Loss of flavin adenine dinucleotide (FAD) impairs sperm function and male reproductive advantage in C. elegans

Abstract
Data availability
Article and author information
Metrics

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).-

The following data sets were generated

1. Yen C-A
2. Curran SP
(2020) Loss of mitochondrial proline catabolism depletes FAD, impairing sperm function, and male reproductive advantage
NCBI Gene Expression Omnibus, GSE121920.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE121920

Article and author information

Author details

Chia-An Yen

Gerontology; Molecular and Computational Biology; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Dana L Ruter

Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, United States

Competing interests
The authors declare that no competing interests exist.
Christian D Turner

Gerontology; Molecular and Computational Biology; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Shanshan Pang

School of Life Sciences, Chongqing University, Chongqing, China

Competing interests
The authors declare that no competing interests exist.
Sean P Curran

Gerontology; Molecular and Computational Biology; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, United States

For correspondence
spcurran@usc.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7791-6453

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.

Copyright

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.