Affinage

LDHC

L-lactate dehydrogenase C chain · UniProt P07864

Length
332 aa
Mass
36.3 kDa
Annotated
2026-06-10
32 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LDHC is a testis-specific lactate dehydrogenase isozyme that, as the homotetramer LDH-C4, provides the majority of LDH activity in sperm and is essential for male fertility (PMID:18367675). Functioning in the sperm cytosol and flagellum, it sustains glycolytic flux and ATP production: Ldhc-null sperm deplete ATP rapidly, lose motility, fail to hyperactivate, cannot undergo capacitation-associated tyrosine phosphorylation, and cannot penetrate the zona pellucida (PMID:18367675). LDHC is specifically required to maintain aerobic glycolysis in the presence of glucose, when oxidative phosphorylation is suppressed (Crabtree effect) (PMID:23486916). Its essential contribution is the cytosolic LDH catalytic activity itself rather than unique enzymatic properties, since a cytosolic human LDHA transgene restores motility, capacitation phosphorylation, and fertility in Ldhc-null mice (PMID:23467744), and a humanized human-LDHC knock-in fully rescues fertility while conferring sensitivity to a human-LDHC-selective inhibitor, defining LDHC as a contraceptive target (PMID:36464740). Testis-restricted expression is set by layered control: a minimal promoter directs spermatocyte-specific transcription (PMID:9813024) activated through an Sp1-bound GC-box (PMID:9153323) and through MYBL1 acting at a CRE site via interactions with CBP-KIX and CREB (PMID:21998171), while NF-I proteins repress the promoter in somatic cells (PMID:11447215); promoter CpG methylation silences the gene outside the testis and demethylation permits Sp1 recruitment and expression (PMID:7736669, PMID:36041633). In primates, AU-rich elements in the 3'-UTR destabilize the transcript, accounting for lower expression than in rodents (PMID:8614414). Aberrantly expressed LDHC drives oncogenic phenotypes, enhancing lactate/ATP production, migration, invasion, and tumor growth via PI3K/AKT/GSK-3β signaling (PMID:33301764), modulating STAT3 signaling in a context-dependent manner (PMID:39001513), and shaping anti-tumor immunity through effects on cytokine secretion, PD-L1, and T-cell checkpoint expression (PMID:40108668).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1995 High

    Established that species-specific post-transcriptional control limits LDHC abundance, explaining why primates express far less LDHC mRNA than rodents.

    Evidence Cell-free mRNA stability assays and 3'-UTR AU-rich element mutagenesis in baboon, human, and mouse transcripts

    PMID:8614414

    Open questions at the time
    • Trans-acting destabilizing factors binding the AU-rich elements not identified
    • Physiological consequence of lower primate LDHC levels not addressed
  2. 1995 Medium

    Linked tissue-restricted LDHC expression to promoter DNA methylation, showing the CpG-rich promoter is methylated and silent in somatic tissue but hypomethylated in testis.

    Evidence Methylation mapping by restriction/PCR and in vitro methyl-DNA binding protein complex formation on the human LDH-C promoter

    PMID:7736669

    Open questions at the time
    • Identity of the methyl-DNA binding protein not established
    • Causality between methylation and silencing not tested in vivo
  3. 1997 Medium

    Identified the proximal GC-box as a functional control element and implicated Sp1-mediated transactivation in driving promoter activity in spermatocytes.

    Evidence In vivo DNase I footprinting in pachytene spermatocytes plus CAT reporter mutagenesis

    PMID:9153323

    Open questions at the time
    • Did not resolve whether Sp1 or a germ-cell factor occupies the site in vivo
  4. 1998 High

    Defined the minimal cis-regulatory element sufficient for germ-cell-specific transcription, narrowing testis-specificity to ~100 bp around the start site.

    Evidence lacZ transgenic mice and in vitro transcription with a 60 bp promoter fragment

    PMID:9813024

    Open questions at the time
    • Full set of trans factors binding the minimal promoter not enumerated
  5. 1998 Medium

    Showed the GC-box is bound by a germ-cell-specific factor distinct from Sp1, refining the regulatory logic beyond canonical Sp1 occupancy.

    Evidence EMSA, Sp1 supershift, and methylation interference with germ cell and HeLa nuclear extracts

    PMID:9723175

    Open questions at the time
    • Germ-cell-specific factor not molecularly identified
    • In vitro binding only, no in vivo confirmation
  6. 2001 High

    Provided a mechanism for silencing in non-germ cells by showing NF-I proteins bind a promoter palindrome and repress transcription.

    Evidence EMSA, reporter assays, NF-I overexpression, and binding-site mutagenesis in mouse L cells

    PMID:11447215

    Open questions at the time
    • Repression demonstrated in a somatic cell line, not in germ-cell differentiation context
  7. 2008 High

    Demonstrated that LDHC is required for male fertility, defining its cellular role in sperm energetics, motility, capacitation, and zona penetration.

    Evidence Targeted Ldhc knockout mice with sperm motility, ATP, capacitation phosphorylation, and IVF assays

    PMID:18367675

    Open questions at the time
    • Did not resolve which downstream energetic step limits motility
  8. 2012 High

    Identified MYBL1 as a positive transcriptional activator acting through the CRE site, mechanistically connecting it to CBP and CREB.

    Evidence MYBL1 mutant mice, reporter assays in GC1-spg cells, EMSA, and TAD-CBP-KIX/CREB interaction domain mapping

    PMID:21998171

    Open questions at the time
    • How MYBL1, Sp1, and the germ-cell factor are coordinated at the promoter not integrated
  9. 2013 High

    Clarified that LDHC is essential specifically under glycolytic conditions, since null sperm compensate by oxidative phosphorylation only when glucose is absent.

    Evidence Ldhc knockout across two strains with oxygen consumption, ATP, and motility under defined substrates

    PMID:23486916

    Open questions at the time
    • Molecular basis of the glucose-dependent Crabtree suppression in sperm not defined
  10. 2013 High

    Showed LDHC's role reflects cytosolic LDH catalytic activity rather than unique isozyme properties, since cytosolic LDHA rescues fertility.

    Evidence Human LDHA transgenic rescue in Ldhc-null mice with motility, phosphorylation, fertility, and metabolite readouts

    PMID:23467744

    Open questions at the time
    • Why rescued sperm function despite unchanged ATP/lactate levels not fully explained
  11. 2020 Medium

    Extended LDHC biology to cancer, showing ectopic LDHC drives migration, invasion, and tumor growth via PI3K/AKT/GSK-3β.

    Evidence LDHC overexpression/knockdown in LUAD cells, xenografts, and PI3K inhibitor rescue with Western blot

    PMID:33301764

    Open questions at the time
    • Direct link between LDHC catalytic output and AKT activation not established
    • Single tumor type
  12. 2022 Medium

    Confirmed methylation-gated expression in a developmental context and identified SP1 recruitment to demethylated promoter regions controlling LDHC and lactate output.

    Evidence MeDIP-seq, 5-Aza-CdR demethylation, SP1 ChIP, and overexpression with lactate measurement in porcine Sertoli cells

    PMID:36041633

    Open questions at the time
    • Causality of demethylation versus SP1 binding ordering not resolved
  13. 2022 High

    Validated human LDHC as a species-selective contraceptive target by humanizing the mouse locus and showing inhibitor sensitivity.

    Evidence CRISPR/Cas9 humanized knock-in mice, CASA motility, and IVF with a human-LDHC-selective inhibitor

    PMID:36464740

    Open questions at the time
    • In vivo contraceptive efficacy of the inhibitor not tested
  14. 2024 Medium

    Defined a context-dependent LDHC-STAT3 axis with opposite survival effects across breast cancer subtypes.

    Evidence siRNA knockdown, transcriptomics, viability assays, and STAT3 inhibition in basal-like and Her2-enriched cells

    PMID:39001513

    Open questions at the time
    • Molecular basis of subtype-specific opposite outcomes unclear
    • Whether LDHC catalysis or moonlighting drives STAT3 effects not separated
  15. 2025 Medium

    Linked tumor LDHC to immune evasion, showing knockdown enhances T-cell activation and reduces PD-L1 and checkpoint expression.

    Evidence siRNA knockdown, multiplex cytokine assays, flow cytometry, ELISpot, and cytotoxicity in cancer-T cell co-cultures

    PMID:40108668

    Open questions at the time
    • Mechanism connecting LDHC to PD-L1 and cytokine changes not defined
  16. 2025 Medium

    Confirmed flagellar/cytosolic localization of LDHC across species and its functional requirement for sperm energetics.

    Evidence Sperm proteome/metabolome profiling, fractionation, and specific LDHC inhibitor functional assays in stallion sperm

    PMID:40299647

    Open questions at the time
    • Mechanism of flagellar targeting not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LDHC's catalytic lactate/NAD+ chemistry mechanistically connects to its oncogenic signaling (PI3K/AKT, STAT3) and immunomodulatory effects remains unresolved.
  • No demonstration that enzymatic activity is required for cancer signaling effects
  • No structural model of LDHC distinguishing it from somatic LDH isozymes in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 5 GO:0140098 catalytic activity, acting on RNA 3
Localization
GO:0005829 cytosol 2 GO:0005929 cilium 1
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1430728 Metabolism 4 R-HSA-1474165 Reproduction 4
Partners
CBPCREBMYBL1SP1
Complex memberships
LDH-C4 homotetramer

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Targeted disruption of Ldhc in mice severely impaired male fertility. LDHC homotetramer (LDH-C4) accounts for the majority of LDH enzymatic activity in sperm. Ldhc-null sperm showed more rapid ATP depletion, loss of motility, failure to acquire hyperactivated motility, inability to penetrate the zona pellucida in vitro, and failure to undergo capacitation-associated phosphorylation events. Gene knockout (targeted disruption), sperm motility assay, ATP measurement, in vitro fertilization assay, capacitation phosphorylation assay Biology of reproduction High 18367675
2013 In the absence of glucose, Ldhc-null sperm can produce ATP via oxidative phosphorylation, but when glucose is present, oxidative phosphorylation is suppressed and sperm rely on aerobic glycolysis (Crabtree effect). LDHC is required to maintain glycolytic flux and ATP production specifically in the presence of glucose. Ldhc knockout mouse model (C57BL/6 and 129S6 backgrounds), oxygen consumption measurement, ATP quantification, motility analysis under defined energy substrate conditions Biology of reproduction High 23486916
2013 Human LDHA introduced as a transgene into Ldhc-null mice rescued sperm motility, protein tyrosine phosphorylation (capacitation marker), and fertility, demonstrating that LDHC does not possess unique catalytic properties essential for fertility and that cytosolic LDH activity per se is sufficient. However, ATP and lactate levels in rescued sperm did not significantly differ from Ldhc-null sperm, suggesting localization of LDH to the sperm cytosol (rather than specific enzymatic properties of LDHC) is the main determinant of rescue. Transgenic rescue experiment (LDHA transgene in Ldhc-/- background), sperm motility assay, tyrosine phosphorylation assay, fertility testing, ATP/lactate measurement Biology of reproduction High 23467744
1998 A 100 bp genomic fragment overlapping the LDHC transcription start site is sufficient to drive testis-specific expression in transgenic mice, with expression restricted to leptotene/pachytene primary spermatocytes. Transgenic mice carrying lacZ reporter driven by 100 bp LDHC promoter fragment; in vitro transcription assay with 60 bp promoter The Journal of biological chemistry High 9813024
2001 NF-I/CTF family proteins bind to a palindromic element in the Ldhc promoter and repress its activity in somatic (non-germ) cells. Mutation of the NF-I binding site in the palindrome increased promoter activity ~4-fold in mouse L cells; overexpression of NF-IA, -B, -C, or -X decreased wild-type promoter activity 20–50% but had no effect when the NF-I binding element was mutated. Gel retardation assay, transient transfection reporter assay in mouse L cells, NF-I overexpression, site-directed mutagenesis of promoter The Journal of biological chemistry High 11447215
2012 Transcription factor MYBL1 (A-MYB) stimulates Ldhc expression in spermatocytes via the CRE site in the Ldhc core promoter. MYBL1 transactivation domain (TAD) interacts with the KIX domain of CBP, and TAD and DNA-binding domain of MYBL1 each interact with the CREB N-terminal domain. LDHC expression is lost in 21-day testes of MYBL1 mutant mice. MYBL1 activates Ldhc through CRE elements rather than canonical Myb-binding sites. MYBL1 mutant mouse analysis, reporter assays in GC1-spg cells, EMSA, co-immunoprecipitation/interaction domain mapping between MYBL1-TAD and CBP-KIX/CREB Biology of reproduction High 21998171
1997 DNase I footprinting in isolated mouse pachytene spermatocytes identified a single protected region over the GC-box (Sp1-binding site) in the LDH/C proximal promoter. Functional studies showed that enhancer-assisted Sp1-mediated transactivation drives LDH/C promoter activity; mutation of the GC-box abolished activity. PCR-based in vivo DNase I footprinting in isolated pachytene spermatocytes, CAT reporter assays with wild-type and mutated promoter constructs in germ cell and somatic cell lines Nucleic acids research Medium 9153323
1998 EMSA studies identified at least one germ-cell-specific nuclear transcription factor (distinct from Sp1) that binds the GC-box motif of the LDH/C proximal promoter, with methylation interference identifying a unique 5'G residue within the GC-box as critical for this binding. Somatic cells (HeLa) have at least six different DNA-protein complexes at this element, only one of which involves Sp1. EMSA with nuclear extracts from primary germ cells and HeLa cells, supershift analysis with Sp1 antibody, methylation interference analysis, GC-box mutagenesis The Journal of experimental zoology Medium 9723175
1995 The human LDH-C promoter contains a CpG-rich region of ~230 bp that is heavily methylated at nine sites in somatic cells but specifically hypomethylated at those same sites in expressing tissues (testis). A methylated promoter forms a specific complex in vitro with a methyl-DNA binding protein, linking promoter hypermethylation to LDHC silencing in non-expressing tissues. Endonuclease sensitivity coupled with PCR (methylation mapping), in vitro protein-DNA complex formation with methyl-DNA binding protein Developmental genetics Medium 7736669
1995 The 3'-UTR of primate (baboon, human) but not rodent Ldhc mRNA contains AU-rich elements that destabilize the transcript. Baboon Ldhc mRNA is labile in a cell-free system while mouse mRNA is highly stable. Removal of the human Ldhc 3'-UTR stabilizes the mRNA; mutation of AU-rich motifs also results in stabilization. Steady-state primate Ldhc mRNA levels are 8–12-fold lower than mouse. Cell-free mRNA stability assay, deletion and point mutagenesis of 3'-UTR AU-rich elements, steady-state mRNA quantification in germ cell line Molecular endocrinology High 8614414
2022 During porcine testis development, the LDHC promoter is heavily methylated in pre-pubertal testes and demethylated post-pubertally. Artificial demethylation with 5-Aza-CdR induced LDHC expression in immature Sertoli cells. Transcription factor SP1 was recruited to bind hypomethylated DMRs in the LDHC promoter, upregulating LDHC expression. LDHC overexpression in mature Sertoli cells significantly increases lactate secretion. MeDIP-seq, 5-Aza-CdR demethylation experiment, ChIP (SP1 binding to LDHC promoter DMR), LDHC overexpression with lactate secretion measurement Genomics Medium 36041633
2023 Tanshinone IIA (Tan IIA) covalently binds to LDHC and inhibits its enzymatic activity, as identified by activity-based protein profiling (ABPP) combined with LC-MS/MS. LDHC inhibition by Tan IIA reduces ROS accumulation in osteoclasts, suppressing osteoclast-specific marker expression and osteoclast differentiation. Activity-based protein profiling (ABPP) + LC-MS/MS identification of covalent binding, enzymatic activity assay, ROS measurement, osteoclast differentiation assay Chinese medicine Medium 37189204
2020 LDHC overexpression in lung adenocarcinoma (LUAD) cells increased lactate and ATP production, enhanced cell migration and invasion, and accelerated xenograft tumor growth. LDHC overexpression elevated phosphorylation of AKT and GSK-3β; PI3K inhibition reversed these effects, reducing proliferation, migration, invasion, and EMT-related protein changes. LDHC overexpression/knockdown in LUAD cell lines, in vitro invasion/migration assays, xenograft tumor model, PI3K inhibitor treatment, Western blot for p-AKT/p-GSK3β and EMT markers Experimental cell research Medium 33301764
2024 LDHC silencing in basal-like breast cancer cells (MDA-MB-468, BT-549) compromised cell survival in conjunction with downregulation of STAT3 signaling, whereas LDHC silencing in Her2-enriched breast cancer cells (HCC-1954) enhanced STAT3 activation and promoted survival. STAT3 inhibition reversed the pro-survival effect of LDHC silencing in Her2-enriched cells, establishing a LDHC-STAT3 signaling axis. siRNA knockdown, transcriptomic analysis, cell viability assay, STAT3 inhibitor treatment, Western blot Cancers Medium 39001513
2025 LDHC silencing in breast cancer cells enhanced early T cell activation and cytolytic activity. Mechanistically, LDHC knockdown increased pro-inflammatory cytokine secretion (IFN-γ, GM-CSF, MCP-1, CXCL1), decreased immunosuppressive factors (IL-6, Gal-9), and reduced tumor cell surface PD-L1 expression. In cancer cell–T cell co-cultures, LDHC knockdown reduced immune checkpoint molecule expression (PD-1, CTLA-4, TIGIT, TIM3, VISTA) on CD8+ T cells. siRNA knockdown, multiplex cytokine assay, flow cytometry for immune checkpoints and surface markers, IFN-γ ELISpot, 7-AAD cytotoxicity assay in cancer cell–T cell co-cultures Cell communication and signaling Medium 40108668
2022 Human LDHC knocked into the mouse Ldhc locus (replacing mouse LDHC) fully rescued sperm motility and male fertility. An LDH inhibitor more specific for human LDHC than mouse LDHC reduced in vitro fertilization rates in hLDHC knock-in mice but not wild-type mice, validating hLDHC as a pharmacologically distinct contraceptive target. CRISPR/Cas9 humanized knock-in mouse, CASA sperm motility analysis, IVF with LDH inhibitor treatment Andrology High 36464740
2025 In stallion spermatozoa, LDHC localizes to the cytosol and the motile cilium (flagellum), while LDHA is cytosolic and LDHB is mitochondrial. Functional inhibition of LDHC with a specific inhibitor impaired sperm function, consistent with LDHC playing an essential role in aerobic glycolysis and NAD+ regeneration within the flagellum. Proteomics/metabolomics of sperm metabolic proteome, cellular fractionation/localization, specific LDHC inhibitor functional assay, sperm motility and viability assays Reproduction (Cambridge, England) Medium 40299647

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Expression of the gene for mouse lactate dehydrogenase C (Ldhc) is required for male fertility. Biology of reproduction 175 18367675
2009 LDHC: the ultimate testis-specific gene. Journal of andrology 114 19875487
2013 Glycolysis and mitochondrial respiration in mouse LDHC-null sperm. Biology of reproduction 71 23486916
1998 Transgenic mice demonstrate a testis-specific promoter for lactate dehydrogenase, LDHC. The Journal of biological chemistry 56 9813024
2020 Cancer/testis antigen LDHC promotes proliferation and metastasis by activating the PI3K/Akt/GSK-3β-signaling pathway and the in lung adenocarcinoma. Experimental cell research 46 33301764
1988 Mapping of human lactate dehydrogenase-A, -B, and -C genes and their related sequences: the gene for LDHC is located with that for LDHA on chromosome 11. Cytogenetics and cell genetics 43 3180843
1987 Locus determining the human sperm-specific lactate dehydrogenase, LDHC, is syntenic with LDHA. Developmental genetics 32 2844458
2020 Identification of two HLA-A*0201 immunogenic epitopes of lactate dehydrogenase C (LDHC): potential novel targets for cancer immunotherapy. Cancer immunology, immunotherapy : CII 27 31932876
2013 Human lactate dehydrogenase A (LDHA) rescues mouse Ldhc-null sperm function. Biology of reproduction 23 23467744
2023 Tanshinone IIA inhibits osteoclastogenesis in rheumatoid arthritis via LDHC-regulated ROS generation. Chinese medicine 17 37189204
1995 The CpG-rich promoter of human LDH-C is differentially methylated in expressing and nonexpressing tissues. Developmental genetics 17 7736669
2012 A-MYB (MYBL1) stimulates murine testis-specific Ldhc expression via the cAMP-responsive element (CRE) site. Biology of reproduction 16 21998171
1989 Regional localization of the sperm-specific lactate dehydrogenase, LDHC, gene on human chromosome 11. Annals of human genetics 16 2596827
1999 cDNA copies of the testis-specific lactate dehydrogenase (LDH-C) mRNA are present in spermatogenic cells in mice, but processed pseudogenes are not derived from mRNAs that are expressed in haploid and late meiotic spermatogenic cells. Mammalian genome : official journal of the International Mammalian Genome Society 15 9892725
2025 Immunomodulatory effects of tumor Lactate Dehydrogenase C (LDHC) in breast cancer. Cell communication and signaling : CCS 14 40108668
1997 Molecular and functional characterization of the promoter region of the mouse LDH/C gene: enhancer-assisted, Sp1-mediated transcriptional activation. Nucleic acids research 14 9153323
2016 Effect of Hypoxia on Ldh-c Expression in Somatic Cells of Plateau Pika. International journal of environmental research and public health 12 27490559
2001 ldhc expression in non-germ cell nuclei is repressed by NF-I binding. The Journal of biological chemistry 12 11447215
1995 Posttranscriptional regulation of primate Ldhc mRNA by its AUUUA-like elements. Molecular endocrinology (Baltimore, Md.) 11 8614414
2022 MeDIP-seq and RNA-seq analysis during porcine testis development reveals functional DMR at the promoter of LDHC. Genomics 6 36041633
2011 LDH-C can be differentially expressed during fermentation of CHO cells. BMC proceedings 6 22373157
2022 Generation of humanized LDHC knock-in mice as a tool to assess human LDHC-targeting contraceptive drugs. Andrology 5 36464740
2017 The expression of Ldh-c in the skeletal muscle of plateau pika (Ochotona curzoniae) enhances adaptation to a hypoxic environment. Biology open 4 28916706
2025 Stallion spermatozoa express LDH isoforms A, B, and C, with LDHC playing a crucial role in sustaining sperm viability. Reproduction (Cambridge, England) 3 40299647
2024 The LDHC-STAT3 Signaling Network Is a Key Regulator of Basal-like Breast Cancer Cell Survival. Cancers 3 39001513
1998 Cell-type-specific transcription factor interactions with cis-elements present in the mouse LDH/C proximal promoter region. The Journal of experimental zoology 3 9723175
2025 Lactylation Genes LDHA and LDHC Alleviate Osteoarthritis by Reducing Specific B-Cell Expression: Mechanistic Exploration and Experimental Validation. Journal of cellular and molecular medicine 2 41339282
2015 [The expression of the sperm-specific lactate dehydrogenase gene Ldh-c in plateau pika (Ochotona curzoniae) cardiac muscle and its effect on the anaerobic glycolysis]. Sheng li xue bao : [Acta physiologica Sinica] 2 26109304
2025 Identification of new HLA-A*0201-restricted cytotoxic T lymphocyte epitopes from LDHC in lung adenocarcinoma. Frontiers in immunology 1 40270965
2026 Cell-Penetrating Peptide-Mediated siRNA Targeting of LDHC Suppresses Tumor Growth in a Triple-Negative Breast Cancer Zebrafish Xenograft Model. Pharmaceutics 0 41599186
2026 Comparative study on the functions of LDHA and LDHC in triple-negative breast cancer. Discover oncology 0 41879946
2025 Machine Learning-Based Validation of LDHC and SLC35G2 Methylation as Epigenetic Biomarkers for Food Allergy. Biomedicines 0 41153772

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