Affinage

MPV17L

Mpv17-like protein · UniProt Q2QL34

Length
196 aa
Mass
22.1 kDa
Annotated
2026-06-10
21 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

MPV17L (M-LP/M-LPH) is a mitochondrially-enriched protein that protects cells from oxidative stress and safeguards mitochondrial DNA integrity (PMID:22306510, PMID:30310528). It functions as an atypical cyclic nucleotide phosphodiesterase: in vitro-synthesized protein hydrolyzes cyclic nucleotides in an IBMX-inhibitable manner, and its loss raises mitochondrial cAMP and enhances PKA-dependent phosphorylation of matrix proteins, including TFAM (PMID:32621840). Through this restraint of mitochondrial cAMP/PKA signaling, MPV17L maintains the levels of TFAM, OGG1, and LIG3 — proteins required for mtDNA stability and base excision repair — so that its knockout increases mtDNA damage and reduces mtDNA-encoded gene expression (PMID:26165189, PMID:30310528). MPV17L also directly binds the serine protease HtrA2 via a PDZ-mediated interaction and activates its protease activity, thereby suppressing mitochondrial superoxide generation, stabilizing membrane potential, and preventing apoptosis (PMID:18772386). In vivo, loss of M-LP/Mpv17L in mice de-represses Wnt/β-catenin and TGF-β signaling downstream of PKA, producing β-cell hyperplasia with improved glucose tolerance and physiological cardiac hypertrophy (PMID:34883249, PMID:37851308). Although the protein is enriched in mitochondria, it also localizes to peroxisomes and the nucleus, consistent with a broader role in reactive oxygen species metabolism (PMID:16631601, PMID:26165189).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2006 Medium

    Established the first cellular context for MPV17L by placing it in peroxisomes and linking it to ROS-handling gene expression, framing it as a redox-relevant protein.

    Evidence GFP-fusion confocal co-localization with peroxisomal markers and mRNA analysis of ROS enzymes in COS-7 cells

    PMID:16631601

    Open questions at the time
    • Does not establish a direct enzymatic activity
    • Peroxisomal localization later contrasted with predominantly mitochondrial/nuclear localization
    • Mechanism by which transfection alters glutathione peroxidase/catalase expression unresolved
  2. 2008 High

    Identified a direct molecular partner and effector mechanism, showing MPV17L binds and activates the protease HtrA2 to constrain superoxide and apoptosis.

    Evidence Co-IP and direct interaction assays plus superoxide, membrane potential, and apoptosis readouts in mitochondria; PDZ-mediated binding characterized

    PMID:18772386

    Open questions at the time
    • How HtrA2 activation suppresses superoxide mechanistically not defined
    • Relationship between HtrA2 activation and later-defined PDE activity unknown
  3. 2012 Medium

    Demonstrated bidirectional control of oxidative stress resistance through gain- and loss-of-function, and identified the transcriptional repressor RhitH/ZNF205 controlling M-LPH levels.

    Evidence siRNA knockdown of RhitH, M-LPH overexpression, H2O2 and membrane potential assays under antimycin A challenge

    PMID:22306510

    Open questions at the time
    • Does not define the molecular basis of ROS protection
    • Upstream regulation by RhitH not connected to physiological signals
  4. 2015 High

    Refined localization to predominantly nuclear with a mitochondrial nucleoid-associated pool and connected MPV17L to mtDNA maintenance, identifying new binding partners.

    Evidence Co-IP partner identification, subcellular fractionation, immunofluorescence co-localization with TFAM/mtDNA, RNAi with mtDNA damage and POLG/LIG3 localization readouts

    PMID:26165189

    Open questions at the time
    • Functional significance of H2AX, RPS14, RPS3, Bap31 interactions not mechanistically resolved
    • How a predominantly nuclear protein controls mitochondrial protein localization unexplained
  5. 2018 High

    Used genetic knockout to establish that MPV17L preserves mtDNA integrity by maintaining levels of TFAM, OGG1, and LIG3, key mtDNA stability and repair factors.

    Evidence CRISPR-Cas9 knockout in HepG2 cells with mtDNA damage quantitation, 8-OHdG, immunofluorescence, and Western blot of mitochondrial fractions

    PMID:30310528

    Open questions at the time
    • Mechanism by which MPV17L loss lowers these protein levels not yet defined (resolved later via PKA)
    • Whether effect is transcriptional, translational, or degradative not distinguished here
  6. 2020 High

    Provided the core molecular mechanism: MPV17L is an atypical phosphodiesterase whose loss raises mitochondrial cAMP and drives PKA-dependent phosphorylation of TFAM and other matrix proteins.

    Evidence CRISPR KO with cAMP measurement, PDE activity assay on in vitro-synthesized protein with IBMX inhibition, phosphorylation Western blots

    PMID:32621840

    Open questions at the time
    • Catalytic residues and structural basis of the atypical PDE activity undefined
    • Substrate specificity (cAMP vs cGMP) not fully characterized
    • Link from PKA phosphorylation to reduced TFAM/OGG1/LIG3 stability not fully mapped
  7. 2021 Medium

    Extended the PDE/PKA mechanism to a whole-organism phenotype, showing MPV17L loss activates Wnt/β-catenin and TGF-β signaling to produce β-cell hyperplasia and improved glucose tolerance.

    Evidence Knockout mice and siRNA in rat insulinoma cells, glucose tolerance tests, qRT-PCR of Lef1/Tcf7, Western blot of phospho-β-catenin and phospho-GSK-3β

    PMID:34883249

    Open questions at the time
    • Direct mechanistic link from PKA to Wnt/TGF-β activation not fully defined
    • Tissue-specific contribution versus systemic effects not separated
  8. 2023 Medium

    Showed the same cAMP/PKA-driven signaling axis manifests in heart as physiological cardiac hypertrophy, broadening the in vivo phenotypic spectrum.

    Evidence Knockout mice with cardiomyocyte morphometry, hypertrophic and Wnt target gene qRT-PCR, Western blot of phospho-β-catenin/RyR2/PLN/cTnI and MEK1-ERK1/2

    PMID:37851308

    Open questions at the time
    • Causal chain from PDE loss to specific cardiac signaling not directly tested
    • Why hypertrophy is physiological (no fibrosis/dysfunction) unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural and catalytic basis of the atypical PDE activity and how a predominantly nuclear protein coordinates mitochondrial cAMP/PKA signaling and mtDNA maintenance remain unresolved.
  • No structure or defined catalytic mechanism for the PDE activity
  • Mechanism connecting nuclear localization to mitochondrial/peroxisomal functions unknown
  • No reported human disease link via causative mutation in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 1 GO:0098772 molecular function regulator activity 1 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005739 mitochondrion 3 GO:0005634 nucleus 1 GO:0005777 peroxisome 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-73894 DNA Repair 1 R-HSA-8953897 Cellular responses to stimuli 1
Partners
BCAP31H2AXHTRA2RPS14RPS3TFAM

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Mpv17l directly interacts with the serine protease HtrA2 in mitochondria via a PDZ domain, inducing protease activation of HtrA2, which in turn inhibits mitochondrial superoxide generation, stabilizes mitochondrial membrane potential, and prevents apoptosis at baseline and in response to extracellular inducers of mitochondrial stress. Co-immunoprecipitation, direct interaction assays, mitochondrial functional assays (superoxide measurement, membrane potential), apoptosis assays; PDZ domain-mediated interaction characterized Proceedings of the National Academy of Sciences of the United States of America High 18772386
2006 Human M-LPH1 (MPV17L) protein is localized in peroxisomes, as demonstrated by dual-color confocal analysis with GFP-tagged M-LPH1 in transfected COS-7 cells. Transfection with M-LPH1 down-regulates expression of plasma glutathione peroxidase and catalase genes, indicating a role in reactive oxygen species metabolism. GFP fusion protein confocal co-localization with peroxisomal markers; mRNA expression analysis of ROS-related enzymes after transfection Biochemical and biophysical research communications Medium 16631601
2012 Knockdown of human RhitH (zinc-finger protein 205, the transcriptional repressor of M-LPH) or overexpression of M-LPH reduces intracellular H2O2 generation and loss of mitochondrial membrane potential caused by antimycin A (a respiratory chain inhibitor), demonstrating M-LPH protects cells from oxidative stress and mitochondrial apoptotic cascade. siRNA knockdown, overexpression, H2O2 measurement, mitochondrial membrane potential assay Free radical biology & medicine Medium 22306510
2015 M-LPH (MPV17L) interacts with H2AX, RPS14, RPS3, and Bap31 as binding partners. Subcellular fractionation and immunofluorescence revealed M-LPH localizes predominantly in the nucleus, partially in a subset of mitochondria (co-localizing with TFAM and mtDNA in nucleoid-like foci), and marginally in the cytosol. RNAi-mediated knockdown of M-LPH increased mtDNA damage, reduced mtDNA-encoded gene expression, and impaired mitochondrial localization of POLG and DNA ligase III (LIG3) upon oxidative stress. Co-immunoprecipitation to identify binding partners, immunofluorescence, subcellular fractionation, RNAi knockdown, mtDNA damage quantification, qRT-PCR Free radical biology & medicine High 26165189
2018 CRISPR-Cas9 knockout of M-LPH in HepG2 cells increased mtDNA damage (quantified by PCR and 8-OHdG) and reduced protein levels of TFAM, OGG1, and LIG3 in mitochondria, indicating M-LPH maintains mtDNA integrity by protecting proteins essential for mtDNA stability and base excision repair. CRISPR-Cas9 knockout, PCR-based mtDNA damage quantitation, 8-OHdG measurement, confocal immunofluorescence, Western blot of mitochondrial fractions Oxidative medicine and cellular longevity High 30310528
2020 M-LPH knockout in HepG2 cells caused increased mitochondrial cAMP levels and reduced total cellular cyclic nucleotide phosphodiesterase (PDE) activity. In vitro-synthesized M-LPH exhibited PDE activity inhibitable by IBMX. M-LPH-KO also promoted PKA-dependent phosphorylation of mitochondrial proteins, including TFAM, linking M-LPH to cAMP/PKA signaling in the mitochondrial matrix as an atypical PDE. CRISPR-Cas9 KO, cAMP measurement, PDE activity assay with in vitro-synthesized protein, IBMX inhibition, phosphorylation analysis by Western blot Biochimica et biophysica acta. Molecular cell research High 32621840
2021 M-LP/Mpv17L-KO mice developed β-cell hyperplasia and improved glucose tolerance. In islets from KO mice and siRNA-treated rat insulinoma cells, Lef1 and Tcf7 (Wnt pathway effectors) were markedly upregulated, and phosphorylation of β-catenin and GSK-3β increased, indicating activation of Wnt and TGF-β signaling pathways downstream of PKA, triggered by loss of M-LP/Mpv17L PDE activity. Knockout mice, siRNA knockdown, glucose tolerance tests, qRT-PCR, Western blot for phospho-β-catenin and phospho-GSK-3β Biochimica et biophysica acta. Molecular basis of disease Medium 34883249
2023 M-LP/Mpv17L-KO mice developed physiological afferent cardiac hypertrophy with increased cardiomyocyte diameter and cross-sectional area, upregulation of hypertrophic marker genes (BNP, ACTC1, ACTA1) and Wnt/β-catenin target genes, and increased phosphorylation of downstream cAMP/PKA pathway molecules (β-catenin, RyR2, PLN, cTnI) and MEK1-ERK1/2 pathway members, without fibrosis or cardiac dysfunction. Knockout mice, histology, cardiomyocyte morphometry, qRT-PCR, Western blot for phosphorylated signaling proteins Transgenic research Medium 37851308
2012 miR-21 directly represses Mpv17l expression (a mitochondrial inhibitor of ROS generation) in the kidney, correlating with enhanced oxidative kidney damage; loss of miR-21 de-represses Mpv17l. miRNA target analysis and miR-21 knockout mouse model with gene expression profiling; correlation of Mpv17l expression with kidney injury Science translational medicine Low 22344686
2009 The mouse Mpv17l gene encodes two isoforms, M-LPL (ubiquitously expressed) and M-LPS (expressed mostly in aged kidney), both of which regulate ROS production and protect against mitochondrial oxidative stress and apoptosis. A novel predicted isoform, M-LP2, with distinct expression pattern from M-LPS, was identified but not detected in the human genome. EST mapping, expression analysis (RT-PCR), evolutionary conservation analysis Genome Low 19935920

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Science translational medicine 467 22344686
2016 Mitochondrial Pathology and Glycolytic Shift during Proximal Tubule Atrophy after Ischemic AKI. Journal of the American Society of Nephrology : JASN 294 27000065
2008 Mpv17l protects against mitochondrial oxidative stress and apoptosis by activation of Omi/HtrA2 protease. Proceedings of the National Academy of Sciences of the United States of America 78 18772386
2019 Methylation and transcriptome analysis reveal lung adenocarcinoma-specific diagnostic biomarkers. Journal of translational medicine 63 31558162
2006 Human Mpv17-like protein is localized in peroxisomes and regulates expression of antioxidant enzymes. Biochemical and biophysical research communications 33 16631601
1992 Maturation of human lactase-phlorizin hydrolase. Proteolytic cleavage of precursor occurs after passage through the Golgi complex. FEBS letters 32 1446748
2021 Epigenome-wide association study on asthma and chronic obstructive pulmonary disease overlap reveals aberrant DNA methylations related to clinical phenotypes. Scientific reports 25 33658578
1992 Proteolytic processing of human intestinal lactase-phlorizin hydrolase precursor is not a prerequisite for correct sorting in Madin Darby canine kidney (MDCK) cells. FEBS letters 20 1468552
2022 Identification of Novel Key Molecular Signatures in the Pathogenesis of Experimental Diabetic Kidney Disease. Frontiers in endocrinology 14 35432190
2012 Identification of Rhit as a novel transcriptional repressor of human Mpv17-like protein with a mitigating effect on mitochondrial dysfunction, and its transcriptional regulation by FOXD3 and GABP. Free radical biology & medicine 11 22306510
2015 Identification of interacting partners of Human Mpv17-like protein with a mitigating effect of mitochondrial dysfunction through mtDNA damage. Free radical biology & medicine 10 26165189
2023 Integrated analysis of the microbiome and transcriptome in stomach adenocarcinoma. Open life sciences 6 37465100
2018 Knockout of Mpv17-Like Protein (M-LPH) Gene in Human Hepatoma Cells Results in Impairment of mtDNA Integrity through Reduction of TFAM, OGG1, and LIG3 at the Protein Levels. Oxidative medicine and cellular longevity 6 30310528
2021 Deficiency of M-LP/Mpv17L leads to development of β-cell hyperplasia and improved glucose tolerance via activation of the Wnt and TGF-β pathways. Biochimica et biophysica acta. Molecular basis of disease 5 34883249
2020 Human Mpv17-like protein with a mitigating effect on mtDNA damage is involved in cAMP/PKA signaling in the mitochondrial matrix. Biochimica et biophysica acta. Molecular cell research 5 32621840
2013 Three Nonsynonymous Single Nucleotide Polymorphisms in the RhitH Gene Cause Reduction of the Repression Activity That Leads to Upregulation of M-LPH, a Participant in Mitochondrial Function. BioResearch open access 4 24380054
1996 Human lactase-phlorizin hydrolase is not processed by furin, PC1/PC3, PC2, PACE4 and PC5/PC6A of the family of subtilisin-like proprotein processing proteases. Biochimica et biophysica acta 3 8664347
2009 Prediction of novel isoforms of the mouse Mpv17l protein. Genome 2 19935920
2025 Overview of M-LP/MPV17L, a novel atypical PDE and possible target for drug development. European journal of pharmacology 1 40180270
2023 Knockout of M-LP/Mpv17L, a newly identified atypical PDE, induces physiological afferent cardiac hypertrophy in mice. Transgenic research 1 37851308
2025 Charge-dependent mitochondrial targeting of cerium-doped polypyrrole nanoparticles to injured renal tubules for acute kidney injury therapy. Journal of nanobiotechnology 0 41449392

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