2. Academic Validation
  3. An extracellular vesicle-mediated mitochondrial transfer network critical for testosterone synthesis

An extracellular vesicle-mediated mitochondrial transfer network critical for testosterone synthesis

  • Nat Cell Biol. 2026 Apr;28(4):707-724. doi: 10.1038/s41556-026-01896-x.
Kai Xia # 1 2 3,  Suyuan Zhang # 2 3,  Hao Peng # 2 3,  Hainan Chen # 4,  Cuifeng Yang 2,  Jiajie Yu 1,  Peng Luo 5,  Qiying Lu 6,  Hong Chen 7,  Li Huang 4,  Yifei Xiong 2,  Lerong Zhao 2,  Lei Jia 8,  Lu Li 2,  Yuan Qiu 2,  Yan Guo 9,  Congyuan Liu 2,  Hang Fan 2,  Ziran Dai 1,  Guihua Liu 8,  Qiong Ke 2 3,  Tao Wang 2 3,  Weiqiang Li 2 3,  Lili Chen 10,  Chunhua Deng 11 12,  Haipeng Xiao 13,  Andy Peng Xiang 14 15
Affiliations

Affiliations

  • 1 Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China.
  • 3 National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 4 Center of Stem Cell and Regenerative Medicine, Gaozhou People's Hospital, Gaozhou, China.
  • 5 Reproductive Medicine Center, The Key Laboratory for Reproductive Medicine of Guangdong Province, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 6 Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 7 Center for Stem Cells Translational Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, China.
  • 8 Department of Reproductive Medicine Center, Guangdong Engineering Technology Research Center of Fertility Preservation, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 9 Department of Endocrinology and Diabetes Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 10 Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 11 Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 12 Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 13 Department of Endocrinology and Diabetes Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 14 Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 15 National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41760931 DOI: 10.1038/s41556-026-01896-x
Abstract

Testosterone production by testicular Leydig cells (LCs) in male mammals is energetically demanding and prone to mitochondrial damage. Despite these challenges, LCs exhibit remarkable longevity and minimal turnover, suggesting the existence of specialized mechanisms that maintain LC mitochondrial homeostasis under such constrains. Here we identify a mitochondrial transfer network between LCs and different testicular macrophage (tMac) subpopulations. Leydig cells release extracellular vesicles containing defective mitochondria, which are eliminated by CD206hi tMacs in a TREM2-dependent process. Deletion of Trem2 in tMacs disrupts this transfer, leading to impaired testosterone synthesis. Conversely, LCs acquire extracellular vesicles containing functional mitochondria from MHCIIhi tMacs through ITGβ1-VCAM1 interactions. Loss of Vcam1 in LCs hinders this mitochondrial transfer, thereby compromising testosterone production. Together, our findings reveal an unrecognized mitochondrial transfer network between LCs and tMacs that safeguards LC homeostasis and testosterone production, offering valuable insights into intercellular communication mechanisms that maintain tissue homeostasis.

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