SLC25A17

SLC25A17 (PMP34) is a peroxisomal integral membrane carrier of the mitochondrial solute carrier family that supplies the peroxisomal matrix with adenine-containing cofactors required for its metabolic reactions (PMID:9874197, PMID:12445829). Topologically it spans the membrane with both N- and C-termini facing the cytosol, and a basic loop between transmembrane segments 4 and 5, flanked by three essential hydrophobic segments, encodes its peroxisomal targeting and membrane-integration signal (PMID:11121399). Reconstituted in liposomes, the protein operates almost exclusively by saturable counter-exchange, importing CoA, FAD, and NAD+ (with AMP, FMN, PAP, and ADP as additional substrates) in exchange for intraperoxisomally generated metabolites, and is blocked by pyridoxal 5'-phosphate and other mitochondrial-carrier inhibitors (PMID:22185573). Its principal physiological cargo in vivo is CoA: zebrafish knockdown defects are rescued by CoA but not NAD+ (PMID:31187491), and knockout mice fail to degrade the branched-chain fatty acids phytanic and pristanic acid, accumulating their free acids and CoA esters in a partly PPARα-dependent manner (PMID:32266253). SLC25A17 also maintains peroxisomal redox homeostasis, since its inactivation shifts the glutathione couple toward a reductive state and perturbs peroxisomal NADPH metabolism (PMID:38159891). Its protein abundance is set by opposing post-translational inputs: PEX3 binds and stabilizes SLC25A17 to drive JAK2/STAT3 signaling and lipid accumulation (PMID:40885408), while the E3 ligase MARCH1 directly ubiquitinates it to promote degradation, influencing macrophage polarization and chemoresistance (PMID:41758657).

1. 1998 Medium

   Established that SLC25A17 is a bona fide peroxisomal membrane protein of the mitochondrial carrier family, raising the question of what it transports across the peroxisomal membrane.

   Evidence GFP fusion localization and co-localization with peroxisomal thiolase in HepG2 and fibroblasts, with altered pattern in PEX5-knockout cells

   PMID:9874197

   Open questions at the time

   • No transport substrate identified
   • Membrane topology not yet resolved
2. 2000 High

   Defined the protein's membrane topology and the topogenic signal directing it to peroxisomes, explaining how the carrier is correctly inserted and targeted.

   Evidence Differential permeabilization, epitope-tagged topology mapping, and deletion/alanine-substitution mutagenesis in HeLa and CHO-K1 cells

   PMID:11121399

   Open questions at the time

   • Does not identify the import machinery recognizing the loop signal
   • Transport function still unknown
3. 2002 High

   Provided the first direct functional evidence that SLC25A17 transports adenine nucleotides, addressing what the carrier actually moves.

   Evidence Complementation of yeast ANT1 deletion and in vitro transport assay of reconstituted purified PMP34 in proteoliposomes

   PMID:12445829

   Open questions at the time

   • Full substrate range and exchange mechanism not yet defined
   • Physiological substrate in mammals not established
4. 2012 High

   Expanded and refined the substrate spectrum and demonstrated a counter-exchange mechanism, defining how cofactors enter the peroxisome.

   Evidence Recombinant protein reconstitution into liposomes with transport kinetics and inhibitor profiling

   PMID:22185573

   Open questions at the time

   • In vitro substrate preference not yet validated as the in vivo physiological function
   • Counter-exchange partners inside peroxisome inferred, not directly measured in cells
5. 2019 Medium

   Identified CoA as the primary physiological cargo in a whole organism, resolving which substrate matters most in vivo.

   Evidence Zebrafish morpholino knockdown with lipid profiling and substrate-specific rescue (CoA but not NAD+)

   PMID:31187491

   Open questions at the time

   • Morpholino knockdown subject to off-target effects
   • Does not exclude additional roles for FAD/NAD+ transport
6. 2020 High

   Linked the carrier to a specific metabolic pathway, showing it is required for peroxisomal degradation of branched-chain fatty acids in mammals.

   Evidence Slc25a17 gene-trap knockout mice under dietary phytol with acyl-CoA, free fatty acid, bile acid, and PPARα pathway profiling

   PMID:32266253

   Open questions at the time

   • Why other peroxisomal pathways (VLCFA, plasmalogens, bile acids) are spared is unexplained
   • Mechanistic coupling between CoA import and SCPx-catalyzed cleavage not directly demonstrated
7. 2023 High

   Established a role in peroxisomal redox homeostasis, broadening the functional consequence of cofactor transport beyond fatty acid catabolism.

   Evidence CRISPR/genetic inactivation in three cell lines with redox sensor measurements, CbPmp47 rescue, and DEHA pharmacological dissection

   PMID:38159891

   Open questions at the time

   • Variable NADPH/NAD+ effects not fully resolved
   • Direct mechanistic link between altered cofactor import and glutathione redox shift not pinpointed
8. 2025 Medium

   Identified PEX3 as a stabilizer of SLC25A17 protein driving a JAK2/STAT3 lipid-accumulation axis, introducing upstream regulation and a disease-relevant signaling output.

   Evidence USF2 chromatin binding to PEX3 promoter, PEX3-SLC25A17 co-IP, overexpression/knockdown, and AG490 JAK2 inhibition in lung adenocarcinoma cells

   PMID:40885408

   Open questions at the time

   • Single Co-IP for PEX3-SLC25A17 without reciprocal validation
   • Mechanism linking SLC25A17 transport activity to JAK2/STAT3 activation unclear
9. 2026 Medium

   Identified MARCH1 as the E3 ligase that ubiquitinates and degrades SLC25A17, defining a post-translational control point with consequences for macrophage polarization and chemoresistance.

   Evidence Co-IP, in vitro ubiquitination assay, and rescue overexpression in lung adenocarcinoma with flow cytometry and ELISA readouts

   PMID:41758657

   Open questions at the time

   • Ubiquitination site(s) on SLC25A17 not mapped
   • Relationship between MARCH1-mediated degradation and PEX3 stabilization not integrated

• How cofactor import by SLC25A17 is mechanistically coupled to specific peroxisomal pathways (branched-chain fatty acid catabolism, glutathione/NADPH redox) and how its abundance is balanced by PEX3 stabilization versus MARCH1 degradation in physiological versus tumor contexts remain unresolved.
• No structural model of the transport cycle
• Counter-exchange partners not directly measured inside peroxisomes
• Interplay of opposing regulatory inputs on protein level not reconciled