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Showing MUL1 — MULAN is a alias.

MUL1

Mitochondrial ubiquitin ligase activator of NFKB 1 · UniProt Q969V5

Length
352 aa
Mass
39.8 kDa
Annotated
2026-06-10
64 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MUL1 (MULAN/MAPL/GIDE) is a mitochondrial outer-membrane E3 ligase that governs mitochondrial dynamics, quality control, metabolism, and cell death through a single cytosol-exposed RING domain capable of both ubiquitin and SUMO conjugation (PMID:18213395, PMID:19407830). It is anchored in the outer membrane by two transmembrane segments, and both an intact RING finger and correct localization are required for its control of mitochondrial morphology (PMID:18213395); the RING adopts a canonical cross-brace βββαβ zinc-coordinating fold and engages substrates such as the p53 transactivation domain while recruiting E2~ubiquitin conjugates (UBE2D2~Ub) into a closed, transfer-competent conformation (PMID:31235254, PMID:35048531). As the first mitochondria-anchored SUMO ligase, MUL1 SUMOylates the fission GTPase DRP1 to stimulate fission (PMID:19407830), and DRP1 SUMOylation stabilizes ER–mitochondrial contact sites that serve as hotspots for constriction, calcium flux, and cytochrome c release downstream of BAX/BAK during apoptosis (PMID:26384664). In its ubiquitin-ligase capacity, MUL1 targets mitofusins to control fusion and acts in parallel to the PINK1/Parkin axis to maintain mitochondrial integrity, with combined loss producing neurodegeneration (PMID:24898855); MUL1 and Parkin also act redundantly in mitophagic elimination of paternal mitochondria in embryos (PMID:27852436). MUL1 ubiquitinates active AKT and HIF-1α/Akt2 via K48 chains to suppress proliferation and restrain a glycolytic metabolic shift (PMID:22410793, PMID:35846359), and its expression is driven by FOXO3 under oxidative stress (PMID:29299162). It additionally regulates ER–mitochondria tethering and calcium homeostasis, where its loss triggers biphasic hyperfusion-then-fragmentation responses (PMID:31409786), modulates antiviral RIG-I signaling through SUMOylation (PMID:28273895), controls bile-acid synthesis by SUMOylating the peroxisomal transporter ABCD3 (PMID:37962001), and drives mtDNA–cGAS–gasdermin-dependent pyroptosis via mitochondria-derived vesicle trafficking to lysosomes (PMID:41083601). MUL1 loss in oocytes elevates outer-membrane ROS and triggers a DNA-damage response causing infertility, rescued by antioxidant (PMID:38639871).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2008 High

    Established MUL1 as a topologically defined mitochondrial outer-membrane RING E3 ligase whose activity and localization jointly control mitochondrial dynamics, defining the protein's physical platform.

    Evidence Imaging screen, fractionation, domain mutagenesis and RNAi in cells

    PMID:18213395

    Open questions at the time
    • Direct ubiquitination substrates not yet identified
    • Mechanism linking RING activity to morphology unresolved at this stage
  2. 2008 Medium

    Placed MUL1 (GIDE) within an apoptotic pathway upstream of cytochrome c/Smac release and caspase-9 activation, showing RING-dependent pro-death function.

    Evidence Overexpression with dominant-negative caspase-9, XIAP, and JNK/cytochrome c release assays

    PMID:18591963

    Open questions at the time
    • No direct ubiquitination substrate in the apoptotic pathway identified
    • JNK activation mechanism not defined
  3. 2009 High

    Defined MUL1 as the first mitochondria-anchored SUMO E3 ligase and identified DRP1 as a direct SUMO substrate, revealing a non-ubiquitin enzymatic mode driving fission.

    Evidence In vitro SUMO conjugation assays, Co-IP, RNAi phenotype

    PMID:19407830

    Open questions at the time
    • DRP1 SUMO-acceptor residues not mapped here
    • Opposing deSUMOylase unidentified at this stage
  4. 2012 High

    Identified active AKT as a direct K48-ubiquitination substrate, establishing MUL1 as a negative regulator of pro-survival/proliferative signaling.

    Evidence In vitro and in vivo ubiquitination assays, Co-IP, RING mutagenesis, proliferation assays

    PMID:22410793

    Open questions at the time
    • Preference for phosphorylated AKT not structurally explained
    • In vivo physiological relevance not established here
  5. 2012 Medium

    Linked MUL1 to inflammatory and antiviral signaling, showing complex formation with TRAF2/NF-κB activation and interaction with MAVS to negatively modulate RIG-I responses.

    Evidence Co-IP, NF-κB/IFN-β reporter assays, knockdown, viral challenge

    PMID:23399697 PMID:24841215

    Open questions at the time
    • Direct vs indirect modification of RIG-I unresolved
    • Apparent inhibitory role conflicts with later activating SUMOylation finding
  6. 2014 High

    Demonstrated MUL1 acts in a pathway parallel to PINK1/Parkin to degrade mitofusin and preserve mitochondrial integrity, with combined loss causing degeneration.

    Evidence Drosophila genetic epistasis, mouse cortical neuron assays, mitofusin degradation assays

    PMID:24898855

    Open questions at the time
    • Molecular basis of parallelism with PINK1/Parkin not detailed
    • Relative substrate contribution in vivo unclear
  7. 2014 Medium

    Mapped the E2 partners of MUL1 and an LIR motif in its RING that recruits GABARAP, providing a mechanistic link from the ligase to the autophagy machinery, and identified Omi/HtrA2 as a protease that turns MUL1 over.

    Evidence Modified yeast two-hybrid (RING-E2 fusions), Co-IP, LIR mutagenesis; in vitro protease assay in mnd2 mouse tissues

    PMID:24709290 PMID:25224329

    Open questions at the time
    • E2 selectivity for ubiquitin vs SUMO outputs unclear
    • GABARAP-dependent mitophagy substrate cargo not defined
  8. 2015 High

    Connected MUL1-dependent DRP1 SUMOylation to ER–mitochondrial contact-site stabilization required for cytochrome c release, positioning MUL1 downstream of BAX/BAK in apoptosis.

    Evidence Loss-of-function, SUMOylation and contact-site imaging, calcium flux and cytochrome c release assays, BAX/BAK epistasis

    PMID:26384664

    Open questions at the time
    • Structural basis of contact-site stabilization by SUMO-DRP1 not resolved
    • Link to upstream apoptotic triggers incomplete
  9. 2015 Medium

    Showed MUL1 ubiquitinates ULK1 upon its mitochondrial translocation, integrating MUL1 into ATG5/ULK1-dependent stress-induced mitophagy.

    Evidence Co-IP, ubiquitination assays, genetic dependency on ATG5/ULK1, mitophagy assays

    PMID:26018823

    Open questions at the time
    • Ubiquitin chain type and consequence on ULK1 not defined here
    • Selectivity of ULK1 targeting unclear
  10. 2016 High

    Established functional redundancy between MUL1 and Parkin in developmental mitophagy, eliminating paternal mitochondria via a PINK1/FIS1/P62-dependent route.

    Evidence Genetic knockout in mouse embryos and fibroblasts, double-mutant analysis, mitophagy imaging

    PMID:27852436

    Open questions at the time
    • Whether MUL1 acts via ubiquitin or SUMO output here untested
    • Substrate driving paternal mitochondrial clearance unidentified
  11. 2017 High

    Resolved MUL1's antiviral role as a positive one, showing MAPL-dependent RIG-I SUMOylation is required upstream of RIG-I activation for antiviral transcription.

    Evidence BioID interactome during Sendai infection, in vivo/in vitro KO, RIG-I SUMOylation assay, epistasis with constitutively active RIG-I

    PMID:28273895

    Open questions at the time
    • Reconciliation with earlier inhibitory RIG-I report not addressed
    • RIG-I SUMO-acceptor sites not mapped
  12. 2019 High

    Determined the RING domain solution structure and mapped its direct interaction with the p53 transactivation domain, giving the first atomic view of substrate engagement.

    Evidence NMR structure determination and chemical-shift perturbation, in vitro binding

    PMID:31235254

    Open questions at the time
    • Functional consequence of p53-TAD ubiquitination on p53 activity not shown
    • Cellular context of p53 targeting undefined
  13. 2019 High

    Defined MUL1 as an ER–mitochondria tethering antagonist whose loss drives a biphasic hyperfusion-then-calcineurin/DRP1-fragmentation/Parkin-mitophagy response, linking the ligase to calcium homeostasis.

    Evidence Neuronal KO, Ca2+ flux, calcineurin inhibition, contact-site imaging, Mfn2/PTPIP51 epistasis and rescue

    PMID:31409786

    Open questions at the time
    • Direct substrate at the tether unresolved
    • How a single ligase produces opposing temporal phases not fully mechanistic
  14. 2022 High

    Provided the mechanistic basis for MUL1 ubiquitinating intrinsically disordered substrates, showing the RING recruits p53-TAD together with UBE2D2~Ub and induces a closed, transfer-competent E2 conformation.

    Evidence Crystal/NMR of RING:UBE2D2, ubiquitin oxyester mimetics, hydrolysis assays, UBE2D2 N77A mutagenesis, affinity measurements

    PMID:35048531

    Open questions at the time
    • In-cell p53 regulation by this mechanism not demonstrated
    • Generalizability to other disordered substrates untested
  15. 2022 High

    Established MUL1 as a metabolic gatekeeper through K48 degradation of Akt2 and HIF-1α (and via UBXN7), restraining the shift from oxidative phosphorylation to glycolysis and lipid remodeling.

    Evidence KO cells, metabolomics/lipidomics, Seahorse flux, substrate KO and chemical modulators; UBXN7 substrate identification with K48 assays

    PMID:32005965 PMID:35846359

    Open questions at the time
    • Hierarchy among Akt2/HIF-1α/UBXN7 outputs unclear
    • Tissue-specific metabolic relevance not fully mapped
  16. 2023 High

    Extended MUL1 substrate range beyond mitochondria, identifying SUMOylation of the peroxisomal transporter ABCD3 as a cell-autonomous regulator of hepatic bile-acid synthesis in viable KO mice.

    Evidence KO mice, BioID interactome, SUMO conjugation assays, bile-acid measurement, primary hepatocytes

    PMID:37962001

    Open questions at the time
    • Mechanism by which ABCD3 SUMOylation alters transport not defined
    • Cross-organelle access of a mitochondrial ligase to peroxisomal substrate unexplained
  17. 2024 Medium

    Demonstrated MUL1 SUMOylates HSPA9 to drive its nuclear export and downstream SUZ12/EZH2 degradation, coupling MUL1 to chromatin-modifier turnover and tumor suppression; also showed DRP1 SUMOylation drives mitochondrial dysfunction in septic cardiomyocytes and ROS/DDR control in oocytes.

    Evidence SUMO assays with site mutagenesis, nuclear fractionation, ubiquitination assays, xenografts; cardiomyocyte- and germline-specific KO mice with functional readouts and NAC rescue

    PMID:38639871 PMID:39113711 PMID:39529130

    Open questions at the time
    • How nuclear-exported HSPA9 acquires ubiquitin-targeting of SUZ12/EZH2 mechanistically unclear
    • Single-lab models for each disease context
  18. 2025 High

    Identified MUL1 as an inducer of pyroptosis via MDV-mediated mtDNA trafficking to lysosomes and cGAS–gasdermin activation, embedding the ligase in an inflammatory cell-death and Parkinson's-gene (VPS35/LRRK2) network.

    Evidence Genome-wide screen, MAPL gain/loss, mtDNA trafficking and lysosomal permeabilization assays, cGAS epistasis, primary macrophages

    PMID:41083601

    Open questions at the time
    • Enzymatic output (ubiquitin vs SUMO) driving MDV trafficking unresolved
    • Direct substrate controlling mtDNA packaging unidentified
  19. 2025 Medium

    Expanded MUL1 mitophagy/fission control with FUNDC1 ubiquitination, CPT2 degradation (enhanced by SLC44A2) restraining fatty-acid oxidation, and DRP1 SUMO1-driven fission in nucleus pulposus cells opposed by SENP5.

    Evidence Co-IP, ubiquitination/SUMOylation assays, site mutagenesis, FAO assays, AAV in vivo models, xenografts

    PMID:40592838 PMID:40796734 PMID:41697489

    Open questions at the time
    • Context-specific selection among many substrates unresolved
    • Single-lab cancer/disease models for each finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MUL1 selects between ubiquitin and SUMO outputs, and which E2/E3 cofactors and signals route it to specific substrates across mitochondria, peroxisomes, and the nucleus, remains the central open question.
  • No unifying model for ubiquitin-vs-SUMO substrate choice
  • Regulation of MUL1 access to non-mitochondrial substrates undefined
  • PINK1 SUMOylation control of basal mitophagy rests on a preprint only

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 7 GO:0140096 catalytic activity, acting on a protein 6 GO:0031386 protein tag activity 5 GO:0016874 ligase activity 4
Localization
GO:0005739 mitochondrion 5
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-9612973 Autophagy 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 2
Partners
ABCD3AKTDRP1HIF1AMAVSPINK1TRAF2ULK1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 MUL1/MULAN is a mitochondrial outer membrane protein with two transmembrane domains mediating its localization; its C-terminal RING finger domain is exposed to the cytosol and is required for E3 ubiquitin ligase activity. Both an intact RING finger and correct subcellular localization are required for regulation of mitochondrial dynamics. Imaging-based screen, ectopic expression, RNAi knockdown, domain mutagenesis, subcellular fractionation PloS one High 18213395
2008 GIDE/MUL1 induces apoptosis via a pathway requiring its RING finger E3 ligase activity, involving JNK activation upstream of cytochrome c and Smac release, and downstream caspase activation; XIAP and dominant-negative caspase-9 block GIDE-induced apoptosis. Overexpression, caspase inhibitor treatment, dominant-negative constructs, cytochrome c/Smac release assays, JNK activation assays Cell research Medium 18591963
2009 MAPL/MUL1 functions as the first mitochondrial-anchored SUMO E3 ligase and directly SUMOylates DRP1, the mitochondrial fission GTPase, thereby stimulating mitochondrial fission. Biochemical SUMO conjugation assays, overexpression, RNAi, Co-IP to identify DRP1 as substrate EMBO reports High 19407830
2012 MULAN/MUL1 activates NF-κB through a pathway dependent on mitochondrial hyperfusion; MULAN forms a complex with TRAF2 and modulates its ubiquitylation, with NF-κB activation requiring the RING domain of MULAN and being TAK1- and IKK-dependent. Expression of dominant-negative Drp1 and MARCH5 to induce hyperfusion, MULAN knockdown, NF-κB reporter assays, Co-IP of MULAN with TRAF2 The FEBS journal Medium 24841215
2012 MUL1 ubiquitinates and promotes degradation of the mitochondrial fusion protein Mfn2, leading to mitophagy; FoxO1/3 transcription factors regulate MUL1 expression upstream of this pathway during muscle wasting. NOTE: This paper (PMID 23140641) was subsequently retracted due to data falsification (PMID 26973995); findings should be treated with very low confidence. Overexpression, siRNA knockdown, ubiquitination assays, muscle wasting models — RETRACTED Cell metabolism Low 23140641 26973995
2012 MUL1 interacts with MAVS at the mitochondrial outer membrane and catalyzes post-translational modifications of RIG-I that inhibit RIG-I-dependent NF-κB and IFN-β signaling; MUL1 depletion potentiates RIG-I-mediated antiviral responses. Co-IP of MUL1 with MAVS, RIG-I modification assays, MUL1 siRNA knockdown, NF-κB/IFN-β reporter assays, Sendai virus and poly I:C challenge Immunology and cell biology Medium 23399697
2012 MULAN/MUL1 directly interacts with and ubiquitinates AKT (preferentially phosphorylated AKT), leading to proteasomal degradation of AKT and suppression of cell proliferation and viability. Co-IP of AKT with MULAN, in vitro ubiquitination assay, in vivo ubiquitination assay, RING finger domain mutagenesis, cell proliferation/viability assays Cell research High 22410793
2014 MUL1 acts in parallel to the PINK1/Parkin pathway to ubiquitinate and degrade Mitofusin (Mfn), maintaining mitochondrial integrity; removing MUL1 in PINK1 or parkin mutant background aggravates phenotypes leading to lethality in Drosophila and neuronal degeneration in mice. Drosophila genetic epistasis (double mutants), mouse cortical neuron degeneration assays, ubiquitin-dependent degradation assays for Mitofusin eLife High 24898855
2014 Mulan/MUL1 interacts with four specific E2 ubiquitin conjugating enzymes (Ube2E2, Ube2E3, Ube2G2, Ube2L3); the Mulan-Ube2E3 complex specifically recruits GABARAP via an LIR motif in the RING finger domain of Mulan, providing a mechanism for MUL1's role in mitophagy. Modified yeast two-hybrid screen using RING finger-E2 fusions, Co-IP, LIR motif mutagenesis Cellular signalling Medium 25224329
2014 Omi/HtrA2 protease degrades Mulan/MUL1 as a substrate during H2O2 exposure; loss of Omi/HtrA2 protease activity leads to Mulan accumulation, decreased Mfn2 protein, and increased mitophagy in mnd2 mutant mice and Omi/HtrA2-/- MEFs. In vitro protease assay, western blot of Mulan in mnd2 mice tissues and KO MEFs, Mfn2 protein quantification, mitophagy assays Biochimica et biophysica acta Medium 24709290
2015 MUL1/MAPL-dependent SUMOylation of DRP1 is required for cytochrome c release during apoptosis; SUMOylated DRP1 stabilizes ER/mitochondrial contact sites that act as hotspots for mitochondrial constriction, calcium flux, cristae remodeling, and cytochrome c release. MAPL acts downstream of BAX/BAK activation. MAPL loss-of-function, SUMOylation assays, ER/mitochondrial contact site imaging, cytochrome c release assays, BAX/BAK assembly assays, calcium flux measurements Molecular cell High 26384664
2015 MUL1 ubiquitinates ULK1 (after ULK1 translocates to mitochondria following selenite treatment) and interacts with ULK1; MUL1 regulates selenite-induced mitophagy in an ATG5- and ULK1-dependent manner. Co-IP of ULK1 with MUL1, ubiquitination assays, ATG5/ULK1 dependency experiments, mitophagy assays Autophagy Medium 26018823
2016 MUL1 and PARKIN play redundant roles in elimination of paternal mitochondria in mouse pre-implantation embryos via mitophagy; the process requires mitochondrial depolarization of paternal mitochondria, FIS1, the autophagy adaptor P62, and PINK1 kinase. Genetic knockout of PARKIN and MUL1 in mouse embryos and fibroblasts, mitophagy assays (autophagosome sequestration, lysosomal delivery), double mutant analysis eLife High 27852436
2017 MAPL/MUL1 is required for RIG-I SUMOylation in a Sendai virus infection context; this SUMOylation is required for RIG-I activation and drives antiviral gene transcription. MAPL was not required for signaling downstream of constitutively active RIG-I, placing it upstream of RIG-I activation. BioID proximity labeling proteomics of MAPL interactors during Sendai infection, MAPL knockout in vivo and in vitro, RIG-I SUMOylation assay, epistasis with constitutively active RIG-I Scientific reports High 28273895
2017 FOXO3 transcriptionally regulates MUL1 expression; cisplatin-induced ROS activates FOXO3, which upregulates MUL1, leading to ubiquitylation of active (phosphorylated) AKT. FOXO3 knockdown, ROS quantification, MUL1 expression analysis, AKT ubiquitylation assays Oncotarget Medium 29299162
2018 MUL1 ubiquitinates HSPA5/GRP78 at K48-linked polyubiquitin chains at the K446 residue, leading to HSPA5 degradation; HSPA5 negatively regulates lysosomal activity and MUL1 knockdown prevents HSPA5 ubiquitination. Co-IP, ubiquitination assay (K48-linkage specificity), CRISPR/Cas9 MUL1 KO, site-directed mutagenesis of K446, in vivo xenograft model Autophagy Medium 29260979
2019 MUL1 deficiency leads to increased Mfn2 activity, triggering mitochondrial hyperfusion as a first phase response, and acts as an ER-mitochondria tethering antagonist; reduced ER-Mito coupling increases cytoplasmic Ca2+ load, which activates calcineurin and induces DRP1-dependent mitochondrial fragmentation and Parkin-mediated mitophagy as a second phase. MUL1 KO in neurons, Ca2+ flux measurements, calcineurin inhibitor experiments, ER-Mito contact site quantification, Mfn2/Mfn1 overexpression epistasis, PTPIP51 overexpression rescue Nature communications High 31409786
2019 The NMR solution structure of the MUL1 RING domain was determined; the RING domain adopts a ββαβ fold with a canonical cross-brace motif coordinating two zinc ions. NMR chemical shift perturbation experiments showed the RING domain interacts with the p53 transactivation domain (p53-TAD), primarily through the TAD2 subdomain (residues 39-57). NMR spectroscopy (structure determination and chemical shift perturbation), in vitro binding assays Biochemical and biophysical research communications High 31235254
2020 MUL1 stabilizes PINK1 on the outer mitochondrial membrane in a Parkin-independent manner during gemcitabine treatment, inducing mitophagy without mitochondrial depolarization. MUL1 knockdown/KO, PINK1 stability assays, mitophagy assays, gemcitabine treatment in Parkin-deficient cells Scientific reports Medium 32001742
2020 MUL1 ubiquitinates and degrades UBXN7 (cofactor of the CRL2VHL E3 complex) via K48-linked polyubiquitination; inactivation of MUL1 leads to UBXN7 accumulation, increased HIF-1α protein levels, reduced oxidative phosphorylation, and increased glycolysis under normoxic conditions. UBXN7 identification as MUL1 substrate, K48 ubiquitination assays, MUL1 KO cells, HIF-1α protein level measurement, metabolic flux analysis Scientific reports Medium 32005965
2021 MUL1 ubiquitinates ULK1 leading to its degradation; miR-135b-5p targets MUL1 mRNA to suppress MUL1 expression, thereby preventing ULK1 degradation and inducing protective autophagy that promotes oxaliplatin resistance in colorectal cancer. miRNA target validation (luciferase reporter), MUL1 overexpression/knockdown, ULK1 ubiquitination assays, autophagy assays, xenograft models Oncogene Medium 34140641
2022 MUL1 RING domain recruits the substrate p53-TAD as a complex with UBE2D2-ubiquitin (UBE2D2~UB) conjugate; the presence of UBE2D2~UB thioester mimetic enhances TADp53 binding affinity for the RING:E2 complex, and RING-binding induces closed conformation of UBE2D2 to activate ubiquitin transfer. This mechanism underlies ubiquitylation of intrinsically disordered p53-TAD. Crystal/NMR structure of RING:UBE2D2 complex, oxyester UB mimetics, hydrolysis assays, UBE2D2 mutagenesis (N77A), binding affinity measurements The FEBS journal High 35048531
2022 MUL1 regulates mitochondrial metabolism through K48-specific polyubiquitination and degradation of both Akt2 and HIF-1α; absence of MUL1 leads to accumulation and activation of both substrates, causing a shift from oxidative phosphorylation to glycolysis and altered lipid metabolism. MUL1 KO cells, metabolomics, lipidomics, gene expression profiling, metabolic flux analysis (Seahorse), specific chemical inhibitors/activators of HIF-1α and Akt2, Akt2 KO cells Frontiers in cell and developmental biology High 35846359
2023 MAPL/MUL1 interacts with and SUMOylates the peroxisomal bile acid transporter ABCD3; MAPL loss leads to increased bile acid production and defective regulatory feedback in liver, identifying MAPL as a regulator of bile acid synthesis with cell-autonomous function in hepatocytes. MAPL KO mice (viable), BioID proximity labeling identifying ABCD3 as primary interactor, SUMO conjugation assays, bile acid measurement, primary hepatocyte isolation EMBO reports High 37962001
2024 MUL1 SUMOylates HSPA9 at the K612 residue, promoting HSPA9 export from mitochondria to the nucleus where it interacts with SUZ12; nuclear HSPA9 leads to MUL1-induced ubiquitination-mediated degradation of SUZ12 and EZH2, and downstream STAT3 pathway inhibition, suppressing lymph node metastasis of bladder cancer. Co-IP, SUMO conjugation assays, site-directed mutagenesis of K612, nuclear fractionation, HSPA9 localization imaging, SUZ12/EZH2 ubiquitination assays, in vivo xenograft/metastasis models International journal of biological sciences Medium 39113711
2024 MAPL/MUL1 promotes SUMOylation of DRP1 in cardiomyocytes under septic conditions; MAPL deficiency reduces DRP1 SUMOylation, alleviates mitochondrial dysfunction (restores membrane potential, reduces ROS, increases ATP), and reduces cardiac injury in CLP sepsis model. Cardiomyocyte-specific MAPL KO mice, CLP model, SUMOylation assays, mitochondrial membrane potential measurement, ROS measurement, ATP quantification Journal of translational medicine Medium 39529130
2024 MUL1 deficiency in oocytes increases reactive oxygen species (ROS) concentrations at the mitochondrial outer membrane, triggering a DNA damage response (DDR) and abnormal preimplantation embryogenesis; this phenotype is rescued by NAC (antioxidant) addition. Female Mul1 KO mice (infertility phenotype), ROS measurement in oocytes, DDR marker assays, NAC rescue experiments FEBS letters Medium 38639871
2025 MUL1 ubiquitinates and promotes degradation of CPT2 (carnitine palmitoyltransferase 2); SLC44A2 enhances the MUL1-CPT2 interaction (without changing MUL1 expression levels) to promote CPT2 degradation and suppress mitochondrial fatty acid oxidation in colorectal cancer. Co-IP of MUL1 with CPT2, ubiquitination assays, SLC44A2 overexpression/knockdown, fatty acid oxidation assays, in vivo tumor models Cell death & disease Medium 40592838
2025 MAPL/MUL1 induces pyroptosis by promoting mitochondrial DNA (mtDNA) trafficking via mitochondria-derived vesicles (MDVs) to lysosomes, which are then permeabilized via gasdermin pores; released mtDNA activates cytosolic cGAS, triggering inflammatory cell death. VPS35 and LRRK2 (Parkinson's disease genes) regulate this pathway. Genome-wide functional genetic screen, MAPL overexpression/depletion, mtDNA trafficking assays, lysosomal permeabilization assay, cGAS knockdown epistasis, primary macrophage depletion experiments, LRRK2/VPS35 genetic interaction Nature cell biology High 41083601
2025 MAPL/MUL1 promotes SUMO-2/3 modification of PINK1, suppressing basal mitophagy; MAPL depletion reduces PINK1 SUMOylation and enhances basal mitophagy, while targeted deSUMOylation increases PINK1 stabilization and augments mitophagy. MAPL depletion, PINK1 SUMO-2/3 conjugation assays, targeted deSUMOylation, mitophagy assays bioRxiv (preprint)preprint Low
2025 MAPL/MUL1 SUMOylates DRP1 (via SUMO1 modification), promoting DRP1 mitochondrial translocation and mitochondrial fission in nucleus pulposus cells; mutation of SUMO-acceptor lysine residues on DRP1 blocks its SUMOylation and rescues MAPL-induced mitochondrial fragmentation. SENP5 acts as the opposing deSUMOylase. MAPL overexpression/knockdown in NPCs, SUMO1 modification assays for DRP1, DRP1 SUMO-site mutagenesis, SENP5 overexpression, AAV-mediated MAPL expression in rat IVDD model Bone research Medium 40796734
2025 MUL1 ubiquitinates FUNDC1, reducing FUNDC1 protein stability; reduced FUNDC1 leads to decreased DRP1 expression and inhibition of DRP1-dependent mitophagy in cervical cancer cells. Co-IP, ubiquitination assay for FUNDC1, MUL1 overexpression/knockdown, mitophagy assays, DRP1 expression analysis, in vivo xenograft Journal of molecular histology Medium 41697489

Source papers

Stage 0 corpus · 64 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling. PloS one 647 18213395
2009 MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission. EMBO reports 287 19407830
2016 Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. eLife 279 27852436
2015 MAPL SUMOylation of Drp1 Stabilizes an ER/Mitochondrial Platform Required for Cell Death. Molecular cell 278 26384664
2014 MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin. eLife 265 24898855
2004 Mulan: multiple-sequence local alignment and visualization for studying function and evolution. Genome research 195 15590941
2015 Mitochondrial outer-membrane E3 ligase MUL1 ubiquitinates ULK1 and regulates selenite-induced mitophagy. Autophagy 130 26018823
2012 The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli. Cell metabolism 130 23140641
2019 Mul1 restrains Parkin-mediated mitophagy in mature neurons by maintaining ER-mitochondrial contacts. Nature communications 128 31409786
2012 Akt is negatively regulated by the MULAN E3 ligase. Cell research 94 22410793
2016 Melatonin rescues zebrafish embryos from the parkinsonian phenotype restoring the parkin/PINK1/DJ-1/MUL1 network. Journal of pineal research 72 27064726
2014 Mulan E3 ubiquitin ligase interacts with multiple E2 conjugating enzymes and participates in mitophagy by recruiting GABARAP. Cellular signalling 71 25224329
2018 HSPA5 negatively regulates lysosomal activity through ubiquitination of MUL1 in head and neck cancer. Autophagy 69 29260979
2008 GIDE is a mitochondrial E3 ubiquitin ligase that induces apoptosis and slows growth. Cell research 68 18591963
2021 The HSF1/miR-135b-5p axis induces protective autophagy to promote oxaliplatin resistance through the MUL1/ULK1 pathway in colorectal cancer. Oncogene 58 34140641
2014 Inactivation of Omi/HtrA2 protease leads to the deregulation of mitochondrial Mulan E3 ubiquitin ligase and increased mitophagy. Biochimica et biophysica acta 57 24709290
2015 Non-thermal plasma induces AKT degradation through turn-on the MUL1 E3 ligase in head and neck cancer. Oncotarget 50 26450902
2020 Gemcitabine induces Parkin-independent mitophagy through mitochondrial-resident E3 ligase MUL1-mediated stabilization of PINK1. Scientific reports 49 32001742
2014 Mitochondrial hyperfusion promotes NF-κB activation via the mitochondrial E3 ligase MULAN. The FEBS journal 49 24841215
2010 Molecular analysis of parasitoid linkages (MAPL): gut contents of adult parasitoid wasps reveal larval host. Molecular ecology 46 21083857
2013 Mitochondrially localised MUL1 is a novel modulator of antiviral signaling. Immunology and cell biology 40 23399697
2022 Ginsenoside compound K protects against cerebral ischemia/reperfusion injury via Mul1/Mfn2-mediated mitochondrial dynamics and bioenergy. Journal of ginseng research 36 37252276
2023 MuLan-Methyl-multiple transformer-based language models for accurate DNA methylation prediction. GigaScience 33 37489753
2019 Defending stressed mitochondria: uncovering the role of MUL1 in suppressing neuronal mitophagy. Autophagy 27 31679452
2017 The dynamic interacting landscape of MAPL reveals essential functions for SUMOylation in innate immunity. Scientific reports 26 28273895
2020 Mitochondrial MUL1 E3 ubiquitin ligase regulates Hypoxia Inducible Factor (HIF-1α) and metabolic reprogramming by modulating the UBXN7 cofactor protein. Scientific reports 25 32005965
2022 Mitochondrial E3 ubiquitin ligase 1 (MUL1) as a novel therapeutic target for diseases associated with mitochondrial dysfunction. IUBMB life 24 35638168
2019 Effects of MUL1 and PARKIN on the circadian clock, brain and behaviour in Drosophila Parkinson's disease models. BMC neuroscience 19 31138137
2017 FOXO3 induces ubiquitylation of AKT through MUL1 regulation. Oncotarget 17 29299162
2022 Regulation of Metabolism by Mitochondrial MUL1 E3 Ubiquitin Ligase. Frontiers in cell and developmental biology 14 35846359
2019 Natural compound methyl protodioscin protects rat brain from ischemia/reperfusion injury through regulation of Mul1/SOD2 pathway. European journal of pharmacology 14 30716316
2019 MUL1 E3 ligase regulates the antitumor effects of metformin in chemoresistant ovarian cancer cells via AKT degradation. International journal of oncology 14 30816444
2024 SUMO E3 ligase MUL1 inhibits lymph node metastasis of bladder cancer by mediating mitochondrial HSPA9 translocation. International journal of biological sciences 13 39113711
2022 Inhibition of Prostaglandin E2 Receptor EP3 Attenuates Oxidative Stress and Neuronal Apoptosis Partially by Modulating p38MAPK/FOXO3/Mul1/Mfn2 Pathway after Subarachnoid Hemorrhage in Rats. Oxidative medicine and cellular longevity 13 36531208
2014 C13orf18 and C1orf166 (MULAN) DNA genes methylation are not associated with cervical cancer and precancerous lesions of human papillomavirus genotypes in Iranian women. Asian Pacific journal of cancer prevention : APJCP 13 25169519
2023 NDP52 SUMOylation contributes to low-dose X-rays-induced cardiac hypertrophy through PINK1/Parkin-mediated mitophagy via MUL1/SUMO2 signalling. Journal of cellular physiology 12 37942585
2012 Innate immune genes including a mucin-like gene, mul-1, induced by ionizing radiation in Caenorhabditis elegans. Radiation research 12 22967128
2025 MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death. Nature cell biology 9 41083601
2022 MUL1-RING recruits the substrate, p53-TAD as a complex with UBE2D2-UB conjugate. The FEBS journal 9 35048531
2019 Solution structure of MUL1-RING domain and its interaction with p53 transactivation domain. Biochemical and biophysical research communications 9 31235254
2012 The missing link: Mul1 signals mitophagy and muscle wasting. Cell metabolism 8 23140636
2024 Deletion of MAPL ameliorates septic cardiomyopathy by mitigating mitochondrial dysfunction. Journal of translational medicine 7 39529130
2022 Influence of melatonin associated with the Bio-Gide® membrane on osteoblast activity: an in vitro Study. Acta odontologica latinoamericana : AOL 7 36260939
2020 NR4A2 Exacerbates Cerebral Ischemic Brain Injury via Modulating microRNA-652/Mul1 Pathway. Neuropsychiatric disease and treatment 7 33116527
2025 The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degeneration. Bone research 6 40796734
2023 MAPL loss dysregulates bile and liver metabolism in mice. EMBO reports 6 37962001
2025 SLC44A2 negatively regulates mitochondrial fatty acid oxidation to suppress colorectal progression by blocking the MUL1-CPT2 interaction. Cell death & disease 5 40592838
2024 Inactivation of mitochondrial MUL1 E3 ubiquitin ligase deregulates mitophagy and prevents diet-induced obesity in mice. Frontiers in molecular biosciences 5 38725872
2023 Myristate induces mitochondrial fragmentation and cardiomyocyte hypertrophy through mitochondrial E3 ubiquitin ligase MUL1. Frontiers in cell and developmental biology 5 37051468
2019 MUL1 gene polymorphisms and Parkinson's disease risk. Acta neurologica Scandinavica 5 30793286
2015 The Evolutionary History of MAPL (Mitochondria-Associated Protein Ligase) and Other Eukaryotic BAM/GIDE Domain Proteins. PloS one 5 26047467
2012 MULAN related gene (MRG): a potential novel ubiquitin ligase activator of NF-kB involved in immune response in Atlantic salmon (Salmo salar). Developmental and comparative immunology 5 22989998
2011 Cloning and expression analysis of the mitochondrial ubiquitin ligase activator of NF-κB (MULAN) in Atlantic salmon (Salmo salar). Molecular immunology 5 22056942
2008 MICROPATTERNING OF GOLD SUBSTRATES BASED ON POLY(PROPYLENE SULFIDE-BL-ETHYLENE GLYCOL), (PPS-PEG) BACKGROUND PASSIVATION AND THE MOLECULAR-ASSEMBLY PATTERNING BY LIFT-OFF (MAPL) TECHNIQUE. Surface science 4 19578480
2025 MULAN: multimodal protein language model for sequence and structure encoding. Bioinformatics advances 2 40989496
2024 MUL1 identified as mitochondria-linked biomarker promoting cisplatin resistance in OC cells. Gene 2 39134101
2024 Increased ROS levels in mitochondrial outer membrane protein Mul1-deficient oocytes result in abnormal preimplantation embryogenesis. FEBS letters 1 38639871
2015 Retraction Notice to: The Ubiquitin Ligase Mul1 Induces Mitophagy in Skeletal Muscle in Response to Muscle-Wasting Stimuli. Cell metabolism 1 26973995
2026 MUL1 suppresses cervical cancer progression by targeting FUNDC1 for ubiquitination and inhibiting DRP1-dependent mitophagy. Journal of molecular histology 0 41697489
2026 Glypican-3 Upregulated by YTHDF1 in an m6A-Dependent Manner Interacts With MUL1 to Repress HSF1 Ubiquitination Degradation, Boost CD276 Transcription, and Mediate Immune Escape in Gastric Cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41944736
2026 18-β-glycyrrhetinic acid facilitates nuclear-mitochondrial communications to alleviate oxidative stress through HMGB1-cGAS-Mul1 axis in tendinopathy. Journal of translational medicine 0 41998635
2026 Multiple ShKT domain-containing MUL-1 proteins act as redox-responsive modulators of oxidative stress signaling in C. elegans. Molecules and cells 0 42173292
2025 The tumor suppressor role of mitochondrial E3 ubiquitin ligase MUL1 in osteosarcoma. Biochimica et biophysica acta. Molecular cell research 0 41468924
2023 Retraction: Protective effect of hsa-miR-570-3p targeting CD274 on triple negative breast cancer by blocking PI3K/AKT/mTOR signaling pathway. Li-Li Wang, Wei-Wei Huang, Jing Huang, Rong-Fang Huang, Na-Ni Li, Yi Hong, Mu-Lan Chen, Fan Wu, Jian Liu, Kaohsiung J Med Sci. 2020; 36(8): 581-591 (https://doi.org/10.1002/kjm2.12212). The Kaohsiung journal of medical sciences 0 38088487

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