2. Academic Validation
  3. β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial functions

β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial functions

  • Mol Cell. 2025 Mar 14:S1097-2765(25)00183-2. doi: 10.1016/j.molcel.2025.02.022.
Min Tang 1,  Yingfeng Tu 1,  Yanqiu Gong 2,  Qin Yang 1,  Jinrui Wang 1,  Zhenzhen Zhang 3,  Junhong Qin 1,  Shenghui Niu 1,  Jiamin Yi 1,  Zehua Shang 1,  Hongyu Chen 1,  Yingying Tang 1,  Qian Huang 4,  Yanmei Liu 3,  Daniel D Billadeau 5,  Xingguo Liu 6,  Lunzhi Dai 2,  Da Jia 7
Affiliations

Affiliations

  • 1 Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China.
  • 2 National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, China.
  • 3 Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Institute for Brain Research and Rehabilitation, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, China.
  • 4 Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 5 Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA.
  • 6 CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China.
  • 7 Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China; Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu 610041, China. Electronic address: jiada@scu.edu.cn.
PMID: 40118051 DOI: 10.1016/j.molcel.2025.02.022
Abstract

Mitochondrial dynamics and metabolites reciprocally influence each Other. Mitochondrial-derived vesicles (MDVs) transport damaged mitochondrial components to lysosomes or the extracellular space. While many metabolites are known to modulate mitochondrial dynamics, it is largely unclear whether they are involved in MDV generation. Here, we discovered that the major component of ketone body, β-hydroxybutyrate (BHB), improved mitochondrial functions by facilitating the biogenesis of MDVs. Mechanistically, BHB drove specific lysine β-hydroxybutyrylation (Kbhb) of sorting nexin-9 (SNX9), a key regulator of MDV biogenesis. Kbhb increased SNX9 interaction with inner mitochondrial membrane (IMM)/matrix proteins and promoted the formation of IMM/matrix MDVs. SNX9 Kbhb was not only critical for maintaining mitochondrial homeostasis in cells but also protected mice from alcohol-induced liver injury. Altogether, our research uncovers the fact that metabolites influence the formation of MDVs by directly engaging in post-translational modifications of key protein machineries and establishes a framework for understanding how metabolites regulate mitochondrial functions.

Keywords

MDV; PTMs; metabolite; mitochondrial functions.

Figures
Products