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

Area of Science:

• Reproductive biology
• Cellular biology
• Immunology

Background:

• Testosterone production by Leydig cells (LCs) is energy-intensive and susceptible to mitochondrial damage.
• LCs display longevity and low turnover, implying robust mitochondrial maintenance mechanisms.

Purpose of the Study:

• To identify mechanisms responsible for maintaining mitochondrial homeostasis in testicular Leydig cells.
• To investigate the role of intercellular communication in supporting LC mitochondrial health and function.

Main Methods:

• Investigated extracellular vesicle-mediated mitochondrial transfer between LCs and testicular macrophages (tMacs).
• Utilized genetic manipulation (Trem2, Vcam1 deletion) to assess the impact on mitochondrial transfer and testosterone synthesis.
• Characterized tMac subpopulations (CD206hi and MHCIihi) involved in the network.

Main Results:

• LCs release defective mitochondria via extracellular vesicles for clearance by CD206hi tMacs (TREM2-dependent).
• Loss of TREM2 in tMacs impairs testosterone synthesis.
• LCs receive functional mitochondria from MHCIihi tMacs via ITGβ1-VCAM1 interactions.
• Vcam1 deficiency in LCs compromises mitochondrial transfer and testosterone production.

Conclusions:

• A novel mitochondrial transfer network exists between LCs and tMacs.
• This network is essential for maintaining LC mitochondrial homeostasis and testosterone production.
• Intercellular mitochondrial exchange is a key mechanism for tissue homeostasis in the testis.