Abstract
Macroautophagy (hereafter autophagy) is an evolutionarily highly conserved cellular process that participates in the maintenance of intracellular homeostasis through the degradation of most long-lived proteins and entire organelles. Autophagy participates in some reproductive events; however, there are not reports regarding the role of autophagy in the regulation of sperm physiology. Hence, the aim of this study was to investigate whether autophagy-related proteins are present and functionally active in human spermatozoa. Proteins related to autophagy/mitophagy process (LC3, Atg5, Atg16, Beclin 1, p62, m-TOR, AMPKα 1/2, and PINK1) were present in human spermatozoa. LC3 colocalized with p62 in the middle piece of the spermatozoa. Autophagy activation induced a significant increase in motility and a decrease in PINK1, TOM20 expression and caspase 3/7 activation. In contrast, autophagy inhibition resulted in decreased motility, viability, ATP and intracellular calcium concentration whereas PINK1, TOM20 expression, AMPK phosphorylation and caspase 3/7 activation were significantly increased. In conclusion our results show that autophagy related proteins and upstream regulators are present and functional in human spermatozoa. Modification of mitochondrial proteins expression after autophagy activation/inhibition may be indicating that a specialized form of autophagy named mitophagy may be regulating sperm function such as motility and viability and may be cooperating with apoptosis.
Highlights
Phagophore, autophagosome and autophagolysosome formation is finely regulated by at least 30 autophagy-related proteins (Atg)
Autophagy is a very intriguing pathway controlled by multiple proteins: those involved in the regulation of the formation of the autophagolysosome (at least 30 autophagy-related proteins (Atg) and those proteins involved in the activation of the process such as Beclin 1, PI3K class III, m-TOR, AMPK, among others[1,11]
In the present study we show that human spermatozoa contain both series of proteins: Atg 5, Atg 16, p62 and light chain 3 (LC3) involved in the formation of the autophagolysosome and m-TOR, Beclin 1 and AMPK described as the main regulators of autophagy[1,10,11]
Summary
Phagophore, autophagosome and autophagolysosome formation is finely regulated by at least 30 autophagy-related proteins (Atg). Autophagy activation in the oocyte participates in the elimination of sperm mitochondrial DNA (mtDNA) to prevent both the transmission of paternal mtDNA to the offspring and the establishment of heteroplasmy[12,13,14,15]; this role is not completely clear, existing discrepancies among studies[16,17,18]. Autophagy markers, such as LC3-II and autophagosomes, have been previously detected in rat and mice spermatogenic cells[19,20]. It has been shown that autophagy and apoptosis cooperate to induce germ cell death during spermatogenesis, in mice[20]
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