Phosphoglycerate Kinase 2 (PGK2) Is Essential for Sperm Function and Male Fertility in Mice1

Danshina, Polina V.; Geyer, Christopher B.; Dai, Qunsheng; Goulding, Eugenia H.; Willis, William D.; Kitto, G. Barrie; McCarrey, John R.; Eddy, Edward M.; O’Brien, Deborah A.

doi:10.1095/biolreprod.109.079699

Cited by 201 publications

(161 citation statements)

References 53 publications

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“…S3). The proteins that had considerably low concentrations in sperm from Ht mice were glycolytic enzymes required for sperm motility (16,17). The three lower levels of isozymes present in sperm from Ht mice were confirmed using antibodies (Fig.…”

Section: Resultsmentioning

confidence: 64%

A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility

Takasaki

Tachibana

Ogasawara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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For normal fertilization in mammals, it is important that functionally mature sperm are motile and have a fully formed acrosome. The glycosyltransferase-like gene, human polypeptide N-acetylgalactosaminyltransferase-like protein 5 (GALNTL5), belongs to the polypeptide N-acetylgalactosamine-transferase (pp-GalNAc-T) gene family because of its conserved glycosyltransferase domains, but it uniquely truncates the C-terminal domain and is expressed exclusively in human testis. However, glycosyltransferase activity of the human GALNTL5 protein has not been identified by in vitro assay thus far. Using mouse Galntl5 ortholog, we have examined whether GALNTL5 is a functional molecule in spermatogenesis. It was observed that mouse GALNTL5 localizes in the cytoplasm of round spermatids in the region around the acrosome of elongating spermatids, and finally in the neck region of spermatozoa. We attempted to establish Galntl5-deficient mutant mice to investigate the role of Galntl5 in spermiogenesis and found that the heterozygous mutation affected male fertility due to immotile sperm, which is diagnosed as asthenozoospermia, an infertility syndrome in humans. Furthermore, the heterozygous mutation of Galntl5 attenuated glycolytic enzymes required for motility, disrupted protein loading into acrosomes, and caused aberrant localization of the ubiquitin-proteasome system. By comparing the protein compositions of sperm from infertile males, we found a deletion mutation of the exon of human GALNTL5 gene in a patient with asthenozoospermia. This strongly suggests that the genetic mutation of human GALNTL5 results in male infertility with the reduction of sperm motility and that GALNTL5 is a functional molecule essential for mammalian sperm formation.

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Section: Resultsmentioning

confidence: 64%

A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility

Takasaki

Tachibana

Ogasawara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Accumulation of pathogenic mtDNA-derived ETC defects; male infertility Nakada et al (2006) R168 A Amaral and others (Danshina et al 2010), lactate dehydrogenase-C4 (LDHC; Odet et al 2008) and glyceraldehyde 3-phosphate dehydrogenase-S (Miki et al 2004) have impaired sperm function (notably in terms of motility) and suffer fertility loss, with the latter model maintaining normal mitochondrial activity. However, recent data have shown that, at least for LDHC, the severity of the results depends on the mouse strain, with some strains relying more on glycolysis than others (Odet et al 2013).…”

Section: Sperm Metabolism: Not a Linear Storymentioning

confidence: 99%

Mitochondria functionality and sperm quality

Amaral¹,

Lourenço²,

Marques³

et al. 2013

Reproduction

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Although mitochondria are best known for being the eukaryotic cell powerhouses, these organelles participate in various cellular functions besides ATP production, such as calcium homoeostasis, generation of reactive oxygen species (ROS), the intrinsic apoptotic pathway and steroid hormone biosynthesis. The aim of this review was to discuss the putative roles of mitochondria in mammalian sperm function and how they may relate to sperm quality and fertilisation ability, particularly in humans. Although paternal mitochondria are degraded inside the zygote, sperm mitochondrial functionality seems to be critical for fertilisation. Indeed, changes in mitochondrial integrity/functionality, namely defects in mitochondrial ultrastructure or in the mitochondrial genome, transcriptome or proteome, as well as low mitochondrial membrane potential or altered oxygen consumption, have been correlated with loss of sperm function (particularly with decreased motility). Results from genetically engineered mouse models also confirmed this trend. On the other hand, increasing evidence suggests that mitochondria derived ATP is not crucial for sperm motility and that glycolysis may be the main ATP supplier for this particular aspect of sperm function. However, there are contradictory data in the literature regarding sperm bioenergetics. The relevance of sperm mitochondria may thus be associated with their role in other physiological features, particularly with the production of ROS, which in controlled levels are needed for proper sperm function. Sperm mitochondria may also serve as intracellular Ca 2C stores, although their role in signalling is still unclear.

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“…Mutations in multiple genes in mouse models have been identified that disrupt the formation of the flagellum or the function of the flagellum (9,10). For example, mutations in Akap4, Tekt3, Tekt4, and Cabyr in mice lead to structural defects in the flagellum, whereas mutations in CatSper1, Pgk2, Gapdhs, and Ldhc lead to functional defects in the flagellum, some of which cause defective metabolism or glycolysis (11)(12)(13)(14)(15)(16)(17)(18). In men, mutations in CATSPER, DNAH1, DNAH11, and TEKT2 have been shown to lead to asthenozoospermia and sterility (19)(20)(21)(22).…”

Section: Significancementioning

confidence: 99%

TCTE1 is a conserved component of the dynein regulatory complex and is required for motility and metabolism in mouse spermatozoa

Castaneda

Hua

Miyata

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Flagella and cilia are critical cellular organelles that provide a means for cells to sense and progress through their environment. The central component of flagella and cilia is the axoneme, which comprises the "9+2" microtubule arrangement, dynein arms, radial spokes, and the nexin-dynein regulatory complex (N-DRC). Failure to properly assemble components of the axoneme leads to defective flagella and in humans leads to a collection of diseases referred to as ciliopathies. Ciliopathies can manifest as severe syndromic diseases that affect lung and kidney function, central nervous system development, bone formation, visceral organ organization, and reproduction. T-Complex-Associated-Testis-Expressed 1 (TCTE1) is an evolutionarily conserved axonemal protein present from Chlamydomonas (DRC5) to mammals that localizes to the N-DRC. Here, we show that mouse TCTE1 is testis-enriched in its expression, with its mRNA appearing in early round spermatids and protein localized to the flagellum. TCTE1 is 498 aa in length with a leucine rich repeat domain at the C terminus and is present in eukaryotes containing a flagellum. Knockout of Tcte1 results in male sterility because Tcte1-null spermatozoa show aberrant motility. Although the axoneme is structurally normal in Tcte1 mutant spermatozoa, Tcte1-null sperm demonstrate a significant decrease of ATP, which is used by dynein motors to generate the bending force of the flagellum. These data provide a link to defining the molecular intricacies required for axoneme function, sperm motility, and male fertility. male infertility | asthenozoospermia | glycolysis | mutant mouse | testis-specific gene F lagella are ancient, analogous cellular structures used for locomotion and as sensory organelles present in all three domains of life (bacteria, archaea, and eukaryotes). The advantages conferred by this organelle are highlighted by the flagella's apparent independent evolution in all three domains (1-3). Of all of the different flagella present among eukaryotes, flagella attached to gametes play a critical function in uniting gametes for fertilization and the perpetuation of a species. Mammalian spermatozoa have a specialized flagellum that contains a midpiece, principal piece, and end piece with the axoneme running along the entire length (4). The flagellum equips sperm with the capability to deliver half of the male's genetic material to the female gamete, the oocyte. In addition to flagella, eukaryotes contain another related structure called cilia. The defining feature of flagella and cilia is the axoneme, the "9+2" microtubule arraignment of two central pairs of microtubules surrounded by nine pairs of microtubule doublets (5). The microtubule motor dynein is anchored to the outer microtubules and responsible for generating the force required to produce the beating pattern of flagella and cilia (6). The force generated by dynein causes sliding of the microtubules among each other; however, the nexin complex anchors the microtubules in place. The nexin complex [or nexin-dynei...

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Phosphoglycerate Kinase 2 (PGK2) Is Essential for Sperm Function and Male Fertility in Mice1

Cited by 201 publications

References 53 publications

A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility

A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility

Mitochondria functionality and sperm quality

TCTE1 is a conserved component of the dynein regulatory complex and is required for motility and metabolism in mouse spermatozoa

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