2. Academic Validation
  3. Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender

Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender

  • Cell Metab. 2025 Dec 3:S1550-4131(25)00486-3. doi: 10.1016/j.cmet.2025.11.002.
Yan Huang 1,  Biao Hu 1,  Ya Liu 1,  Ling-Qi Xie 1,  Yu Dai 1,  Yu-Ze An 1,  Xin-Yi Peng 1,  Ya-Lun Cheng 1,  Yi-Fan Guo 1,  Wei-Hong Kuang 1,  Yao Xiao 1,  Xin Chen 1,  Yong-Jun Zheng 2,  Gen-Qing Xie 3,  Jian-Ping Wang 4,  Hui Peng 5,  Xiang-Hang Luo 6
Affiliations

Affiliations

  • 1 Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China.
  • 2 Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China.
  • 3 Department of Endocrinology, The First People's Hospital of Xiangtan City, Xiangtan 411200, Hunan, China.
  • 4 Department of Metabolism and Endocrinology, The Second Hospital, University of South China, Hengyang 421001, Hunan, China.
  • 5 Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China. Electronic address: [email protected].
  • 6 Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha 410008, Hunan, China; Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Hunan 410008, China; FuRong Laboratory, Changsha 410078, Hunan, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha 410008, Hunan, China. Electronic address: [email protected].
PMID: 41344322 DOI: 10.1016/j.cmet.2025.11.002
Abstract

Excessive exercise impairs cognitive function, but the underlying mechanism remains unclear. Here, we show that excessive vigorous exercise-induced lactate accumulation stimulates muscles to secrete mitochondria-derived vesicles (MDVs), driving cognitive impairment. These MDVs (named otMDVs) are characterized by high mtDNA levels and the surface marker PAF. They tend to migrate into hippocampal neurons, substituting endogenous mitochondria and triggering a synaptic energy crisis. Mechanistically, otMDVs release mtDNA, which activates cGAS-STING-dependent inhibition of Kinesin family member 5, preventing hippocampal mitochondria from transporting to synapses. Simultaneously, the otMDV marker PAF cooperates with syntaphilin to occupy mitochondrial anchoring sites, impairing synaptic energy supply. Blocking otMDVs migration into the hippocampus with a PAF-neutralizing antibody alleviates excessive vigorous exercise-induced synapse loss and cognitive dysfunction. Notably, human studies link high circulating otMDV levels to cognitive impairment. Together, our findings reveal that a unique muscle-derived MDV subpopulation, which displaces hippocampal mitochondria and disrupts their function, causes cognitive decline.

Keywords

MDVs; cognitive decline; excessive vigorous exercise.

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