Affinage

PPA2

Inorganic pyrophosphatase 2, mitochondrial · UniProt Q9H2U2

Length
334 aa
Mass
37.9 kDa
Annotated
2026-06-10
18 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPA2 is a mitochondrial inorganic pyrophosphatase whose hydrolysis of inorganic pyrophosphate is essential for mitochondrial energy transduction, maintenance of the inner-membrane electrical potential, and preservation of mitochondrial DNA (PMID:1648084, PMID:27523597, PMID:27523598). The enzyme carries a mitochondrial targeting leader sequence, and its activity is responsive to the energetic state of the organelle, being stimulated by uncoupling (PMID:1648084). Biallelic hypomorphic missense mutations reduce pyrophosphatase activity in patient mitochondria, and thermolabile loss of activity correlates with disease severity; these variants rapidly collapse the membrane potential and cannot rescue PPA2-null yeast, defining PPA2 deficiency as a cause of mitochondrial energy failure presenting as cardiomyopathy (PMID:27523597, PMID:27523598, PMID:34400813). Beyond its core metabolic role, PPA2 participates in mitochondrial dynamics and signaling: it interacts with the inner-membrane protein MTFP1 to drive DNM1L (Drp1) S616 phosphorylation and mitochondrial translocation, directing either MFF-dependent midzone fission for proliferation or FIS1-dependent peripheral fission and mitophagy under stress (PMID:40873007). PPA2 also acts as a protein phosphatase that dephosphorylates the E3 ligase NEDD4 at T758 to promote non-canonical ubiquitin-mediated degradation of HIF-1alpha, a function relieved under hypoxia by SIRT5-mediated desuccinylation of PPA2 at K176, which dissociates PPA2 from NEDD4 and stabilizes HIF-1alpha to promote glycolysis and metastasis (PMID:40164945). PPA2 transcription is regulated by Hippo-YAP signaling acting through the copper chaperone ATOX1, linking PPA2 expression to copper stress and ATP production (PMID:39706439).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1991 High

    Established the founding identity of PPA2 as a mitochondrial inorganic pyrophosphatase whose activity is required for respiratory growth and mitochondrial DNA maintenance, defining its core metabolic function.

    Evidence Gene cloning, disruption, and PPase activity assay with FCCP uncoupling in S. cerevisiae

    PMID:1648084

    Open questions at the time
    • Did not resolve how PPase activity mechanistically supports membrane potential or mtDNA maintenance
    • Yeast model only
  2. 1993 High

    Identified a fission yeast ppa2 as a type 2A-like protein phosphatase that negatively regulates mitotic entry, establishing a protein-phosphatase activity in the cdc2/wee1/cdc25 cell cycle pathway.

    Evidence Gene deletion/overexpression, genetic epistasis with cdc25-22 and wee1-50, okadaic acid sensitivity, microscopy in S. pombe

    PMID:8389306

    Open questions at the time
    • Relationship between this cytoplasmic phosphatase activity and the mitochondrial pyrophosphatase role unresolved
    • Direct substrates not identified
  3. 2000 Medium

    Placed fission yeast Ppa2 in the HIV-1 Vpr-induced G2/M arrest pathway, extending its cell-cycle checkpoint role to a virally-triggered context.

    Evidence Genetic analysis of Vpr-induced arrest in S. pombe deletion strains

    PMID:10684278

    Open questions at the time
    • Single morphological readout
    • Molecular mechanism linking Ppa2 to Vpr signaling not defined
  4. 2016 High

    Connected human PPA2 to Mendelian disease by demonstrating that biallelic missense mutations reduce pyrophosphatase activity and that wild-type but not mutant PPA2 sustains membrane potential, establishing PPA2 deficiency as a cause of mitochondrial energy failure.

    Evidence Whole-exome sequencing, PPase assays in patient fibroblast mitochondria, recombinant enzyme assays, and yeast complementation with membrane potential measurement

    PMID:27523597 PMID:27523598

    Open questions at the time
    • Did not explain tissue-specific cardiac vulnerability
    • Mechanism linking PPi accumulation to potential collapse not fully resolved
  5. 2021 Medium

    Refined the pathogenic mechanism by showing recombinant variants are thermolabile, indicating temperature-dependent loss of enzymatic activity underlies disease severity.

    Evidence Recombinant enzyme activity assays at multiple temperatures for 11 variants

    PMID:34400813

    Open questions at the time
    • In vitro thermolability not confirmed in vivo
    • Single lab
  6. 2024 Medium

    Identified upstream transcriptional control of PPA2 by Hippo-YAP signaling via the copper chaperone ATOX1, linking PPA2 expression to copper-stress adaptation and ATP production.

    Evidence Organoid/sheep pancreas copper-stress model, YAP manipulation, ATOX1-PPA2 promoter binding, ATP and membrane potential readouts

    PMID:39706439

    Open questions at the time
    • Promoter binding is indirect
    • Generality beyond copper stress unknown
    • Single lab
  7. 2025 High

    Revealed a protein-phosphatase signaling function for human PPA2: direct dephosphorylation of NEDD4 at T758 activates NEDD4 to degrade HIF-1alpha, with SIRT5 desuccinylation of PPA2 K176 acting as a hypoxia switch that releases NEDD4 and stabilizes HIF-1alpha.

    Evidence Co-IP, direct dephosphorylation assay on NEDD4 T758, SIRT5 desuccinylation assay, proteasomal degradation and metastasis readouts

    PMID:40164945

    Open questions at the time
    • How a mitochondrial pyrophosphatase accesses NEDD4 spatially not clarified
    • Structural basis of K176 succinylation regulation unknown
  8. 2025 Medium

    Defined a role for PPA2 in mitochondrial dynamics through MTFP1, showing PPA2 drives DNM1L activation to switch between MFF-dependent proliferative fission and FIS1-dependent mitophagic fission.

    Evidence Co-IP of PPA2-MTFP1, MTFP1 knockdown epistasis, CCCP mitophagy assay, DNM1L phosphorylation and live fission-site imaging

    PMID:40873007

    Open questions at the time
    • Whether fission control requires PPA2 catalytic activity not established
    • Direct phosphatase substrate in this pathway not identified
    • Single lab
  9. 2026 Medium

    Demonstrated in fission yeast that Ppa2 dephosphorylates the mitophagy receptor Atg43 at Ser32/35/36 to restrain excessive mitophagy, with the AAA-ATPase Yta4 competitively blocking the Atg43-Ppa2 interaction.

    Evidence Protein-protein interaction assays, phosphosite mutagenesis, competitive binding, and mitophagy assays in deletion strains

    PMID:41759732

    Open questions at the time
    • Conservation of Atg43 dephosphorylation in mammals not tested
    • Single lab, yeast model

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how PPA2's enzymatic pyrophosphatase activity and its protein-phosphatase signaling functions (NEDD4, mitochondrial fission, mitophagy receptors) are mechanistically integrated within a single protein and whether these activities share or use distinct catalytic mechanisms.
  • No structural model reconciling pyrophosphatase and protein-phosphatase activities
  • Spatial coordination of mitochondrial and cytosolic/signaling roles undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-9612973 Autophagy 2
Partners
ATG43ATOX1DNM1LMTFP1NEDD4SIRT5YTA4

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 PPA2 encodes a mitochondrial inorganic pyrophosphatase (PPase) in S. cerevisiae. The protein carries a mitochondrial leader sequence enriched in basic and hydroxylated residues. Overproduction caused a 47-fold increase in mitochondrial PPase activity, which was further stimulated 3-fold by the uncoupler FCCP, suggesting energy-linked activity. Gene disruption showed PPA2 is required for growth on respiratory carbon sources and for maintenance of mitochondrial DNA. Gene cloning, gene disruption, PPase activity assay, FCCP uncoupler treatment, fluorescence microscopy for mitochondrial DNA The Journal of biological chemistry High 1648084
1993 Fission yeast ppa2+ encodes a type 2A-like protein phosphatase that negatively regulates entry into mitosis, likely through regulation of cdc2 tyrosine phosphorylation. Genetic epistasis showed ppa2 deletion is lethal with wee1-50 and partially suppresses cdc25-22 lethality, placing ppa2 in the cdc2/wee1/cdc25 cell cycle regulatory pathway. Ppa2 protein is abundant in the cytoplasm, and overproduction leads to accumulation near the nuclear periphery and interphase arrest. ppa2 deletion produces hyperphosphorylated proteins similar to okadaic acid treatment, and ppa2 is the genetic locus controlling okadaic acid sensitivity. Gene deletion and overexpression, genetic epistasis with cdc25-22 and wee1-50 mutants, okadaic acid treatment, subcellular localization by fluorescence microscopy, protein phosphorylation analysis Genes & development High 8389306
2000 Fission yeast ppa2 is required for HIV-1 Vpr-induced G2/M cell cycle arrest. Deletion of ppa2 (Δppa2) abolished the elongated cdc phenotype caused by Vpr expression, placing Ppa2 in the pathway by which Vpr activates the G2/M checkpoint, upstream of or parallel to Wee1 and Rad24. Genetic analysis of Vpr-induced cell cycle arrest in S. pombe deletion strains, cell morphology assay Journal of virology Medium 10684278
2016 Human PPA2 functions as a mitochondrial inorganic pyrophosphatase whose activity is essential for mitochondrial function. Biallelic missense mutations in PPA2 significantly reduce inorganic pyrophosphatase activity in patient fibroblast mitochondria. Recombinant mutant PPA2 enzymes modeling hypomorphic missense mutations have decreased enzymatic activity that correlates with disease severity. Whole-exome sequencing, inorganic pyrophosphatase activity assay in patient fibroblast mitochondria, recombinant enzyme activity assays American journal of human genetics High 27523597
2016 Human PPA2 is essential for mitochondrial function: wild-type human PPA2, but not PPA2 containing patient-identified mutations, rescues mitochondrial function in ppa2Δ yeast. Pathogenic PPA2 mutations rapidly inactivate the mitochondrial energy transducing system and prevent maintenance of sufficient electrical potential across the inner membrane, leading to subsequent loss of mitochondria. Yeast complementation assay with wild-type vs. mutant human PPA2, doxycycline-repressible gene expression system, mitochondrial membrane potential measurement American journal of human genetics High 27523598
2021 Eleven novel PPA2 missense variants show significantly decreased recombinant enzyme activity compared to wild-type PPA2, and the enzymatic activity is sensitive to temperature, consistent with thermolability as a pathogenic mechanism. Recombinant enzyme activity assays at multiple temperatures for 11 variants Genetics in medicine Medium 34400813
2024 Hippo-YAP signaling regulates PPA2 transcription through the copper chaperone ATOX1: YAP interacts with TEAD to upregulate ATOX1, which then binds indirectly to the PPA2 promoter and increases its transcription. PPA2 overexpression restores mitochondrial ATP production under copper stress, which facilitates intracellular copper efflux. Organoid and sheep pancreas model of copper stress, YAP overexpression/inhibition, ATOX1-PPA2 promoter binding assay, ATP production and mitochondrial membrane potential measurement International journal of biological macromolecules Medium 39706439
2025 PPA2 suppresses HIF-1alpha stability through non-canonical ubiquitin-mediated proteasomal degradation by recruiting E3 ligase NEDD4 and directly dephosphorylating NEDD4 at threonine 758, resulting in NEDD4 activation. Under hypoxia, SIRT5 desuccinylates PPA2 at lysine 176, promoting dissociation of PPA2 from NEDD4 and thereby stabilizing HIF-1alpha, promoting glycolysis and tumor metastasis. Co-immunoprecipitation, phosphatase activity assay (direct dephosphorylation of NEDD4 T758 by PPA2), SIRT5 desuccinylation assay, proteasomal degradation assay, loss-of-function with metastasis readout The EMBO journal High 40164945
2025 PPA2 activates mitochondrial fission signaling by interacting with MTFP1 (inner mitochondrial membrane protein) to induce DNM1L S616 phosphorylation and mitochondrial translocation. In physiological conditions, PPA2 directs midzone fission through MFF-DNM1L leading to mitochondrial proliferation; during mitochondrial stress (CCCP), PPA2 triggers peripheral fission through FIS1-DNM1L for mitophagy. PPA2 uses the C-terminal LIR motif of MTFP1 for mitophagy-mediated clearance of damaged mitochondria. Knockdown of MTFP1 in PPA2-overexpressing cells abolishes DNM1L activation and fission. Co-immunoprecipitation (PPA2-MTFP1 interaction), PPA2 overexpression/knockdown, MTFP1 knockdown epistasis, CCCP-induced mitophagy assay, DNM1L phosphorylation assay, live imaging of mitochondrial fission site Autophagy Medium 40873007
2026 In fission yeast, the phosphatase Ppa2 dephosphorylates the mitophagy receptor Atg43 at Ser32, Ser35, and Ser36, inhibiting excessive mitophagy. The AAA-ATPase Yta4 physically interacts with both Atg43 and Ppa2, binding to the same cytosolic region of Atg43, and inhibits the Atg43-Ppa2 interaction to promote Atg43 phosphorylation and mitophagy. Physical interaction assay (Yta4-Atg43, Yta4-Ppa2, Atg43-Ppa2 binding), phosphorylation site mutagenesis (Ser32/35/36), mitophagy assay in deletion strains, competitive binding assay The Journal of biological chemistry Medium 41759732

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 Yeast PPA2 gene encodes a mitochondrial inorganic pyrophosphatase that is essential for mitochondrial function. The Journal of biological chemistry 152 1648084
1993 Negative regulation of mitosis by the fission yeast protein phosphatase ppa2. Genes & development 124 8389306
2000 Genetic studies with the fission yeast Schizosaccharomyces pombe suggest involvement of wee1, ppa2, and rad24 in induction of cell cycle arrest by human immunodeficiency virus type 1 Vpr. Journal of virology 66 10684278
2016 Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2. American journal of human genetics 57 27523597
2016 Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy. American journal of human genetics 49 27523598
2021 PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families. Genetics in medicine : official journal of the American College of Medical Genetics 21 34400813
2019 Characterization of long living yeast deletion mutants that lack mitochondrial metabolism genes DSS1, PPA2 and AFG3. Gene 10 31082499
2024 Hippo-YAP signaling alleviates copper-induced mitochondrial dysfunction and oxidative damage via the ATOX1-PPA2 pathway. International journal of biological macromolecules 8 39706439
2023 Only one beer can be mortal: a case report of two sisters with cardiac arrest due to a homozygous mutation in PPA2 gene. European journal of pediatrics 8 37269378
2024 Sudden cardiac death triggered by minimal alcohol consumption in the context of novel PPA2 mutations in 2 unrelated families. Gene 7 38582264
2025 SIRT5-mediated desuccinylation of PPA2 enhances HIF-1alpha-dependent adaptation to hypoxic stress and colorectal cancer metastasis. The EMBO journal 6 40164945
1999 DNA sequencing and analysis of a 67.4 kb region from the right arm of Schizosaccharomyces pombe chromosome II reveals 28 open reading frames including the genes his5, pol5, ppa2, rip1, rpb8 and skb1. Yeast (Chichester, England) 5 10407269
2025 PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy. Autophagy 4 40873007
2023 Alcohol-Induced Sudden Cardiac Death in a Teenager With PPA2 Gene Mutations. The American journal of forensic medicine and pathology 4 37249496
2021 Long-read sequencing identified a novel nonsense and a de novo missense of PPA2 in trans in a Chinese patient with autosomal recessive infantile sudden cardiac failure. Clinica chimica acta; international journal of clinical chemistry 4 33826954
2025 PPA2-associated cardiac arrest survivor. Cardiology in the young 1 39882621
2026 The AAA-ATPase Yta4 inhibits the interaction between Ppa2 and Atg43 to promote Atg43 phosphorylation and mitophagy. The Journal of biological chemistry 0 41759732
2025 Nonischemic Cardiomyopathy in Adult-Onset PPA2-Deficient Mitochondrial Disease. JACC. Case reports 0 40846385

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