LDHC: The Ultimate Testis‐Specific Gene

Goldberg, Erwin; Eddy, Edward M.; Duan, Chongwen; Odet, Fanny

doi:10.2164/jandrol.109.008367

Cited by 123 publications

(119 citation statements)

References 86 publications

(107 reference statements)

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“…4D). The protein levels of two genes, lactate hehydrogenase c (Ldhc) and calmegin (Clgn) that are essential for sperm energy production and movement (58,59), were confirmed by immunohistochemistry and Western blots (Fig. 4E, 4F).…”

Section: ϫ59mentioning

confidence: 80%

Integrative Proteomic and Transcriptomic Analyses Reveal Multiple Post-transcriptional Regulatory Mechanisms of Mouse Spermatogenesis

Gan

Cai

Lin

et al. 2013

Molecular & Cellular Proteomics

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Mammalian spermatogenesis consists of many cell types and biological processes and serves as an excellent model for studying gene regulation at transcriptional and post-transcriptional levels. Many key proteins, miRNAs, and perhaps piRNAs have been shown to be involved in post-transcriptional regulation of spermatogenesis. However, a systematic method for assessing the relationship between protein and mRNA expression has not been available for studying mechanisms of post-transcriptional regulation. In the present study, we used the iTRAQbased quantitative proteomic approach to identify 2008 proteins in mouse type A spermatogonia, pachytene spermatocytes, round spermatids, and elongative spermatids with high confidence. Of these proteins, 1194 made up four dynamically changing clusters, which reflect the mitotic amplification, meiosis, and post-meiotic development of germ cells. We identified five major regulatory mechanisms termed "transcript only," "transcript degradation," "translation repression," "translation de-repression," and "protein degradation" based on changes in protein level relative to changes in mRNA level at the mitosis/meiosis transition and the meiosis/post-meiotic development transition. We found that post-transcriptional regulatory mechanisms are related to the generation of piRNAs and antisense transcripts. Our results provide a valuable inventory of proteins produced during mouse spermatogenesis and contribute to elucidating the mechanisms of the post-transcriptional regulation of gene expression in mammalian spermatogenesis. Molecular &

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Section: ϫ59mentioning

confidence: 80%

Integrative Proteomic and Transcriptomic Analyses Reveal Multiple Post-transcriptional Regulatory Mechanisms of Mouse Spermatogenesis

Gan

Cai

Lin

et al. 2013

Molecular & Cellular Proteomics

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“…Brucella spp. may take advantage of host lactate as an energy source in niches where lactate is naturally abundant, such as the placenta (30) or male reproductive tissue (31). Both lactate and amino acids have been proposed to provide energy to certain intracellular pathogens within the host environment (32).…”

Section: Discussionmentioning

confidence: 99%

Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen

2017

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Intracellular bacterial pathogens exploit host cell resources to replicate and survive inside the host. Targeting these host systems is one promising approach to developing novel antimicrobials to treat intracellular infections. We show that human macrophage-like cells infected with Brucella abortus undergo a metabolic shift characterized by attenuated tricarboxylic acid cycle metabolism, reduced amino acid consumption, altered mitochondrial localization, and increased lactate production. This shift to an aerobic glycolytic state resembles the Warburg effect, a change in energy production that is well described in cancer cells and also occurs in activated inflammatory cells. B. abortus efficiently uses lactic acid as its sole carbon and energy source and requires the ability to metabolize lactate for normal survival in human macrophage-like cells. We demonstrate that chemical inhibitors of host glycolysis and lactate production do not affect in vitro growth of B. abortus in axenic culture but decrease its survival in the intracellular niche. Our data support a model in which infection shifts host metabolism to a Warburg-like state, and B. abortus uses this change in metabolism to promote intracellular survival. Pharmacological perturbation of these features of host cell metabolism may be a useful strategy to inhibit infection by intracellular pathogens.IMPORTANCE Brucella spp. are intracellular bacterial pathogens that cause disease in a range of mammals, including livestock. Transmission from livestock to humans is common and can lead to chronic human disease. Human macrophage-like cells infected with Brucella abortus undergo a Warburg-like metabolic shift to an aerobic glycolytic state where the host cells produce lactic acid and have reduced amino acid catabolism. We provide evidence that the pathogen can exploit this change in host metabolism to support growth and survival in the intracellular niche. Drugs that inhibit this shift in host cell metabolism inhibit intracellular replication and decrease the survival of B. abortus in an in vitro infection model; these drugs may be broadly useful therapeutics for intracellular infections.KEYWORDS infection, Warburg effect, lactate, therapeutics, antimetabolite drug, 3-bromopyruvic acid, NHI-2, 2-deoxy-D-glucose, brucellosis, antibiotic, metabolism, zoonotic infection M acrophages can be activated by pathogen-associated proinflammatory molecules, such as lipopolysaccharide (LPS). Classically activated (i.e., M1) macrophages undergo a major metabolic shift in which the tricarboxylic acid (TCA) cycle is downregulated, and energy production transitions from oxidative phosphorylation to the less efficient process of aerobic glycolysis (1, 2). This change in metabolism, known as the Warburg effect (3), is a well-described metabolic feature of cancer cells (4).

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“…The biological function of TEX101 still remains unknown, although it may play a crucial role in the acrosome reaction (30). LDHC is a testisspecific isozyme discovered in male germ cells and is critical for fertilization (31,32). PTGDS stands for lipocalin-type prostaglandin D synthase, which is expressed in Sertoli cells of the testis and in epithelial cells of the prostate and ductus epididymis (33).…”

Section: Discussionmentioning

confidence: 99%

Verification of Male Infertility Biomarkers in Seminal Plasma by Multiplex Selected Reaction Monitoring Assay

Drabovich

Jarvi

Diamandis

2011

Molecular & Cellular Proteomics

103

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Seminal plasma is a promising biological fluid to use for noninvasive clinical diagnostics of male reproductive system disorders. To verify a list of prospective male infertility biomarkers, we developed a multiplex selected reaction monitoring assay and measured the relative abundance of 31 proteins in 30 seminal plasma samples from normal, nonobstructive azoospermia and post-vasectomy individuals. Median levels of some proteins were decreased by more than 100-fold in nonobstructive azoospermia or post-vasectomy samples, in comparison with normal samples. To follow up the most promising candidates and measure their concentrations in seminal plasma, heavy isotope-labeled internal standards were synthesized and used to reanalyze 20 proteins in the same set of samples. Concentrations of candidate proteins in normal seminal plasma were found in the range 0.1-1000 g/ml but were significantly decreased in nonobstructive azoospermia and post-vasectomy. These data allowed us to select, for the first time, biomarkers to discriminate between normal, nonobstructive azoospermia, and post-vasectomy (simulated obstructive azoospermia) seminal plasma samples. Some testis-specific proteins (LDHC, TEX101, and SPAG11B) performed with absolute or nearly absolute specificities and sensitivities. Cell-specific classification of protein expression indicated that Sertoli or germ cell dysfunction, but not Leydig cell dysfunction, was observed in nonobstructive azoospermia seminal plasma. The proposed panel of biomarkers, pending further validation, could lead to a clinical assay that can eliminate the need for testicular biopsy to diagnose the category of male infertility, thus providing significant benefits to patients as well as decreased costs associated with the differential diagnosis of azoospermia. Molecular & Cellular Proteomics 10: 10.1074/mcp.M110.004127, 1-13, 2011.Human infertility affects ϳ15% of couples, with the male contributing to the infertility in 50% of all cases (1, 2). One of the most severe forms of male infertility is azoospermia, which is characterized by an absence of sperm in the semen (3). Azoospermia is diagnosed in 20% of subfertile men and has two forms: obstructive azoospermia (OA) 1 and nonobstructive azoospermia (NOA). OA is caused by a physical obstruction in the male reproductive tract. The biological outcome of OA is thus identical to that of vasectomy, which is a surgical severance of the vas deferens. NOA is a more complicated infertility syndrome with the azoospermia being secondary to a failure to produce sperm; NOA may be further subclassified as maturation arrest, Sertoli cell-only syndrome, and hypospermatogenesis (4).For most men with azoospermia, testicular biopsy is the only currently used method to definitively distinguish between OA and NOA (5, 6). Thus, there is an urgent need for an alternative noninvasive approach with better diagnostic potential. The differential diagnosis of normal, NOA, and OA (or post-vasectomy (PV)) men is required for the following reasons: (i) in infertile pati...

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LDHC: The Ultimate Testis‐Specific Gene

Cited by 123 publications

References 86 publications

Integrative Proteomic and Transcriptomic Analyses Reveal Multiple Post-transcriptional Regulatory Mechanisms of Mouse Spermatogenesis

Integrative Proteomic and Transcriptomic Analyses Reveal Multiple Post-transcriptional Regulatory Mechanisms of Mouse Spermatogenesis

Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen

Verification of Male Infertility Biomarkers in Seminal Plasma by Multiplex Selected Reaction Monitoring Assay

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