ALDH1L2

ALDH1L2 is a mitochondrial NADP+-dependent 10-formyltetrahydrofolate dehydrogenase that converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 while generating NADPH, functioning as a central node in mitochondrial folate metabolism and redox homeostasis (PMID:20498374). Full dehydrogenase activity requires 4'-phosphopantetheinyl transferase modification at Ser375, whereas the isolated C-terminal ALDH-homologous domain forms a tetramer and retains only esterase/hydrolase activity (PMID:21238436). The NADPH it produces sustains mitochondrial glutathione, which feeds cysteine and CoA biosynthesis to support fatty acid β-oxidation and ATP production; loss of ALDH1L2 in mice and in patient fibroblasts collapses this NADPH→GSH→CoA axis, causing hepatic lipid accumulation, distorted mitochondrial morphology, metabolite accumulation, and energy failure (PMID:31341639, PMID:33168096, PMID:38193334). Enzyme output is controlled post-translationally by acetylation at Lys70, which is reversed by SIRT3-mediated deacetylation to restore NADPH/GSH production (PMID:37507016), and transcriptionally by FOXO1 and NRF2, the latter forming a positive feedback loop by binding the ALDH1L2 promoter (PMID:38923573, PMID:39687603). By limiting ROS and one-carbon byproducts such as formate and formyl-methionine, ALDH1L2 restrains cell migration through formyl-peptide receptor signaling and metaplastic transformation (PMID:37245210, PMID:41922744), and through interactions with the TXN/TRX2-PRDX3 antioxidant network it modulates apoptosis, ferroptosis, and redox-dependent proliferation and chemoresistance across colorectal, glioblastoma, lung, renal, and prostate cancers (PMID:35597868, PMID:35565854, PMID:41764940, PMID:41766916). Compound heterozygous, homozygous missense, and other loss-of-function variants in ALDH1L2 cause a mitochondrial metabolic disorder rescued by re-expression of the functional enzyme (PMID:31341639, PMID:38193334).

1. 2010 High

   Established the basic identity and reaction of ALDH1L2 as a mitochondrial folate enzyme, answering where the protein acts and what chemistry it performs.

   Evidence GFP-fusion localization in COS-7/A549 cells and enzymatic assay of purified pig liver protein

   PMID:20498374

   Open questions at the time

   • Did not resolve cofactor/PTM requirements of the human enzyme
   • No structural model of the full-length protein
2. 2011 High

   Defined the post-translational and domain requirements for catalysis, showing the dehydrogenase reaction depends on phosphopantetheinylation at Ser375 while the C-terminal domain alone is only an esterase.

   Evidence Recombinant human protein, in vitro assays, Ser375 mutagenesis, and isolated domain characterization

   PMID:21238436

   Open questions at the time

   • Identity and regulation of the PPT enzyme acting on ALDH1L2 not established
   • No full-length structure
3. 2019 High

   Linked human ALDH1L2 loss to mitochondrial metabolic disease, establishing the enzyme as physiologically required for mitochondrial morphology and energetics.

   Evidence Compound-heterozygous patient fibroblasts with metabolomics, imaging, energy charge, and re-expression rescue

   PMID:31341639

   Open questions at the time

   • Did not pinpoint the biochemical step bridging enzyme loss and morphology defects
   • Single patient context
4. 2020 High

   Resolved the metabolic chain connecting ALDH1L2 activity to fat oxidation, defining the NADPH→GSH→cysteine→CoA→β-oxidation axis in vivo.

   Evidence Aldh1l2 knockout mice with liver histology, untargeted metabolomics, and folate pool measurement

   PMID:33168096

   Open questions at the time

   • Tissue-specific contributions beyond liver not dissected
   • Did not address regulation of the enzyme
5. 2020 Medium

   Implicated ALDH1L2 in protection against drug-induced mitochondrial injury, positioning it within nephroprotective redox responses.

   Evidence CRISPR knockout in renal tubular cells with UDCA/cisplatin injury models and RNA-seq

   PMID:32004633

   Open questions at the time

   • ALDH1L2 molecular role in UDCA signaling not reconstituted
   • Single lab
6. 2022 Medium

   Connected ALDH1L2 to antioxidant signaling partners and therapy resistance, showing a physical TXN interaction that tunes ROS-dependent apoptosis.

   Evidence Co-IP, colony/comet assays, flow cytometry, and xenografts in colorectal cancer; CRISPR KO with NADPH/ROS readouts in glioblastoma

   PMID:35565854 PMID:35597868

   Open questions at the time

   • TXN interaction lacks reciprocal/structural validation
   • Whether NF-κB and methionine-dependence effects are direct vs. downstream of NADPH unresolved
7. 2023 High

   Identified a reversible acetylation switch controlling enzyme output, establishing SIRT3-K70 as a regulatory axis exploited by 5-FU.

   Evidence K70Q mutagenesis, SIRT3–ALDH1L2 Co-IP, enzymatic and NADPH/GSH assays, and xenografts

   PMID:37507016

   Open questions at the time

   • Acetyltransferase responsible for K70 acetylation not identified
   • Stoichiometry of acetylation in normal tissues unknown
8. 2023 High

   Showed ALDH1L2 controls one-carbon byproduct levels that drive migration, linking formate/fMet accumulation to formyl-peptide receptor signaling and metastasis.

   Evidence Knockdown/overexpression in breast cancer, stable-isotope metabolomics, migration assays, and in vivo metastasis models

   PMID:37245210

   Open questions at the time

   • FPR receptor subtype and downstream effectors not fully mapped
   • Generality across non-breast tumors not tested here
9. 2024 Medium

   Extended disease evidence with a missense variant and added transcriptional/feedback regulators, framing ALDH1L2 within FOXO1- and NRF2-driven metabolic programs.

   Evidence Patient fibroblast enzyme assay (10-FDDF); FOXO1 luciferase/rescue; HCC NRF2 promoter binding and functional assays

   PMID:38193334 PMID:38923573 PMID:39687603

   Open questions at the time

   • Direct vs. indirect nature of NRF2/FOXO1 promoter occupancy needs orthogonal confirmation
   • IL-6/JAK2/STAT3 and macrophage effects mechanistically inferred
10. 2024 Medium

    Defined upstream microRNA control of ALDH1L2 and a role in fibrosis-related fibronectin homeostasis.

    Evidence miR-219a-5p target validation, ALDH1L2 knockdown, PAI-1/fibronectin measurement, UUO mouse model

    PMID:39295147

    Open questions at the time

    • Mechanistic link from GSH to PAI-1 not fully resolved
    • Single lab
11. 2025 Medium

    Identified NXPH4 as a stress-regulated mitochondrial binding partner, linking ALDH1L2 to metabolic reprogramming and antiandrogen resistance.

    Evidence Co-IP, fractionation/immunofluorescence, and gain/loss-of-function in prostate cancer xenografts

    PMID:41639054

    Open questions at the time

    • Functional consequence of NXPH4 binding on enzyme activity not measured
    • Interaction not structurally defined
12. 2026 High

    Consolidated ALDH1L2 as a ROS/ferroptosis gatekeeper across tissues, linking it to PRDX3 antioxidant defense, Akt/mTOR growth signaling, and suppression of metaplastic and tumor progression.

    Evidence TRX2-PRDX3 Co-IP with ferroptosis/cisplatin models (SCLC); siRNA with Akt/mTOR readouts (KIRC); Aldh1l2 genetic pancreatitis/PDAC mouse models with ROS/formate metabolomics

    PMID:41764940 PMID:41766916 PMID:41922744

    Open questions at the time

    • Whether PRDX3 redox effects are direct or NADPH-mediated unresolved
    • Causal hierarchy among ROS, formate, and signaling outputs not separated

• How ALDH1L2's enzymatic NADPH/formate output is mechanistically converted into its diverse protein-protein interactions (TXN, NXPH4, PRDX3) and signaling outcomes remains unresolved.
• No structure of full-length human ALDH1L2 or its complexes
• Direct vs. metabolite-mediated nature of partner interactions undefined
• Tissue-specific regulation by acetylation/transcription not integrated