Slc25a4 (rat, UniProt Q05962) -- manual literature synthesis

No deep-research API was available for this review; this synthesis was
compiled by hand from the cached publications in publications/ and the
UniProt record Slc25a4-uniprot.txt.

Identity

• Rat Slc25a4 (RGD:620352, GeneID 85333) encodes ADP/ATP translocase 1
  (ANT1, AAC1), a 298-aa member of the mitochondrial carrier family
  (TC 2.A.29), with three Solcar repeats (Pfam PF00153 x3), six
  transmembrane helices and the nucleotide-carrier signature motif
  (residues 235-240) [Slc25a4-uniprot.txt: "Belongs to the mitochondrial
  carrier (TC 2.A.29) family."].
• Rat ANT paralogs: Slc25a5 (ANT2, RGD:620353), Slc25a31 (ANT4).
  ANT1 is the heart/skeletal-muscle isoform; adult liver expresses ANT2
  PMID:9468308.

Core activity: ADP/ATP exchange across the inner membrane

• The mammalian carrier imports ADP into the matrix and exports ATP
  PMID:37278158; it is a monomer with a
  single substrate-binding site and operates by a ping-pong alternating-access
  mechanism PMID:37278158. This work was done on human
  SLC25A4; rat Q05962 shares the conserved substrate-binding residues
  (UniProt FT BINDING 80, 92, 235, by similarity to bovine P02722).
• Rat-specific functional data come from transgenic overexpression in rat
  heart: PMID:21325829.

Second transport mode: fatty-acid-dependent H+ leak (uncoupling)

• Patch-clamp of mouse inner membranes showed AAC carries a fatty-acid-
  dependent H+ current that is negatively regulated by ADP/ATP exchange
  PMID:31341297; the current was largely lost in heart and skeletal muscle of
  AAC1-/- mice.
• In rat skeletal-muscle mitochondria, energization-induced proton conductance
  is partly carboxyatractylate/bongkrekate sensitive, i.e. ANT-catalysed
  PMID:18251717. The inhibitors do not distinguish ANT1 from ANT2.

Permeability transition pore (mPTP)

• ANT binds cyclophilin D in inner-membrane preparations, CsA-sensitively
  PMID:9820802 -- liver IMM, so isoform
  identity (ANT2 dominates adult liver) is not established.
• Lin & Lechleiter also detected CyPD-ANT binding PMID:12077116.
• Genetic ablation of Ant1+Ant2 in mouse liver shows ANTs are not essential for
  the pore but regulate it PMID:14749836.
• Rat ANT1 transgenic cardiomyocytes resist TGFb1-induced apoptosis and MPTP
  opening PMID:22564366 -- an overexpression phenotype.

Mitophagy

• ANT promotes PINK1/parkin mitophagy independent of nucleotide exchange, via
  TIM44 and inhibition of TIM23 PMID:31618756 (human
  cells and Ant1-/- mice).

Localization

• Mitochondrial inner membrane, multi-pass (UniProt by similarity to human).
  Rat kidney/testis fractionation used ANT as the IM marker and noted it also
  appears in OM fractions at contact sites PMID:18385140.

Expression studies (no mechanistic role)

• Postnatal rise in heart PMID:12676547, transient perinatal liver expression
  PMID:9468308, IL-1beta induction in brain PMID:15950780. These are
  expression correlations only.

Caveats on rat experimental rows

• The membrane-raft proteomics paper (PMID:14499952) is available only as an
  abstract that does not mention ANT. No other source places ANT1 in
  plasma-membrane rafts; detergent-resistant membrane preparations commonly
  co-purify abundant mitochondrial inner-membrane carriers, so the raft
  assignment cannot be verified here.
• Necroptosis: TNF-induced, RIP-dependent inhibition of ANT ADP import causes
  necrosis, and ectopic ANT prevents it PMID:16507998.