Aging Remodels Mitochondrial Architecture Across the Male Reproductive Axis

Male infertility is recognized as a complex condition associated with aging, yet its association with mitochondrial structural remodeling is poorly understood. Here, we integrated a multi-model approach to investigate how aging and MICOS complex dysfunction influence male reproductive health. Using the All of Us Research Program, we analyzed 121,064 male participants and performed age stratified PheWAS, LabWAS, and GWAS analyses comparing young (20 to 40 years) and older (≥55 years) cohorts. Male infertility was associated with distinct age dependent clinical phenotypes, laboratory alterations, and candidate loci linked to mitochondrial dysfunction. We examined semen samples using confocal microscopy and transmission electron microscopy upon inhibition of MICOS, which resulted in impaired sperm motility dynamics while increasing oxidative stress. We also used Drosophila melanogaster expressing mitochondrial green fluorescent protein in testes. Older flies displayed significant alterations in spermatid mitochondrial architecture, indicating disruption of mitochondrial network organization through aging. Complementary serial block face scanning electron microscopy and three-dimensional reconstructions of mouse testes revealed extensive age associated mitochondrial remodeling across residual, loose, and germ cell populations. Together, these findings identify mitochondrial MICOS complex integrity as a central regulator of age-associated male infertility across species, highlighting it as potential therapeutic target for age-related reproductive decline.