Abstract
Exposure to environmental stress is clinically established to influence male reproductive health, but the impact of normal cellular metabolism on sperm quality is less well-defined. Here we show that impaired mitochondrial proline catabolism, reduces energy-storing flavin adenine dinucleotide (FAD) levels, alters mitochondrial dynamics toward fusion, and leads to age-related loss of sperm quality (size and activity), which diminishes competitive fitness of the animal. Loss of the 1-pyrroline-5-carboxylate dehydrogenase enzyme alh-6 that catalyzes the second step in mitochondrial proline catabolism leads to premature male reproductive senescence. Reducing the expression of the proline catabolism enzyme alh-6 or FAD biosynthesis pathway genes in the germline is sufficient to recapitulate the sperm-related phenotypes observed in alh-6 loss-of-function mutants. These sperm-specific defects are suppressed by feeding diets that restore FAD levels. Our results define a cell autonomous role for mitochondrial proline catabolism and FAD homeostasis on sperm function and specify strategies to pharmacologically reverse these defects.
Highlights
As individuals wait longer to have families, reproductive senescence has become an increasingly prudent topic (Mills et al, 2011; Lemaıtre and Gaillard, 2017)
In support of our model where mitochondrial dynamics act as a major driver of the sperm-specific defects in alh-6 mutants, we discovered that loss of drp-1, which results in increased mitochondrial fusion, reduces sperm activation (Figure 5M)
We investigate the effects of disrupting mitochondrial proline catabolism through the loss of the mitochondrial enzyme gene alh-6 and the resulting changes in flavin adenine dinucleotide (FAD) homeostasis, mitochondrial dynamics, and male fertility (Figure 7)
Summary
As individuals wait longer to have families, reproductive senescence has become an increasingly prudent topic (Mills et al, 2011; Lemaıtre and Gaillard, 2017). While the majority of studies in reproductive senescence have focused on maternal effects, male factors contribute to a large portion of fertility complications with increasing evidence of an inverse relationship between paternal age and sperm health (Lemaıtre and Gaillard, 2017). Clk-1 mutation affects the timing of egg laying, resulting in reduced brood size (Jonassen et al, 2002) Both of these mitochondrial mutations impact fertility, but their role(s) in spermatogenesis are unclear. We identify a genetic pathway that regulates male reproductive decline stemming from the perturbation of mitochondrial proline metabolism leading to redox imbalance, cofactor depletion, and altered mitochondria dynamics; all of which play a role in sperm dysfunction
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