MLDHR (MP31; PTEN uORF micropeptide; UniProt C0HLV8) - review notes

2026-10-03 - initial review (claude-code)

Identity

• 31-aa peptide (MWRDSLCAAAGYALGAGTRLRSVLSSRKLQP) encoded by an upstream ORF in the 5' UTR of
  PTEN (chr10). Separate UniProt entry (C0HLV8, PE1) with its own HGNC symbol MLDHR
  (HGNC:55481), so it gets its own folder. It is NOT PTEN-L (P60484-2), which is an in-frame
  N-terminally extended PTEN isoform.
• InterPro IPR054159 / Pfam PF22001 "MP31" (single-member family). No PANTHER/PAN-GO
  ("0 GO annotations based on evolutionary models").
• UniProt: partial protein sequence 4-19 by MS; S5A and Y12A abolish LDHA/LDHB interaction.

Literature (whole literature is from one lab, Zhang N, Sun Yat-sen Univ.)

• PMID:33406399 (Huang et al. 2021 Cell Metab; abstract-only in cache, no PMC). Primary paper.
  [PMID:33406399 "MP31, a micropeptide encoded by the upstream open reading frame (uORF) of phosphatase and tensin homolog (PTEN) acting as a \"circuit breaker\" that limits lactate-pyruvate conversion in mitochondria by competing with mitochondrial lactate dehydrogenase (mLDH) for nicotinamide adenine dinucleotide (NAD+)"]
• Mouse homolog KO: PMID:33406399
• Tumour suppressor in astrocyte cKO; recombinant peptide crosses BBB.
• Erratum PMID:33535099 (not cached; erratum only).
• PMID:37280112 (Huang et al. 2023 Neuro Oncol; full text in PMC). Second paper.
• PMID:37280112
• recalls first paper: PMID:37280112
• New: MP31 competes with V-ATPase A1 for LDHB binding -> lysosomal alkalinization, block of
  mitophagosome-lysosome fusion, MMP loss, ROS. These are downstream/indirect cellular
  phenotypes of overexpression in GBM cells and KO in normal human astrocytes; no direct
  mitophagy/lysosome activity of MP31 itself. Not proposed as GO terms.
• PMID:41090342 (2025 review of GBM micropeptides; abstract only) - background only.

Mechanistic tension

• Abstract says MP31 "compet[es] with mLDH for NAD+", while UniProt/GOA record binding to
  LDHA/LDHB (IPI) and LDH inhibitor activity (IDA). The GO term GO:0160193 is defined as
  "Binds to and stops, prevents or reduces the activity of L-lactate dehydrogenase" - consistent
  with the LDH-binding mutants (S5A, Y12A). Exact mechanism (NAD+ binding vs. LDH binding) is
  not resolvable from the abstract; curator had full text. Accept MF.
• Direction: inhibits lactate -> pyruvate (lactate oxidation) in mitochondria; existence of an
  "mitochondrial LDH" is itself debated in the field (worth an expert question).

Decisions

• protein binding x2 (LDHA, LDHB) -> MODIFY to GO:0160193 L-lactate dehydrogenase inhibitor activity.
• mitochondrion IDA/IEA -> ACCEPT (two independent papers state mitochondrial localization).
• negative regulation of oxidative phosphorylation (IMP) -> KEEP_AS_NON_CORE: OXPHOS increase is a
  downstream consequence of more pyruvate supply in mouse KO; the direct process is lactate
  oxidation. No GO term "negative regulation of lactate catabolic/oxidation process" found in QuickGO
  search, so no NEW.
• L-lactate dehydrogenase inhibitor activity (IDA) -> ACCEPT (core).
• No NEW terms: mitophagy/lysosome phenotypes are indirect.
• Evidence caveat: single laboratory; no independent replication; human peptide detected in brain;
  low/absent in GBM.

2026-11-03 ORGANELLES batch 4 (mitochondrion rows)

Rows: GO:0005739 IDA (PMID:33406399) and IEA (GO_REF:0000044, SL-0173), both located_in, both ACCEPT.

Checks:
- Evidence is about the uORF peptide itself (own UniProt entry C0HLV8; projects/MICROPROTEINS.md), not PTEN or
PTEN-L: [file:human/MLDHR/MLDHR-uniprot.txt "SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:33406399}."]
- PMID:33406399 abstract-only; PMID:37280112 (full text) uses MitoTracker staining, no sub-mitochondrial assay.
- No UniProt transit peptide or TM feature. The 31-aa sequence (MWRDSLCAAAGYALGAGTRLRSVLSSRKLQP) is Arg-rich and
acid-free, so a presequence is conceivable, but that is one uncorroborated line.

Outcome: both rows stay ACCEPT (rule 2; site of the core activity), reasons record the check. Stays at root.