UQCC6 (BRAWNIN, C12orf73) review notes

2026-09-30 — initial review (claude-code)

Identity

• UniProt Q69YU5, 71 aa, HGNC:34450. Synonyms BR, BRAWNIN, C12orf73. Small ORF-encoded
  peptide (microprotein) that was unannotated as a functional protein until 2020.
• Topology (UniProt FT): residues 1-8 matrix, 9-25 helical signal-anchor (type II), 26-71
  intermembrane space. C-terminal IMS orientation is experimental in both key papers.
• Family: InterPro IPR027858 "Protein BRAWNIN"; Pfam PF14990 (DUF4516); PANTHER PTHR28492.
  Vertebrate-conserved; IBA donors include fly (FBgn0259204), mouse and zebrafish, so the
  PAINT node extends beyond vertebrates.

Discovery and function (Zhang et al. 2020, PMID:32161263, full text cached)

• PMID:32161263
• Localisation: carbonate-resistant IMM protein, C-terminus in IMS
  PMID:32161263.
• Zebrafish KO: PMID:32161263
  CIII-specific: PMID:32161263.
• Mouse MEF KO also reduced CIII2 PMID:32161263.
• Interactions: IP/MS intersection BR, GHITM, UQCRC1; UQCRC1 validated by co-IP in mouse heart
  mitochondria; UQCRQ-FLAG co-IP of BR-HA PMID:32161263.
  This is the basis of the GO:0005515 IPI row (with UniProtKB:P31930 = UQCRC1).
• Induced by AMPK / nutrient stress PMID:32161263

SMIM4/UQCC5 partner and early CIII assembly (Dennerlein et al. 2021, PMID:34969438, full text cached)

• Topology confirmed PMID:34969438
• Early-intermediate complex with UQCC1, UQCC2, SMIM4 (not UQCC3, not RIESKE)
  PMID:34969438
• Binds newly synthesised cytochrome b PMID:34969438
• Contradicts late-subunit (UQCRC1/UQCRQ) interactions from Zhang 2020:
  PMID:34969438
  and the UQCRQ co-IP reproduced only "marginal amounts".
• Complex IV? The only data: siRNA knockdown PMID:34969438
  The paper's own conclusions attribute to C12ORF73 only a CIII biogenesis role. Zebrafish KO
  shows CIV activity unaffected (PMID:32161263) and UniProt's mouse entry (Q8BTC1, from
  PMID:35977508) records that CIV subunits are not affected in Uqcc6 deficiency. The GOA IDA
  row for GO:0033617 complex IV assembly therefore rests on a slight, pleiotropic effect →
  MARK_AS_OVER_ANNOTATED (not removed; it is an experimental curation).

COMB complex (Liang et al. 2022, PMID:35977508, abstract only)

• PMID:35977508
• PMID:35977508
• This is the mouse work behind the ISS row (with UniProtKB:Q8BTC1).
• No GO CC term exists for COMA/COMB/COMC (QuickGO search for "COMB complex" returned nothing
  relevant) → suggested question only, not a NEW annotation.

Dissenting / nuance (Wang et al. 2024, PMID:37769950, abstract only)

• PMID:37769950
• PMID:37769950
• Supports KO-level requirement; knockdown phenotypes are weak. Consistent with CIII assembly
  as core function; argues further against reading knockdown-based CIV effects as function.

Other

• PMID:38514619 (NUAK1, neurons) — BRAWNIN is a NUAK1-regulated transcript; regulates cortical
  axon branching downstream of NUAK1. Contextual, not a direct GO annotation candidate
  (indirect/pleiotropic).
• PMID:34800366 MitoCoP — HTP mitochondrial proteome; supports mitochondrion.

Decisions

• protein binding (IPI, UQCRC1) → REMOVE (uninformative; interaction with late subunits also
  not reproduced by PMID:34969438). No informative MF term: the protein's activity (stabilising
  nascent CYTB within COMB) has no clean GO MF; follow UQCC2 precedent of no MF.
• mitochondrion (HTP, IBA) → ACCEPT; mitochondrial inner membrane (IDA x2, IEA) → ACCEPT.
• complex III assembly (IBA, IEA, IMP, ISS) → ACCEPT (core).
• complex IV assembly (IDA) → MARK_AS_OVER_ANNOTATED.
• Comparators: UQCC2 review (genes/human/UQCC2) uses directly_involved_in GO:0034551 + IMM,
  no MF — same pattern applied here. UQCC3 review exists (cardiolipin binding MF).
• No NEW annotations proposed. Complex III assembly is a process in which UQCC6 does part of the
  work (chaperoning/stabilising nascent CYTB within COMB), so it passes the participation test,
  but it is already annotated.