FBXO24 targets SLC25A26 for K6-linked polyubiquitination to maintain mitochondrial function during spermiogenesis

Asthenozoospermia is one of the major causes for male infertility, typically resulting from malformed flagella and dysfunctional mitochondria. However, the pathogenic mechanisms underlying asthenozoospermia remain unclear. Here, we show an F-box protein within the SCF E3 ubiquitin ligase complex, FBXO24, is required for maintaining mitochondrial function and ATP production during spermiogenesis. Using Fbxo24 knockout mice, we demonstrated that the depletion of FBXO24 leads to male infertility due to malformed sperm head and severe motility defects. The decreased motility comes from dysfunction of mitochondria which was characterized as disorganized mitochondrial clustering, reduced mitochondrial membrane potential, elevated reactive oxygen species levels. Based on quantitative proteomics, we identified SLC25A26, a mitochondrial S-adenosylmethionine transporter, as a novel substrate for FBXO24. Mechanistically, FBXO24 mediates K6-linked polyubiquitination of SLC25A26 at lysine residue 31, targeting it for degradation. Elevated SLC25A26 induced mitochondrial fragmentation, suppressed glycolysis and oxidative phosphorylation, finally decreased ATP production. All these results suggest that FBXO24 safeguards mitochondrial integrity by controlling SLC25A26 stability, ensuring ATP production for sperm motility, and hints some mutations of FBXO24 might be associated with asthenozoospermia in human.