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Di Zhu
,
Di Zhu
(Investigation, Methodology, Resources)
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
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Zhenhua Chen
,
Zhenhua Chen
(Data curation, Validation)
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
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Xiahe Huang
,
Xiahe Huang
(Formal analysis)
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
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Yingchun Wang
,
Yingchun Wang
(Investigation)
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
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Qingfeng Wu
,
Qingfeng Wu
(Methodology)
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
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Ye Tian
(Conceptualization, Funding acquisition, Project administration, Supervision, Writing - review & editing)
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
Correspondence to Ye Tian: [email protected]
Search for other works by this author on:
Jiasheng Li
Conceptualization, Data curation, Formal analysis, Methodology, Validation, Writing - original draft
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
Jimeng Cui
Investigation
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
Xinyu Li
Data curation, Formal analysis, Investigation, Validation, Visualization
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
Di Zhu
Investigation, Methodology, Resources
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
Zhenhua Chen
Data curation, Validation
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
Xiahe Huang
Formal analysis
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
Yingchun Wang
Investigation
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
Qingfeng Wu
Methodology
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
Ye Tian
Conceptualization, Funding acquisition, Project administration, Supervision, Writing - review & editing
1State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
, Beijing, China
2
University of Chinese Academy of Sciences
, Beijing, China
Correspondence to Ye Tian: [email protected]
Disclosures: The authors declare no competing interests exist.
Received:
August 11 2024
Revision Received:
December 11 2024
Accepted:
February 09 2025
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
National Key R&D Program of China
- Award Id(s): 2022YFA1303000,2019YFA0800213
Funder(s):
Chinese Academy of Sciences
- Award Id(s): XDB39000000
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 32430025,31930023,32225025,92254305,32321004,32230031,81891002
Funder(s):
CAS Project for Young Scientists in Basic Research
- Award Id(s): YSBR-076
Funder(s):
Beijing Municipal Science & Technology Commission
- Award Id(s): Z210010
Funder(s):
NIH-Officer of Research Infrastructure Programs
- Award Id(s): P40 OD010440
© 2025 Li et al.
2025
Li et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Cell Biol (2025) 224 (5): e202408050.
Article history
Received:
August 11 2024
Revision Received:
December 11 2024
Accepted:
February 09 2025
Connected Content
Citation
Jiasheng Li, Jimeng Cui, Xinyu Li, Di Zhu, Zhenhua Chen, Xiahe Huang, Yingchun Wang, Qingfeng Wu, Ye Tian; TMBIM-2 orchestrates systemic mitochondrial stress response via facilitating Ca2+ oscillations. J Cell Biol 5 May 2025; 224 (5): e202408050. doi: https://doi.org/10.1083/jcb.202408050
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