Mitochondrial Functionality in Male Fertility: From Spermatogenesis to Fertilization

Abstract

Mitochondria are structurally and functionally distinct organelles that produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS), to provide energy to spermatozoa. They can also produce reactive oxidation species (ROS). While a moderate concentration of ROS is critical for tyrosine phosphorylation in cholesterol efflux, sperm-egg interaction, and fertilization, excessive ROS generation is associated with male infertility. Moreover, mitochondria participate in diverse processes ranging from spermatogenesis to fertilization to regulate male fertility. This review aimed to summarize the roles of mitochondria in male fertility depending on the sperm developmental stage (from male reproductive tract to female reproductive tract). Moreover, mitochondria are also involved in testosterone production, regulation of proton secretion into the lumen to maintain an acidic condition in the epididymis, and sperm DNA condensation during epididymal maturation. We also established the new signaling pathway using previous proteomic data associated with male fertility, to understand the overall role of mitochondria in male fertility. The pathway revealed that male infertility is associated with a loss of mitochondrial proteins in spermatozoa, which induces low sperm motility, reduces OXPHOS activity, and results in male infertility.

Keywords: capacitation; epididymis; fertilization; male infertility; mitochondria; oxidative phosphorylation; spermatozoa; testis.

Figure 1

Schematic image of OXPHOS and glycolysis in spermatozoa. Pyruvate is produced by glycolysis and is then converted to lactate in the principal piece of spermatozoa by lactate dehydrogenase. Then, pyruvate in the principal piece is transported inside into the mitochondria and it is used as fuel for TCA cycles, which produce the NADH. OXPHOS take place in mitochondria of sperm midpiece. Oxidation of NADH in the electron transport chain produce the ATP molecules by OXPHOS.

Figure 2

Signaling Pathways According to Differentially Expressed Genes between Spermatogonia and Spermatocytes/Spermatids. Molecular functions based on the differentially expressed genes in spermatogonia (SSCs) and differentiated male germ cells (spermatocytes and spermatids) were determining using g: Profiler, Cytoscape, and EnrichmentMap. Purple represents enrichment in spermatogonia, while blue represents enrichment in differentiated male germ cells. Node size indicated how many genes are involved to pathways.

Figure 3

Different distribution of mitochondria between clear cells and other cells in the epididymis. Mitochondria were labelled with a Mitotracker (Green) and clear cells (CCs) were labelled with V-ATPase (Red). Representative images (A) show the different distribution of mitochondria between clear cells and other cells, such as principal cells (PCs, unlabeled cells). The fluorescence intensity results (B) indicated that mitochondria are more enriched in clear cells than principal cells. The images were obtained using Nikon Eclipse Ni-U equipped with a Nikon DS-Ri2 camera and the Nikon NIS-Elements Fr software (Version 5.11, Nikon Instruments Inc., Melville, NY, USA).

Figure 4

Signaling pathways according to differentially expressed genes between fertile and infertile human spermatozoa. Signaling pathways based on the differentially expressed proteins in spermatozoa from fertile and infertile men were determined using g: Profiler, Cytoscape, and EnrichmentMap. Blue represents enrichment in spermatozoa from fertile men, while purple represents enrichment in spermatozoa from infertile patients. Node size indicated how many genes are involved with pathways.