Affinage

ATP5PO

ATP synthase peripheral stalk subunit OSCP, mitochondrial · UniProt P48047

Length
213 aa
Mass
23.3 kDa
Annotated
2026-06-09
15 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP5PO encodes the oligomycin sensitivity-conferring protein (OSCP), a structural component of the peripheral stalk that links the F1 and F0 domains of the mitochondrial F1F0-ATP synthase (complex V), expressed ubiquitously but most strongly in muscle and heart (PMID:7490082). Its function is required for proper complex V assembly and activity: a homozygous splice variant (c.87+3A>G) causing skipping of exon 2 reduces ATP5PO protein, destabilizes the peripheral stalk, and lowers complex V hydrolytic activity, and the exon-2-deleted protein fails to complement a yeast OSCP-null strain, establishing exon 2 as essential for function (PMID:35621276, PMID:40913360). This loss of function underlies a mitochondrial disorder presenting as Leigh-like disease in affected patients (PMID:35621276, PMID:40913360). ATP5PO activity is tuned by post-translational modification: SIRT3 binds and deacetylates ATP5PO at K162 in cardiomyocytes to limit mitochondrial damage (PMID:41233904), and HDAC2-regulated crotonylation at K51 controls ATP5PO protein stability and downstream phospholipid metabolism under chronic stress (PMID:38645677). Balanced ATP5PO expression is also required for enteric nervous system development, where it acts genetically in the RET pathway, with both loss and overexpression compromising neuronal differentiation and mitochondrial ATP production (PMID:38128843).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1995 Medium

    Established the molecular identity of ATP5PO as the OSCP stalk subunit of mitochondrial ATP synthase, defining its place in complex V.

    Evidence Exon trapping, cDNA cloning, sequence analysis and chromosomal mapping of the human gene

    PMID:7490082

    Open questions at the time
    • No functional reconstitution of the protein in the synthase
    • Tissue expression described but not linked to phenotype
    • No structural placement within the assembled complex shown directly
  2. 2022 High

    Demonstrated that ATP5PO loss of function impairs complex V assembly and activity, linking the gene to human mitochondrial disease.

    Evidence Patient fibroblast biochemistry (assembly, hydrolytic activity) and yeast complementation of an OSCP-null strain across two families

    PMID:35621276

    Open questions at the time
    • Mechanism by which stalk loss destabilizes the whole complex not resolved at structural level
    • Tissue-specific disease manifestation not fully explained
  3. 2022 Medium

    Placed ATP5PO downstream of CLDN10 in a pathway regulating mitochondrial function and tumor suppression, implicating its acetylation state.

    Evidence CLDN10 gain-of-function with ATP5O knockdown rescue, mitochondrial readouts, and orthotopic mouse model in ccRCC

    PMID:35414767

    Open questions at the time
    • Acetylation sites and writers/erasers not identified here
    • Direct CLDN10–ATP5PO molecular relationship unestablished
    • Single lab, single cancer context
  4. 2022 Medium

    Identified K51 crotonylation as a stress-responsive modification controlling ATP5PO stability and phospholipid metabolism via HDAC2.

    Evidence Quantitative PTM/phospho/metabolomics with site-specific PTM mapping and genetic correction of HDAC2 phosphorylation in mouse

    PMID:38645677

    Open questions at the time
    • Direct enzymatic decrotonylation of ATP5PO by HDAC2 not reconstituted
    • Mechanism linking crotonylation to phospholipid metabolism unclear
    • Single lab
  5. 2023 Medium

    Revealed a non-canonical role for ATP5PO in enteric nervous system development within the RET pathway, where dosage is critical.

    Evidence Zebrafish overexpression ENS quantification, neuroblastoma differentiation/ATP assays, and genetic epistasis with ret

    PMID:38128843

    Open questions at the time
    • Molecular basis of the paradoxical protein decrease upon overexpression unknown
    • Direct biochemical link between ATP5PO and RET signaling not defined
    • Human ENS relevance inferred from model systems
  6. 2025 High

    Established SIRT3 as a writer and K162 as a functional acetylation site governing ATP5PO-dependent mitochondrial protection in the heart.

    Evidence Co-IP, LC-MS/MS site mapping, acetylation mimic mutants, MST/SPR/ITC binding, and AAV9 SIRT3 overexpression / ATP5O knockout mouse models in DCM

    PMID:41233904

    Open questions at the time
    • How K162 acetylation alters complex V function structurally not resolved
    • Interplay between K162 acetylation and K51 crotonylation not examined
    • Cardiac-focused; generality to other tissues untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple PTMs (K162 acetylation, K51 crotonylation) integrate to control complex V assembly and the non-OSCP role of ATP5PO in RET-dependent ENS development remains unresolved.
  • No unified structural model of how stalk modifications affect synthase activity
  • Mechanism linking mitochondrial ATP5PO to RET signaling unknown
  • Cross-talk among PTM sites uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 2
Partners
HDAC2SIRT3
Complex memberships
mitochondrial ATP synthase (complex V)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 ATP5PO (OSCP subunit) was cloned and identified as a key structural component of the stalk of the mitochondrial F1F0-ATP synthase, encoded on chromosome 21q22.1-q22.2, with >80% amino acid identity to bovine and murine OSCP subunits, and expressed in all human tissues, most strongly in muscle and heart. Exon trapping, cDNA cloning, sequence analysis, chromosomal mapping to YAC contigs Genomics Medium 7490082
2022 A homozygous splice variant (c.87+3A>G) in ATP5PO causing skipping of exon 2 results in decreased ATP5PO protein, defective complex V assembly with markedly reduced peripheral stalk proteins, and reduced complex V hydrolytic activity in patient fibroblasts; expression of the exon-2-deleted human ATP5PO in yeast deleted for its homolog (yATP5) failed to rescue oxidative phosphorylation-dependent growth, demonstrating that exon 2 is required for protein function. cDNA splicing analysis, fibroblast biochemical assays (complex V assembly, hydrolytic activity), yeast complementation assay Journal of inherited metabolic disease High 35621276
2022 CLDN10 overexpression upregulates acetylation and expression levels of ATP5PO (ATP5O), leading to mitochondrial dysfunction with increased ROS, increased NDUFS2/SDHB/Cleaved-Caspase 3/E-cadherin, and decreased mitochondrial membrane potential; knockdown of ATP5O in CLDN10-overexpressing cells reverses these effects, placing ATP5O downstream of CLDN10 in regulating mitochondrial function and suppressing ccRCC growth and metastasis. Gain-of-function (CLDN10 overexpression), loss-of-function (ATP5O knockdown), Western blotting, ROS measurement, mitochondrial membrane potential assay, orthotopic mouse model International journal of biological sciences Medium 35414767
2022 Under chronic stress, ATP5O K51 crotonylation is decreased due to HDAC2 hyperphosphorylation at S424 (which enhances HDAC2 decrotonylation activity); this reduction in ATP5O crotonylation causes decreased gross ATP5O protein levels and downregulated phospholipid metabolism. Correcting HDAC2 hyperphosphorylation restored ATP5O levels and partially rescued phospholipid metabolism. Quantitative PTM-omics, phospho-omics, metabolomics, site-specific PTM analysis, genetic correction of HDAC2 phosphorylation in mouse model Research (Washington, D.C.) Medium 38645677
2023 ATP5PO overexpression in zebrafish caused a significant reduction in enteric nervous system (ENS) cells; in vitro, overexpression paradoxically reduced ATP5PO protein levels, impaired neuronal differentiation, and reduced mitochondrial ATP production in a neuroblastoma cell line. Genetic epistasis was demonstrated between ATP5PO and ret (the principal Hirschsprung disease gene), establishing ATP5PO as a regulator of ENS development acting in the same pathway as RET. Zebrafish overexpression screen (ENS cell quantification), in vitro overexpression in neuroblastoma cells (ATP production assay, differentiation assay), genetic epistasis analysis with ret Biochimica et biophysica acta. Molecular basis of disease Medium 38128843
2025 SIRT3 deacetylates ATP5O at the K162 site in primary mouse cardiomyocytes; deacetylation mimics decreased mitochondrial damage while acetylation mimics promoted mitochondrial damage. CVB-D upregulates SIRT3 expression, which increases ATP5O acetylation (at K162) and enhances mitochondrial function. ATP5O knockout inhibited the protective effects of SIRT3 overexpression in DCM, establishing SIRT3 as a writer and K162 as a functional acetylation site on ATP5O. Co-immunoprecipitation, LC-MS/MS acetylation site mapping, acetylation/deacetylation mimic plasmid transfection, MST/SPR/ITC binding assays, AAV9-mediated SIRT3 overexpression and ATP5O knockout mouse models Chinese medicine High 41233904
2025 A homozygous splice variant (c.87+3A>G) in ATP5PO in a patient caused approximately 35% of normal ATPase enzyme activity in fibroblasts (relative to citrate synthase), providing functional evidence that ATP5PO is required for complex V assembly and function. Fibroblast mitochondrial respiratory chain enzyme activity assay, whole-exome sequencing American journal of medical genetics. Part A Medium 40913360

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Competitive antagonism of AMPA receptors by ligands of different classes: crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX. Journal of medicinal chemistry 84 12519060
1998 Mitochondrial ATP synthesis in permeabilized cells: assessment of the ATP/O values in situ. Analytical biochemistry 62 9799528
1995 ATPo but not cAMPi activates a chloride conductance in mouse ventricular myocytes. Cardiovascular research 34 7540110
2022 Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction. International journal of biological sciences 22 35414767
2009 Genetic variation in ATP5O is associated with skeletal muscle ATP50 mRNA expression and glucose uptake in young twins. PloS one 22 19274082
1995 Cloning of the cDNA for the human ATP synthase OSCP subunit (ATP5O) by exon trapping and mapping to chromosome 21q22.1-q22.2. Genomics 22 7490082
2022 A homozygous splice variant in ATP5PO, disrupts mitochondrial complex V function and causes Leigh syndrome in two unrelated families. Journal of inherited metabolic disease 12 35621276
2022 ATP5O Hypo-crotonylation Caused by HDAC2 Hyper-Phosphorylation Is a Primary Detrimental Factor for Downregulated Phospholipid Metabolism under Chronic Stress. Research (Washington, D.C.) 7 38645677
2021 Proteomic Analysis Identifies NDUFS1 and ATP5O as Novel Markers for Survival Outcome in Prostate Cancer. Cancers 5 34885151
2023 ATP5PO levels regulate enteric nervous system development in zebrafish, linking Hirschsprung disease to Down Syndrome. Biochimica et biophysica acta. Molecular basis of disease 4 38128843
2021 Dynamic calculation of ATP/O ratios measured using Magnesium Green (MgGr)™. MethodsX 3 34754791
1998 Studies of the antagonist actions of (RS)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl] propionic acid (ATPO) on non-NMDA receptors in cultured rat neurones. British journal of pharmacology 3 9884081
2025 Cyclovirobuxine D ameliorates cardiomyocyte senescence in diabetic cardiomyopathy mice by enhancing mitochondrial function via sirtuin 3-ATP5O signal axis. Chinese medicine 1 41233904
2024 Evaluation of Anti-Thyroperoxidase (A-TPO) and Anti-Thyroglobulin (A-Tg) Antibodies in Women with Previous Hashimoto's Thyroiditis during and after Pregnancy. Journal of clinical medicine 1 39124785
2025 Mitochondrial Complex V Deficiency Caused by a Homozygous Splice Variant in ATP5PO. American journal of medical genetics. Part A 0 40913360

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