Loss of flavin adenine dinucleotide (FAD) impairs sperm function and male reproductive advantage in C. elegans
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.
Data availability
RNA-Seq data are deposited in GEO database (GSE121920).-
Article and author information
Author details
Funding
National Institutes of Health (GM109028)
- Sean P Curran
National Institutes of Health (AG058610)
- Sean P Curran
National Institutes of Health (AG063947)
- Sean P Curran
National Institutes of Health (AG000037)
- Dana L Ruter
National Institutes of Health (GM118289)
- Christian D Turner
American Federation for Aging Research
- Chia-An Yen
- Sean P Curran
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Hong Zhang, Institute of Biophysics, Chinese Academy of Sciences, China
Version history
- Received: October 19, 2019
- Accepted: February 5, 2020
- Accepted Manuscript published: February 5, 2020 (version 1)
- Version of Record published: February 20, 2020 (version 2)
Copyright
© 2020, Yen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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