Affinage

MAIP1

m-AAA protease-interacting protein 1, mitochondrial · UniProt Q8WWC4

Round 2 corrected
Length
291 aa
Mass
32.5 kDa
Annotated
2026-04-28
40 papers in source corpus 2 papers cited in narrative 2 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAIP1 (C2orf47) is a mitochondrial inner-membrane-associated protein that cooperates with the m-AAA protease (AFG3L2/paraplegin) to chaperone biogenesis of EMRE, a subunit of the mitochondrial calcium uniporter (MCU), thereby ensuring incorporation of gatekeeper subunits MICU1/MICU2 into the channel and preventing constitutive mitochondrial Ca²⁺ influx that triggers permeability transition and neuronal death (PMID:27642048). MAIP1 is also a direct miR-27b target in hepatic cells, where its depletion promotes lipid accumulation and its overexpression rescues miR-27b-induced steatotic phenotypes (PMID:37355744).

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2016 High

    Identification of MAIP1 as an m-AAA protease interactor established its role in EMRE quality control, resolving how the MCU complex acquires gatekeeper subunits and why m-AAA protease loss causes neuronal Ca²⁺ overload and death.

    Evidence Affinity purification-MS interactome, reciprocal co-IP, siRNA knockdown/rescue, mitochondrial Ca²⁺ imaging, and cell death assays in neuronal cells

    PMID:27642048

    Open questions at the time
    • Structural basis of MAIP1–m-AAA protease interaction is unresolved
    • Whether MAIP1 directly contacts EMRE during biogenesis or acts solely through the protease is unclear
    • Contribution of MAIP1 to MCU assembly in non-neuronal tissues has not been systematically tested
  2. 2023 Medium

    Demonstration that miR-27b directly targets MAIP1 mRNA and that MAIP1 loss promotes hepatic lipid accumulation linked MAIP1 to lipid metabolism beyond its known mitochondrial Ca²⁺ uniporter role.

    Evidence Luciferase 3′-UTR reporter assay, siRNA knockdown, MAIP1 overexpression rescue, Oil Red O staining in hepatic cell lines, and high-fat diet mouse model

    PMID:37355744

    Open questions at the time
    • Mechanism connecting MAIP1 depletion to lipid accumulation (metabolic rewiring vs. Ca²⁺-dependent signaling) is undefined
    • Hepatic phenotype has not been confirmed by liver-specific Maip1 knockout in vivo
    • Whether the lipid phenotype depends on EMRE/MCU function remains untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unifying model explaining how MAIP1's mitochondrial chaperone function integrates with its hepatic metabolic role is lacking, as is structural insight into MAIP1–protease–EMRE interactions.
  • No structural or cryo-EM model of MAIP1 in complex with m-AAA protease or EMRE
  • In vivo conditional knockout phenotypes in brain and liver are unavailable
  • Potential roles in other m-AAA protease substrate pathways have not been explored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 1
Localization
GO:0005739 mitochondrion 1
Pathway
R-HSA-1430728 Metabolism 1
Partners
AFG3L2EMRESPG7

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 MAIP1 (C2ORF47) was identified as a binding partner of the mitochondrial m-AAA protease (AFG3L2/paraplegin) in neuronal mitochondria. MAIP1 assists the biogenesis of EMRE, a subunit of the mitochondrial calcium uniporter MCU. The m-AAA protease degrades non-assembled EMRE, ensuring efficient incorporation of gatekeeper subunits (MICU1/MICU2) into the MCU channel. Loss of the m-AAA protease leads to accumulation of constitutively active MCU-EMRE channels lacking gatekeeper subunits, facilitating mitochondrial Ca2+ overload, mitochondrial permeability transition pore opening, and neuronal death. Neuronal interactome mapping (affinity purification-MS), co-immunoprecipitation, siRNA knockdown/rescue, mitochondrial Ca2+ measurements, cell death assays Molecular cell High 27642048
2023 MAIP1 is a direct target of miR-27b in hepatic cells. Knockdown of MAIP1 induces lipid accumulation in human and mouse hepatic cells, while overexpression of MAIP1 ameliorates miR-27b-induced lipid accumulation. Hepatic Maip1 expression declines in mice fed a high-fat diet, implicating reduced MAIP1 expression in fatty liver development. miR-27b transfection, siRNA knockdown of MAIP1, MAIP1 overexpression rescue experiments, lipid accumulation assays (Oil Red O), luciferase 3′-UTR reporter assay confirming direct miR-27b targeting, high-fat diet mouse model Communications biology Medium 37355744

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2013 Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nature genetics 1192 23974872
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2015 SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature 548 25561175
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2018 The shieldin complex mediates 53BP1-dependent DNA repair. Nature 502 30022168
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2018 DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 379 29656893
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2012 Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 319 22810586
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2013 The functional interactome landscape of the human histone deacetylase family. Molecular systems biology 235 23752268
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2016 Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function. Molecular cell 220 27499296
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2009 Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 166 19176441
2016 The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria. Molecular cell 164 27642048
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2011 Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. The Journal of biological chemistry 131 21832049
2016 SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes. Cell reports 115 27545878
2019 Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrity. Genes & development 110 31753913
2021 FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2. Molecular cancer 106 33658012
2022 EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation. Nature communications 99 35013218
2017 Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair. Nature communications 89 29229926
2021 SARS-CoV-2-host proteome interactions for antiviral drug discovery. Molecular systems biology 86 34709727
2017 The STUbL RNF4 regulates protein group SUMOylation by targeting the SUMO conjugation machinery. Nature communications 86 29180619
2016 FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1. PLoS biology 82 26752685
2016 Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways. Cell reports 77 26972000
2019 The midbody interactome reveals unexpected roles for PP1 phosphatases in cytokinesis. Nature communications 74 31586073
2013 TIMMDC1/C3orf1 functions as a membrane-embedded mitochondrial complex I assembly factor through association with the MCIA complex. Molecular and cellular biology 72 24344204
2021 Loss of TRIM31 promotes breast cancer progression through regulating K48- and K63-linked ubiquitination of p53. Cell death & disease 64 34650049
2014 Immunosuppressive PAS-1 is an excretory/secretory protein released by larval and adult worms of the ascarid nematode Ascaris suum. Journal of helminthology 17 24703095
2006 PAS-1, a protein affinity purified from Ascaris suum worms, maintains the ability to modulate the immune response to a bystander antigen. Immunology and cell biology 13 16519731
2008 Helminth products as a potential therapeutic strategy for inflammatory diseases. Inflammation & allergy drug targets 12 18691141
2023 miR-27b targets MAIP1 to mediate lipid accumulation in cultured human and mouse hepatic cells. Communications biology 9 37355744
2022 Whole-Genome Sequencing of 100 Genomes Identifies a Distinctive Genetic Susceptibility Profile of Qatari Patients with Hypertension. Journal of personalized medicine 5 35629146
2022 Identification of Sex-Specific Genetic Variants Associated With Tau PET. Neurology. Genetics 5 36530928
2024 Biomarker Analysis from a Phase I/Ib Study of Regorafenib and Nivolumab in Mismatch Repair-Proficient Advanced Refractory Colorectal Cancer. Cancers 3 38339307
2024 Dysfunctional β-cell longevity in diabetes relies on energy conservation and positive epistasis. Life science alliance 1 39313296