LDHD

LDHD encodes a mitochondria-localized D-lactate dehydrogenase that catabolizes D-lactate to pyruvate, the enzyme responsible for D-lactate clearance in vivo (PMID:30931947, PMID:31638601). Loss-of-function variants in humans elevate serum and urinary D-lactate, and wild-type but not patient-variant LDHD rescues elevated D-lactate in zebrafish, confirming an enzymatic loss-of-function mechanism (PMID:30931947). Pathogenic variants, including a catalytic-site missense mutation, cause D-lactic acidosis and drive hyperuricemia and early-onset gout through excessive renal secretion of D-lactate in exchange for urate reabsorption, reducing fractional clearance of urate (PMID:31638601, PMID:37021930). Beyond catabolism, LDHD activity is integrated into mitochondrial metabolism: its loss is associated with decreased complex IV activity in patient fibroblasts (PMID:34258137), and physical interaction with CSRP3 via a defined 33-amino-acid region couples D-lactate catabolism to mitochondrial biogenesis, oxidative phosphorylation, TCA cycle activity, and skeletal muscle fiber-type remodeling toward an oxidative phenotype (PMID:41812695). In esophageal squamous cell carcinoma cancer stem cells, LDHD expression is transcriptionally driven by a CDK7–YAP1 axis, enabling clearance of D-lactate to escape D-lactate-induced ferroptosis and support self-renewal (PMID:37582812).

1. 2019 High

   Established LDHD as the enzyme responsible for D-lactate catabolism in vivo, answering which gene clears D-lactate and showing that pathogenic variants act through enzymatic loss-of-function.

   Evidence Human homozygous variants plus zebrafish loss-of-function and rescue with wild-type versus patient-variant LDHD

   PMID:30931947

   Open questions at the time

   • Catalytic mechanism and structural basis of D-lactate-to-pyruvate conversion not resolved
   • Cofactor/electron acceptor requirements not defined
2. 2019 High

   Defined the disease mechanism linking LDHD deficiency to hyperuricemia, showing that accumulated D-lactate drives renal D-lactate/urate exchange, and localized LDHD to mitochondria.

   Evidence Human genetics with a catalytic-site missense variant, mitochondrial localization assay of overexpressed LDHD, and D-lactate injection into naive mice producing hyperuricemia

   PMID:31638601

   Open questions at the time

   • Identity of the renal D-lactate/urate exchanger not established
   • Whether mitochondrial localization depends on a specific targeting sequence not defined
3. 2021 Medium

   Connected LDHD loss to a broader mitochondrial respiratory defect, raising the question of whether D-lactate dehydrogenase activity influences the respiratory chain.

   Evidence Whole-exome sequencing of compound heterozygous patient and complex IV enzyme assay in patient fibroblasts

   PMID:34258137

   Open questions at the time

   • Mechanistic link between LDHD and complex IV not directly established
   • Single patient report
4. 2023 High

   Independently confirmed the LDHD loss-of-function/renal urate mechanism as a cause of autosomal recessive early-onset gout across multiple ethnicities.

   Evidence Whole-exome and targeted sequencing of three unrelated families, D-lactate ELISA, and fractional clearance of urate measurement

   PMID:37021930

   Open questions at the time

   • Molecular identity of the urate exchange transporter not resolved
   • Penetrance and modifiers of gout phenotype not defined
5. 2023 Medium

   Placed LDHD downstream of a CDK7–YAP1 transcriptional axis in cancer stem cells, showing its D-lactate catabolism protects against ferroptosis and supports self-renewal.

   Evidence Phosphorylation and transcriptional reporter assays, LDHD knockdown/overexpression with ferroptosis and stemness readouts in esophageal squamous cell carcinoma

   PMID:37582812

   Open questions at the time

   • Direct binding of YAP1 to the LDHD promoter not detailed
   • Generalizability beyond esophageal squamous cell carcinoma unknown
   • Single lab, abstract-level detail
6. 2026 Medium

   Identified CSRP3 as a direct LDHD partner and linked the interaction to mitochondrial biogenesis and muscle fiber-type remodeling, extending LDHD's role beyond simple catabolism.

   Evidence Co-immunoprecipitation mapping a 33-aa interaction domain, AAV-mediated knockdown, mouse exercise models, and mitochondrial functional assays

   PMID:41812695

   Open questions at the time

   • Whether CSRP3 modulates LDHD catalytic activity directly not resolved
   • Reciprocal structural validation of the interaction not performed
   • Single lab

• How LDHD's enzymatic D-lactate clearance is mechanistically coupled to mitochondrial respiratory chain integrity remains unresolved.
• No structural model of LDHD catalysis
• Causal basis for complex IV deficiency upon LDHD loss unknown
• Identity of renal D-lactate/urate exchanger unknown