Incomplete proline catabolism drives premature sperm aging

Infertility is an increasingly common health issue, with rising prevalence in advanced parental age. Environmental stress has established negative effects on reproductive health, however, the impact of altering cellular metabolism and its endogenous reactive oxygen species (ROS) on fertility remains unclear. Here, we demonstrate the loss of proline dehydrogenase, the first committed step in proline catabolism, is relatively benign. In contrast, disruption of alh‐6, which facilitates the second step of proline catabolism by converting 1‐pyrroline‐5‐carboxylate (P5C) to glutamate, results in premature reproductive senescence, specifically in males. The premature reproductive senescence in alh‐6 mutant males is caused by aberrant ROS homeostasis, which can be countered by genetically limiting the first committed step of proline catabolism that functions upstream of ALH‐6 or by pharmacological treatment with antioxidants. Taken together, our work uncovers proline metabolism as a critical component of normal sperm function that can alter the rate of aging in the male reproductive system. The loss of alh‐6, a nuclear encoded mitochondrial enzyme that catalyzes the second step of proline catabolism by converting 1‐pyrroline‐5‐carboxylate (P5C) to glutamate, disrupts endogenous redox imbalance and causes premature reproductive aging in C. elegans males. Mutation in prdh‐1, the upstream enzyme in the proline catabolic pathway which breaks down proline to P5C, suppresses the sperm defects in alh‐6 mutant males by preventing the accumulation of the toxic intermediate P5C. Similarly, dietary antioxidant treatment rescues the premature aging defects in alh‐6 mutant sperm, implicating the role of proline catabolism in maintaining endogenous ROS homeostasis and male reproductive senescence.