Loss of mitochondrial proline catabolism depletes FAD, impairing sperm function, and male reproductive advantage. Loss of mitochondrial proline catabolism depletes FAD, impairing sperm function, and male reproductive advantage

Exposure to environmental stress has a clinically established influence on male reproductive health, but the impact of normal cellular metabolism on sperm quality and function is less well-defined. Here we show that homeostatic changes in mitochondrial dynamics driven by defective mitochondrial proline catabolism result in pleiotropic consequences on sperm quality and competitive fitness. Disruption of alh-6, which converts 1-pyrroline-5-carboxylate (P5C) to glutamate, results in P5C accumulation that drives oxidative stress, activation of the cytoprotective transcription factor SKN-1, and a reduction of energy-storing flavin adenine dinucleotide (FAD) levels. These molecular changes lead to premature male reproductive senescence by reducing sperm quality. These sperm-specific defects are suppressed by abating P5C metabolism, by treatment with antioxidants to combat reactive oxygen species (ROS), or by feeding diets that restore FAD levels. Our results define a role for mitochondrial proline catabolism and FAD homeostasis on sperm function and specify strategies to pharmacologically reverse unintended outcomes from SKN-1/Nrf transcriptional activation. Overall design: Our study aim to look at transcriptional signatures that define the physiological changes in alh-6 mutant animals as young and old animals. 12 RNA samples in total are turned in for high-throughput sequencing. N2 (WT) and lax105 (alh-6) worms are collected in triplicates at two time points: L4 and day 3 adults.