A sperm-specific proteome-scale metabolic network model identifies non-glycolytic genes for energy deficiency in asthenozoospermia

ABSTRACT

About 15% of couples experience difficulty in conceiving a child, of which half of the cases are thought to be male-related. Asthenozoospermia, or low sperm motility, is one of the frequent types of male infertility. Although energy metabolism is suggested to be central to the etiology of asthenozoospermia, very few attempts have been made to identify its underlying metabolic pathways. Here, we reconstructed SpermNet, the first proteome-scale model of the sperm cell by using whole-proteome data and the mCADRE algorithm. The reconstructed model was then analyzed using the COBRA toolbox. Genes were knocked-out in the model to investigate their effect on ATP production. A total of 78 genes elevated ATP production rate considerably of which most encode components of oxidative phosphorylation, fatty acid oxidation, the Krebs cycle, and members of the solute carrier 25 family. Among them, we identified 11 novel genes which have previously not been associated with sperm cell energy metabolism and may thus be implicated in asthenozoospermia. We further examined the reconstructed model by in silico knock out of currently known asthenozoospermia implicated-genes that were not predicted by our model. The pathways affected by knocking out these genes were also related to energy metabolism, confirming previous findings. Therefore, our model not only predicts the known pathways, it also identifies several non-glycolytic genes for deficient energy metabolism in asthenozoospermia. Finally, this model supports the notion that metabolic pathways besides glycolysis such as oxidative phosphorylation and fatty acid oxidation are essential for sperm energy metabolism and if validated, may form a basis for fertility recovery.

Abbreviations: mCADRE: metabolic context-specificity assessed by deterministic reaction evaluation; ATP: adenosine triphosphate; RNA: ribonucleic acid; FBA: flux balance analysis; FVA: flux variability analysis; DAVID: database for annotation, visualization and integrated discovery; OXPHOS: oxidative phosphorylation; ETC: electron transfer chain; SLC: solute carrier; DLD: dihydrolypoamide dehydrogenase; DLST: dihydrolypoamide S-succinyl transferase; OGDH: oxoglutarate dehydrogenase; CS: citrate synthase; FH: fumarate hydratase; IDH: isocitrate dehydrogenase; SUCLG1: succinate-CoA ligase; SD: succinate dehydrogenase; HADHA: hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, subunit A; HADHB: hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, subunit B; PPA2: pyrophosphatase (inorganic) 2; PP_i: inorganic phosphate; GALT: galactose-1-phosphate uridylyltransferase

KEYWORDS:

• Asthenozoospermia
• ATP production
• energy metabolism
• male infertility
• model reconstruction
• sperm motility

Acknowledgments

The authors would like to thank Dr. K. Gilany (Avicenna Research Institute, ACECR, Iran) for his assistance in data collection and helpful discussions. The updated Recon2 model was kindly provided by Dr. Nathan Lewis (UCSD). S-AM acknowledges the financial support of the University of Tehran for this research under Grant Number 28791/1/2.

Declaration of interest

Financial support of the University of Tehran for this research under Grant Number 28791/1/2 (S-AM). The authors report no confliction of interest and none of the authors of the paper are employed by the Government of Iran.

Additional information

Notes on contributors

Arvand Asghari

Conceived and designed the experiments: S-AM, AA; Reconstructed the model, performed the computational experiments, and drafted the original report: AA; Involved in the interpretation of the findings and reviewing and revising the final manuscript: S-AM, AA, NAP.

Sayed-Amir Marashi

Conceived and designed the experiments: S-AM, AA; Reconstructed the model, performed the computational experiments, and drafted the original report: AA; Involved in the interpretation of the findings and reviewing and revising the final manuscript: S-AM, AA, NAP.

Naser Ansari-Pour

Conceived and designed the experiments: S-AM, AA; Reconstructed the model, performed the computational experiments, and drafted the original report: AA; Involved in the interpretation of the findings and reviewing and revising the final manuscript: S-AM, AA, NAP.