Characterization of sperm metabolic pathways and consequences of their deficiencies in humans: from male infertility to metabolic disorders. – SPERMetabo

In mammals, sperm fertilization potential relies on efficient progression within the female genital tract to reach and fertilize the oocyte. This fundamental property is supported by the flagellum that provides the mechanical force for sperm propulsion, and is also conditioned by maturation processes occurring within the male and the female genital tracts. In particular, during capacitation, complex ion exchanges between the sperm cells and the female genital tract milieu activate sperm signaling pathways that increase the amplitude and velocity of flagellar beating. As a consequence, relative to somatic cells, sperm cells require exceptionally high amounts of ATP; moreover, they must adapt their bioenergetic metabolism according to the nutrients and metabolites that are available throughout their journey from the epididymal tract to the fallopian tubes. Thus far, the bioenergetics of sperm cells have only been investigated through the prism of glycolysis and mitochondrial oxidative phosphorylation (OxPhos), whereas lipid metabolism has been little explored. Surprisingly, in contrast to glycolysis, virtually nothing is known about the exact contribution of mitochondrial fatty acid oxidation (mFAO), which is the most efficient pathway for energy production in somatic cells. In addition, the potential switching between these two canonical metabolic pathways in response to sperm micro-environments has never been investigated, leaving this field of research entirely blank.
‘SPERMetabo’ is based on robust preliminary data obtained from genetic analysis of infertile patients displaying asthenozoospermia, a condition defined by reduced or absent sperm motility and observed in nearly 80% of infertile men. By combining molecular, functional, metabolomic, lipidomic, and proteomic approaches, this project aims to:
i.) Decipher the metabolic energy pathways in human and mouse sperm cells with a focus on mFAO and glycolysis, and elucidate their potential mode of regulation and switches in response to nutrient availability and physiological maturation micro-environments,
ii.) Investigate sperm metabolic deficiencies in human asthenozoospermia and develop equivalent mouse disease models to thoroughly decrypt the related pathophysiological mechanisms,
iii.) Provide the proof-of-concept for innovative and straightforward therapeutic strategies based on metabolism in order to treat male infertility,
iv.) Better define the genetic basis and the phenotypical spectrum of male infertility in regard to inborn metabolic disorders.
The project is built on the recognized experience of two partners, each having a complementary expertise in spermatogenesis and metabolism. The consortium is also supported by strong collaborative networks with physicians and geneticists specialized in reproductive and metabolic disorders, assuring patient recruitment, phenotypic characterization, genetic analyses, and favorizing translation from basic science to clinical applications. Altogether, this project will provide the first comprehensive cartography of sperm metabolic energy-producing pathways in physiological and pathophysiological contexts and cues for novel therapeutic strategies of male infertility, therefore improving the genetic diagnosis and treatment of the patients.