MTCH2 acts as a novel inhibitory receptor to suppress germ cell mitophagy by tethering BECN1, thereby maintaining mitochondrial homeostasis and male fertility

Abstract

Mitochondria play a pivotal role in spermatogenesis and male fertility, in which the selective autophagic degradation of mitochondria (mitophagy) constitutes a key process. In this study, we identify mitochondrial carrier homolog 2 (MTCH2) as a novel and critical regulator of germ cell mitophagy. Localized to the mitochondrial outer membrane (OMM), MTCH2 directly interacts with the core autophagy protein BECN1, thereby inhibiting autophagic flux and specifically suppressing mitophagy. Germ cell-specific heterozygous deletion of Mtch2 was sufficient to cause profound spermatogenic defects, including disorganized seminiferous tubules, vacuolization, mitochondrial sheath abnormalities, and significantly impaired sperm fertilization capacity. Transcriptomic profiling revealed that MTCH2 deficiency dysregulates pathways central to mitochondrial function and programmed cell death. Importantly, augmenting autophagy ameliorated mitochondrial dysfunction induced by MTCH2 deficiency, as characterized by impaired mitochondrial membrane potential, elevated mitochondrial reactive oxygen species (mtROS) production and cellular ROS levels. Collectively, our findings establish MTCH2 as an essential negative regulator of mitophagy that partners with BECN1 to maintain mitochondrial homeostasis, thereby ensuring normal spermatogenesis and male fertility.