Affinage

FUNDC1

FUN14 domain-containing protein 1 · UniProt Q8IVP5

Length
155 aa
Mass
17.2 kDa
Annotated
2026-06-09
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FUNDC1 is an integral mitochondrial outer-membrane protein that serves as a receptor for hypoxia-induced mitophagy, directly engaging LC3 through its LIR motif (Y18xxL21) to nucleate autophagosomal capture of mitochondria (PMID:22267086). Its receptor activity is governed by a reversible phosphorylation code: ULK1 translocates to mitochondria and phosphorylates Ser17 to strengthen LC3 binding (PMID:24671035), a crystal structure of LC3B bound to a pSer17 FUNDC1 peptide showing LC3B Lys49 coordinating the phosphate, while phosphorylation at Tyr18 or Ser13 sterically blocks the interaction (PMID:27757847); CK2α phosphorylates Ser13 to inactivate mitophagy (PMID:29540794), and the phosphatase PGAM5 reverses these inhibitory marks to license mitophagy, itself controlled by an oxidative-stress-driven multimerization switch and release from BCL-xL (PMID:31367011). FUNDC1 couples this receptor function to mitochondrial dynamics, dissociating from OPA1 and recruiting DRP1 under stress to drive fission prior to engulfment, and operating at mitochondria-associated ER membranes (MAMs) where it associates with calnexin (PMID:27050458, PMID:27145933). Protein abundance is set by opposing inputs—MARCH5 ubiquitinates FUNDC1 at Lys119 for proteasomal degradation (PMID:28104734), a step potentiated by lysophosphatidylinositol-driven monomerization and K104 acetylation (PMID:36847607) and counteracted by the ER deubiquitinase USP19 (PMID:33978709)—and by transcriptional upregulation via NRF1 binding the FUNDC1 promoter under PGC-1α control (PMID:33554448) and post-transcriptional repression by miR-137 (PMID:24573672). Beyond mitophagy, FUNDC1 maintains MAM/MERC integrity to regulate Ca2+ homeostasis through the FBXL2/IP3R3 axis (PMID:32938669), drives angiogenesis via a Ca2+/SRF/VEGFR2 transcriptional cascade in endothelium (PMID:33972548), and acts as an import platform: it binds HSC70 to translocate unfolded cytosolic proteins for LONP1-mediated degradation (PMID:30591555) and engages LonP1 to preserve oxidative phosphorylation complex V independent of its receptor role (PMID:32723812). Through these activities FUNDC1 governs mitochondrial quality control with physiological consequences for adaptive thermogenesis (PMID:33554448), ischemia-reperfusion and sepsis injury (PMID:29540794, PMID:40520006), and endothelial senescence; inducible endothelial FUNDC1 loss alone is sufficient to cause pulmonary hypertension via an mtROS–HIF2α–IGFBP2 axis (PMID:39655444).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2012 High

    Established the founding mechanism: how does a cell selectively target mitochondria for autophagy under hypoxia? FUNDC1 was identified as an outer-membrane mitophagy receptor that bridges mitochondria to LC3 via a LIR motif.

    Evidence Co-IP, LIR mutagenesis, and knockdown/rescue mitophagy imaging in hypoxic cells

    PMID:22267086

    Open questions at the time
    • Did not define the kinases/phosphatases setting the dephosphorylation switch
    • No structural basis for LC3 binding
  2. 2014 High

    Resolved the activating arm of the phospho-switch: ULK1 phosphorylates FUNDC1-Ser17 to enhance LC3 binding, and FUNDC1 reciprocally recruits ULK1 to mitochondria.

    Evidence In vitro kinase assay, phospho-mimetic rescue in ULK1-null cells, mitophagy flux

    PMID:24671035

    Open questions at the time
    • Did not address inhibitory phosphosites
    • Structural mechanism of enhanced binding unresolved
  3. 2014 Medium

    Identified a post-transcriptional brake on FUNDC1 abundance: hypoxia-responsive miR-137 represses FUNDC1 to limit mitophagy.

    Evidence 3'UTR reporter assays, miR-137 gain/loss of function, rescue with miR-137-resistant FUNDC1

    PMID:24573672

    Open questions at the time
    • Single lab
    • Physiological contexts of miR-137 regulation not mapped
  4. 2016 High

    Connected the mitophagy receptor to mitochondrial dynamics and membrane contact sites: FUNDC1 switches between OPA1 (fusion) and DRP1 (fission) binding and localizes to MAMs via calnexin.

    Evidence Reciprocal Co-IP with OPA1-K70 mutagenesis, subcellular fractionation, knockdowns of FUNDC1/DRP1/calnexin under stress

    PMID:27050458 PMID:27145933

    Open questions at the time
    • Order of fission relative to LC3 engagement not fully resolved
    • How dephosphorylation drives the partner switch mechanistically unclear
  5. 2016 High

    Provided the structural explanation for the phospho-code: LC3B Lys49 coordinates FUNDC1 pSer17 while Tyr18/Ser13 phosphorylation sterically blocks binding.

    Evidence X-ray crystallography of LC3B–phospho-FUNDC1 peptide, ITC, mutagenesis

    PMID:27757847

    Open questions at the time
    • Full-length receptor structure not determined
    • Conformational changes in the cytosolic loop not captured
  6. 2017 High

    Defined ubiquitin-dependent control of receptor abundance: MARCH5 ubiquitinates FUNDC1 at Lys119 for proteasomal turnover to fine-tune mitophagy magnitude.

    Evidence Ubiquitination assay, K119 mutagenesis, MARCH5 knockdown/overexpression

    PMID:28104734

    Open questions at the time
    • Did not identify the opposing deubiquitinase
    • Signals triggering MARCH5 engagement undefined
  7. 2018 High

    Placed CK2α as the physiological inhibitory kinase: CK2α phosphorylates FUNDC1-Ser13 to suppress mitophagy and worsen cardiac ischemia-reperfusion injury.

    Evidence Kinase assay, cardiac-specific CK2α KO and CK2α/FUNDC1 double-KO epistasis, mitophagy flux

    PMID:29540794

    Open questions at the time
    • Upstream regulators of CK2α toward FUNDC1 not defined
  8. 2019 High

    Identified the phosphatase that resets the switch and its regulation: PGAM5 dephosphorylates FUNDC1, gated by oxidative-stress-driven multimerization and release from BCL-xL.

    Evidence Phosphatase activity assays, PGAM5 multimerization analysis, BCL-xL Co-IP

    PMID:31367011

    Open questions at the time
    • Which residues PGAM5 targets in vivo not pinpointed
    • Cross-talk with CK2α/Src kinase activity not integrated
  9. 2019 High

    Revealed a mitophagy-independent role: FUNDC1 partners with HSC70 to import unfolded cytosolic proteins for LONP1 degradation or MAPA formation, with senescence as a consequence of overload.

    Evidence Co-IP, APEX proximity labeling, csCLEM, knockdown with proteasome inhibition

    PMID:30591555

    Open questions at the time
    • Substrate selectivity of the import route undefined
    • Relationship to the receptor's LIR function not delineated
  10. 2019 Medium

    Demonstrated an organismal developmental requirement: zebrafish Fundc1 is needed for proper body-axis formation, linking mitochondrial function to midline patterning.

    Evidence shRNA knockdown with mRNA rescue in zebrafish, mitochondrial/lysosomal marker colocalization

    PMID:31827208

    Open questions at the time
    • Mechanism connecting mitophagy to axis formation unknown
    • Mammalian developmental relevance untested here
  11. 2020 High

    Extended FUNDC1 to Ca2+ homeostasis: FUNDC1 binds FBXL2 to gate IP3R3 degradation, preventing mitochondrial Ca2+ overload.

    Evidence Mass spectrometry, Co-IP with domain mapping, FUNDC1-/- mice, IP3R3 inhibition rescue

    PMID:32938669

    Open questions at the time
    • How FUNDC1 controls FBXL2 stability mechanistically unclear
  12. 2020 Medium

    Identified a mitophagy-independent OXPHOS role: FUNDC1 interacts with inner-membrane LonP1 and complex V to preserve ATP synthase function and limit ROS.

    Evidence Metabolomics, interactome proteomics, FUNDC1 knockdown in cancer cells

    PMID:32723812

    Open questions at the time
    • Single lab
    • How an outer-membrane receptor accesses inner-membrane partners unresolved
  13. 2021 High

    Linked mitophagy to mitochondrial biogenesis transcriptionally: NRF1 (under PGC-1α) binds the FUNDC1 promoter, and FUNDC1 is required for brown-fat adaptive thermogenesis.

    Evidence ChIP for NRF1 binding, BAT-specific Fundc1 KO with cold-stress phenotyping

    PMID:33554448

    Open questions at the time
    • Quantitative coupling between biogenesis and turnover not modeled
  14. 2021 High

    Identified the deubiquitinase opposing MARCH5: ER-resident USP19 deubiquitinates FUNDC1 at contact sites and promotes DRP1 oligomerization and GTPase activity for fission.

    Evidence Deubiquitination assay, DRP1 GTPase assay, USP19 knockdown, contact-site localization

    PMID:33978709

    Open questions at the time
    • How deubiquitination mechanistically activates DRP1 not fully defined
  15. 2021 High

    Established FUNDC1 as a MAM organizer driving angiogenesis: MAM-dependent Ca2+ rise phosphorylates SRF to transactivate VEGFR2 in endothelium.

    Evidence Endothelial-specific KO, Ca2+ imaging, ChIP for SRF on VEGFR2 promoter, angiogenesis assays

    PMID:33972548

    Open questions at the time
    • Direct tether partners forming endothelial MAMs not fully enumerated
  16. 2021 Medium

    Connected the phospho-state to downstream adaptor selection: phosphorylated FUNDC1 fails to bind NIPSNAP1/2, and NLRX1 modulates this, gating mitophagy initiation.

    Evidence Phospho-dependent Co-IP, NLRX1 gain/loss, in vivo intestinal IR model

    PMID:33432610

    Open questions at the time
    • Single lab
    • Hierarchy between NIPSNAP and LC3 binding unresolved
  17. 2022 Medium

    Defined an mtDNA-protective role: FUNDC1 binds TUFM via its 96-133 domain to prevent cytosolic mtDNA release and PANoptosis in cardiomyocytes.

    Evidence Co-IP, domain truncation, TUFM knockdown rescue, mtDNA cytosolic-release assay

    PMID:36470869

    Open questions at the time
    • Single lab
    • Whether mtDNA stabilization is independent of mitophagy not fully separated
  18. 2023 High

    Linked nutrient lipids to receptor turnover: palmitate-driven LPI monomerizes FUNDC1, promoting K104 acetylation (Tip60/HDAC3) and MARCH5-dependent degradation that lowers mitophagy capacity in NASH.

    Evidence Dimerization, acetylation and ubiquitination assays, HDAC3/Tip60 Co-IP, lipidomics, NASH model

    PMID:36847607

    Open questions at the time
    • Structural basis of the dimer-to-monomer shift undefined
  19. 2023 Medium

    Implicated FUNDC1 in ferroptosis: it recruits GPx4 to mitochondria via its 96-133 domain through TOM/TIM for mitophagic degradation, triggering hepatocyte ferroptosis.

    Evidence Co-IP, domain mapping, colocalization, FUNDC1 KO mice with ferroptosis readouts

    PMID:36828120

    Open questions at the time
    • Single lab
    • Overlap of GPx4 and TUFM binding at the same 96-133 domain not reconciled
  20. 2023 Medium

    Showed a LIR-independent import function in proteinopathy: FUNDC1 promotes TDP-43/TOM70 and DNAJA2/TOM70 interactions and raises LONP1 to clear cytosolic TDP-43.

    Evidence Co-IP, LIR-mutant analysis, Drosophila TDP-43 epistasis, mitophagy flux

    PMID:37951930

    Open questions at the time
    • Single lab
    • Whether enhanced import is protective or pathogenic context-dependent
  21. 2023 Medium

    Refined the Lon/EMC interplay: mitochondrial Lon localizes to ER-mitochondria contacts under hypoxia, associates with the FUNDC1-ULK1 complex and NCLX to promote mitophagy.

    Evidence Co-IP of Lon-FUNDC1-ULK1 and Lon-NCLX, EMC fractionation, hypoxia models

    PMID:36927870

    Open questions at the time
    • Single lab
    • Causal role of NCLX Ca2+ flux in mitophagy initiation unresolved
  22. 2023 Medium

    Identified a pharmacological activation route: dapagliflozin engages a PKM2/PP1 axis to dephosphorylate FUNDC1 and activate cardioprotective mitophagy.

    Evidence Co-IP, docking, PKM2 and FUNDC1 cardiomyocyte-specific KO epistasis, phospho-state analysis

    PMID:37541471

    Open questions at the time
    • Single lab
    • Which FUNDC1 residues PP1 dephosphorylates not specified
  23. 2024 Medium

    Connected FUNDC1 to ferroptosis via ACSL4: FUNDC1 binds ACSL4 and its loss elevates ACSL4 to accentuate cardiomyocyte ferroptosis in sepsis.

    Evidence Co-IP, interface analysis, FUNDC1-/- CLP model, ACSL4 inhibitor rescue

    PMID:39326685

    Open questions at the time
    • Single lab
    • Mechanism by which FUNDC1 restrains ACSL4 levels undefined
  24. 2024 Medium

    Generalized FUNDC1's role to autophagosome biogenesis: in cardiomyocytes it maintains MERC structure required for ATG5-ATG12/ATG16L1 assembly, not mitophagy alone.

    Evidence Confocal/TEM MERC imaging, autophagic flux reporter, ATG complex blotting, AAV cardiac overexpression

    PMID:38948070

    Open questions at the time
    • Single lab
    • How MERC integrity templates ATG complex formation mechanistically unclear
  25. 2024 High

    Demonstrated FUNDC1 sufficiency for vascular disease: endothelial Fundc1 loss alone causes pulmonary hypertension via impaired basal mitophagy, mtROS-HIF2α pseudohypoxia, senescence and IGFBP2 secretion.

    Evidence Endothelial inducible KO, global KO/TG mice, PH models, transcriptomic/metabolic profiling, IGFBP2 assay

    PMID:39655444

    Open questions at the time
    • IGFBP2 receptor signaling in remodeling not fully mapped
  26. 2025 Medium

    Linked FUNDC1 mitophagy to innate immunity: CK2-driven FUNDC1 phosphorylation suppresses mitophagy and promotes mtROS-dependent NLRP3 inflammasome activation in sepsis.

    Evidence CK2 kinase assay, mitophagy flux, NLRP3 KO and macrophage-specific FUNDC1 KO sepsis model

    PMID:40520006

    Open questions at the time
    • Single lab
    • Direct coupling between mitophagy defect and NLRP3 priming vs activation not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple LIR-independent functions (HSC70/LONP1 import, complex V preservation, TUFM/mtDNA stabilization, GPx4/ACSL4 ferroptosis) are coordinated with the canonical receptor role on a single outer-membrane protein, and what determines context-specific partner selection, remains unresolved.
  • No integrated structural/topology model explaining how one cytosolic loop services so many partners
  • Residue-level rules governing partner switching across stresses undefined
  • Most non-canonical functions rest on single-lab studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005739 mitochondrion 3 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
DRP1HSC70MAP1LC3BMARCH5OPA1PGAM5ULK1USP19
Complex memberships
ER-mitochondria contact site (MAM/MERC)FUNDC1-ULK1 mitophagy initiation complexMARCH5 ubiquitination complexPGAM5-BCL-xL regulatory complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 FUNDC1 is an integral mitochondrial outer-membrane protein that acts as a receptor for hypoxia-induced mitophagy by directly interacting with LC3 through its LIR motif (Y18xxL21). Mutation of this LIR motif abolishes LC3 interaction and mitophagy. Hypoxia induces dephosphorylation of FUNDC1, enhancing its interaction with LC3. Co-immunoprecipitation, site-directed mutagenesis of LIR motif, knockdown/rescue experiments, live-cell imaging of mitophagy Nature cell biology High 22267086
2014 ULK1 translocates to mitochondria upon mitophagy induction and phosphorylates FUNDC1 at Ser17, which enhances FUNDC1 binding to LC3 and promotes mitophagy. A FUNDC1 mutant that cannot bind ULK1 prevents ULK1 translocation to mitochondria. Phospho-mimicking FUNDC1(S17) rescues mitophagy in ULK1-null cells. In vitro kinase assay, Co-IP, ULK1-null cell complementation, site-directed mutagenesis, mitophagy flux assays EMBO reports High 24671035
2016 FUNDC1 interacts with both OPA1 (via OPA1 Lys70) and DRP1 to coordinate mitochondrial fission/fusion and mitophagy. Under mitochondrial stress, dephosphorylation of FUNDC1 promotes dissociation from OPA1 and enhanced association with DRP1, coupling mitochondrial dynamics to mitophagy. Co-immunoprecipitation, site-directed mutagenesis (OPA1-K70A/K70R), FCCP/selenite stress treatments, mitophagy and fission assays Autophagy High 27050458
2016 FUNDC1 localizes to the MAM (mitochondria-associated membrane) by associating with ER-resident protein calnexin. During hypoxia-induced mitophagy, FUNDC1 dissociates from calnexin and its cytosolic loop instead recruits DRP1 to MAM sites to drive mitochondrial fission prior to autophagosome engulfment. Co-immunoprecipitation, subcellular fractionation, confocal microscopy, siRNA knockdown of FUNDC1/DRP1/calnexin with mitophagy/fission readouts The EMBO journal High 27145933
2016 Crystal structure of LC3B in complex with a phosphorylated FUNDC1 LIR peptide (pSer17) reveals that LC3B Lys49 forms a hydrogen bond and electrostatic interaction with the phosphate group of FUNDC1 pSer17, explaining how phosphorylation at Ser17 enhances binding. Phosphorylation at Tyr18 or Ser13 sterically inhibits LC3B interaction. X-ray crystallography, isothermal titration calorimetry (ITC), mutagenesis of key residues Protein & cell High 27757847
2017 MARCH5 (a mitochondrial E3 ubiquitin ligase) directly interacts with FUNDC1 and ubiquitinates it at Lys119, targeting FUNDC1 for proteasomal degradation and thereby fine-tuning hypoxia-induced mitophagy. Knockdown of MARCH5 leads to FUNDC1 accumulation and exaggerated mitophagy. Co-immunoprecipitation, ubiquitination assay, MARCH5 knockdown/overexpression, site-directed mutagenesis (K119) EMBO reports High 28104734
2019 PGAM5 phosphatase exists in an equilibrium between dimeric and multimeric states and dephosphorylates FUNDC1 to activate mitofission and mitophagy. Oxidative stress increases PGAM5 multimerization, freeing it from BCL-xL and enabling FUNDC1 dephosphorylation to initiate mitophagy. Co-immunoprecipitation, phosphatase activity assays, PGAM5 multimerization analysis, BCL-xL interaction studies Cell death and differentiation High 31367011
2018 CK2α (casein kinase 2α) phosphorylates FUNDC1 at Ser13, inactivating mitophagy. Cardiac-specific CK2α knockout mice are protected from ischemia-reperfusion injury; double knockout of both CK2α and FUNDC1 abolishes this protection, placing CK2α upstream of FUNDC1 in mitophagy regulation. Kinase assay showing CK2α phosphorylates FUNDC1-Ser13, cardiac-specific CK2α KO mice, double KO epistasis, mitophagy flux assays Cell death and differentiation High 29540794
2019 FUNDC1 interacts with the chaperone HSC70 at the mitochondrial outer membrane to promote mitochondrial translocation of unfolded cytosolic proteins for degradation by LONP1 or formation of mitochondrion-associated protein aggregates (MAPAs). Excessive unfolded protein accumulation through this pathway impairs mitochondrial integrity and activates AMPK, leading to cellular senescence. Co-immunoprecipitation, APEX proximity labeling, csCLEM, biochemical fractionation, FUNDC1 knockdown with proteasome inhibition The EMBO journal High 30591555
2021 PGC-1α and NRF1 (master regulators of mitochondrial biogenesis) transcriptionally upregulate FUNDC1 expression by NRF1 binding to the classic consensus site in the FUNDC1 promoter, coupling mitochondrial biogenesis and mitophagy. Specific knockout of Fundc1 in brown adipose tissue impairs adaptive thermogenesis. ChIP assay (NRF1 binding to FUNDC1 promoter), BAT-specific Fundc1 KO mice, cold-stress experiments, mitochondrial turnover assays EMBO reports High 33554448
2021 USP19, an ER-resident deubiquitinase, accumulates at ER-mitochondria contact sites under hypoxia and deubiquitinates FUNDC1, which facilitates DRP1 oligomerization and GTP-binding/hydrolysis activity, thereby promoting mitochondrial fission. Co-immunoprecipitation, deubiquitination assay, DRP1 GTPase activity assay, USP19 knockdown, confocal localization at ER-mitochondria contacts The Journal of cell biology High 33978709
2020 FUNDC1 interacts with FBXL2 (F-box subunit of SCF E3 ubiquitin ligase) via co-immunoprecipitation identified by mass spectrometry. This interaction gates mitochondrial Ca2+ homeostasis by regulating IP3R3 degradation. FUNDC1 deficiency accelerates FBXL2 degradation and stabilizes IP3R3, causing Ca2+ overload. Mass spectrometry, co-immunoprecipitation, FUNDC1-/- mice, truncated mutant analysis (Delta-F-box), IP3R3 inhibition rescue experiments Science advances High 32938669
2021 FUNDC1 mediates formation of mitochondria-associated ER membranes (MAMs) in endothelial cells. FUNDC1-dependent MAM formation increases cytosolic Ca2+ levels, promotes phosphorylation of SRF, and enhances SRF binding to the VEGFR2 promoter, resulting in increased VEGFR2 production and angiogenesis. Endothelial-specific FUNDC1 deletion disrupts MAM formation and impairs angiogenesis. Endothelial cell-specific FUNDC1 KO, MAM formation assays, Ca2+ imaging, ChIP (SRF binding to VEGFR2 promoter), tube formation/spheroid sprouting assays, in vivo angiogenesis models Nature communications High 33972548
2020 FUNDC1 independently of its mitophagy receptor role interacts at the mitochondrial inner membrane with the AAA+ protease LonP1 and subunits of oxidative phosphorylation complex V (ATP synthase). This FUNDC1-LonP1 axis enables LonP1 proteostasis, preserving complex V function and decreasing ROS generation. Global metabolomics, proteomics/interactome profiling, FUNDC1 knockdown in cancer cells with specific readouts for LonP1 activity and complex V function Science signaling Medium 32723812
2023 FUNDC1 interacts with GPx4 (glutathione peroxidase 4) via its 96-133 amino acid domain, facilitating GPx4 recruitment from cytoplasm to mitochondria through the TOM/TIM import complex. Mitophagy then degrades GPx4 in mitochondria, triggering ferroptosis in hepatocytes. Co-immunoprecipitation, domain truncation mapping, immunofluorescence colocalization, FUNDC1 KO mice with ferroptosis readouts Journal of advanced research Medium 36828120
2022 FUNDC1 interacts with mitochondrial Tu translation elongation factor (TUFM) via its 96-133 amino acid domain. This interaction stabilizes mtDNA by preventing cytoplasmic release of mtDNA and activation of PANoptosis. TUFM knockdown reverses FUNDC1-dependent protection against DOX-induced cardiomyocyte PANoptosis. Co-immunoprecipitation, domain truncation analysis, TUFM knockdown rescue experiments, mtDNA cytosolic release assay Cell death & disease Medium 36470869
2023 Saturated fatty acids (palmitic acid) increase lysophosphatidylinositol (LPI) production, which shifts FUNDC1 from dimer to monomer. Monomeric FUNDC1 shows increased acetylation at K104 due to dissociation of HDAC3 and increased interaction with Tip60. Acetylated FUNDC1 is then ubiquitinated by MARCH5 for proteasomal degradation, reducing mitophagy capacity. Biochemical dimerization assays, acetylation/ubiquitination assays, HDAC3/Tip60 Co-IP, MARCH5 interaction, lipidomics (LPI quantification), NASH mouse model validation EMBO reports High 36847607
2023 FUNDC1 promotes mitochondrial translocation of TDP-43 by facilitating TDP-43-TOM70 and DNAJA2-TOM70 interactions (independent of its LIR domain). FUNDC1 also increases LONP1 levels and activates mitophagy to regulate cytosolic TDP-43 clearance. In a Drosophila TDP-43 proteinopathy model, overexpressing FUNDC1 enhances TDP-43-induced mitochondrial damage while downregulating FUNDC1 reverses it. Co-immunoprecipitation (TDP-43/TOM70/DNAJA2), LIR mutant analysis, Drosophila transgenic model, LONP1 activity measurement, mitophagy flux assays Cell death & disease Medium 37951930
2023 Mitochondrial Lon protease localizes at ER-mitochondria contact sites (EMC) under hypoxia and associates with the FUNDC1-ULK1 complex via chaperone activity. Lon also binds to mitochondrial Na+/Ca2+ exchanger (NCLX) to promote FUNDC1-ULK1-mediated mitophagy at the EMC. Co-immunoprecipitation (Lon-FUNDC1-ULK1, Lon-NCLX), subcellular fractionation to EMC, in vitro and in vivo hypoxia experiments Cell death & disease Medium 36927870
2024 FUNDC1 deficiency in endothelial cells impairs basal mitophagy, leading to accumulation of dysfunctional mitochondria, metabolic reprogramming toward aerobic glycolysis, pseudohypoxia via mtROS-HIF2α signaling, and cellular senescence. Fundc1-deficient endothelial cells increase IGFBP2 secretion that drives pulmonary arterial remodeling. Inducible loss of endothelial Fundc1 alone is sufficient to spontaneously cause pulmonary hypertension. Endothelial cell-specific inducible Fundc1 KO mice, global KO and TG mice, HySu and chronic hypoxia PH models, transcriptomic/metabolic profiling, mtROS and HIF2α pathway studies, IGFBP2 secretion assay Circulation research High 39655444
2014 miR-137 (a hypoxia-responsive microRNA) targets the 3'UTR of FUNDC1 mRNA to reduce FUNDC1 protein expression, thereby decreasing mitophagy receptor availability and inhibiting hypoxia-induced mitophagy. Re-expression of FUNDC1 lacking miR-137 recognition sites rescues mitophagy. miRNA target validation, 3'UTR reporter assays, miR-137 overexpression/inhibition, mitophagy assays, rescue with miR-137-resistant FUNDC1 The Journal of biological chemistry Medium 24573672
2021 Phosphorylated (inactive) FUNDC1 cannot interact with the mitophagy adaptor proteins NIPSNAP1 and NIPSNAP2 on the outer membrane of damaged mitochondria, preventing mitophagy initiation. NLRX1 regulates FUNDC1 phosphorylation state to control this interaction. Co-immunoprecipitation demonstrating phospho-FUNDC1 fails to bind NIPSNAP1/2, NLRX1 overexpression/knockdown, in vivo intestinal IR model Cell proliferation Medium 33432610
2019 FUNDC1 is an outer mitochondrial membrane protein required for proper body axis formation in zebrafish. Fundc1 colocalized with mitochondria markers and induced LC3B activation. Knockdown of zebrafish Fundc1 causes midline bifurcation (two notochords and two spinal cords), which is rescued by co-injection of Fundc1 mRNA. shRNA knockdown, mRNA rescue in zebrafish embryos, co-immunostaining with mitochondrial/lysosomal markers, TUNEL, BrdU incorporation in HEK293T cells Scientific reports Medium 31827208
2024 FUNDC1 interacts with ACSL4 (acyl-CoA synthetase long-chain family member 4). Co-immunoprecipitation and interaction interface analysis revealed this direct interaction. FUNDC1 ablation in sepsis leads to upregulated ACSL4 and accentuated ferroptosis and mitochondrial injury in cardiomyocytes. Co-immunoprecipitation, interaction interface analysis, FUNDC1-/- mice CLP model, ACSL4 inhibitor rescue experiments Free radical biology & medicine Medium 39326685
2024 FUNDC1 maintains ER-mitochondria contact sites (MERCs) in cardiomyocytes; FUNDC1 downregulation by doxorubicin disrupts MERC structure and blocks autophagosome biogenesis (not mitophagy specifically) by impairing ATG5-ATG12/ATG16L1 complex formation. FUNDC1 overexpression restores autophagosome biogenesis and protects against doxorubicin cardiotoxicity. Confocal microscopy and TEM for MERC structure, mCherry-EGFP-LC3B autophagic flux assay, ATG complex western blotting, AAV-mediated cardiac-specific FUNDC1 overexpression, echocardiography Theranostics Medium 38948070
2023 Dapagliflozin activates FUNDC1-dependent mitophagy through a PKM2/PP1 axis: PKM2 directly interacts with protein phosphatase 1 (PP1) and FUNDC1, leading to PP1-mediated FUNDC1 dephosphorylation and mitophagy activation. Ablation of FUNDC1 abolishes dapagliflozin's protective effects on myocardium in cardiorenal syndrome type 4. Co-IP, molecular docking, PKM2CKO and FUNDC1CKO mice, phosphorylation state analysis, mitochondrial function assays International journal of biological macromolecules Medium 37541471
2025 CK2-mediated phosphorylation of FUNDC1 suppresses mitophagy and promotes NLRP3 inflammasome activation via mitochondrial ROS. Emodin inhibits CK2-mediated FUNDC1 phosphorylation, thereby promoting FUNDC1-dependent mitophagy and preventing mtROS-induced NLRP3 assembly. Macrophage-specific FUNDC1 deletion abolishes emodin's protective effects in sepsis. CK2 kinase assay on FUNDC1, RNA-seq, mitophagy flux assay, FUNDC1 genetic silencing, NLRP3 KO and macrophage-specific FUNDC1 KO in vivo sepsis model International journal of biological sciences Medium 40520006

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nature cell biology 1391 22267086
2016 Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy 484 27050458
2014 ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO reports 479 24671035
2018 Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2α-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy. Cell death and differentiation 357 29540794
2016 FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions. The EMBO journal 302 27145933
2017 Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury. Redox biology 282 28732308
2018 NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. Basic research in cardiology 277 29744594
2017 Mitochondrial E3 ligase MARCH5 regulates FUNDC1 to fine-tune hypoxic mitophagy. EMBO reports 261 28104734
2019 BNIP3L/NIX and FUNDC1-mediated mitophagy is required for mitochondrial network remodeling during cardiac progenitor cell differentiation. Autophagy 254 30741592
2017 Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways. Journal of pineal research 227 28749565
2022 Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway. Redox biology 206 35325804
2019 Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fission. Redox biology 203 31901590
2019 Deficiency of mitophagy receptor FUNDC1 impairs mitochondrial quality and aggravates dietary-induced obesity and metabolic syndrome. Autophagy 198 30898010
2017 Mitophagy receptor FUNDC1 regulates mitochondrial homeostasis and protects the heart from I/R injury. Autophagy 175 28323531
2020 FUNDC1-dependent mitophagy induced by tPA protects neurons against cerebral ischemia-reperfusion injury. Redox biology 174 33212415
2016 FUNDC1 is a novel mitochondrial-associated-membrane (MAM) protein required for hypoxia-induced mitochondrial fission and mitophagy. Autophagy 167 27314574
2023 FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner. Journal of advanced research 164 36828120
2019 DNA-PKcs promotes alcohol-related liver disease by activating Drp1-related mitochondrial fission and repressing FUNDC1-required mitophagy. Signal transduction and targeted therapy 157 31839999
2021 Mitophagy receptor FUNDC1 is regulated by PGC-1α/NRF1 to fine tune mitochondrial homeostasis. EMBO reports 136 33554448
2021 FUNDC1 insufficiency sensitizes high fat diet intake-induced cardiac remodeling and contractile anomaly through ACSL4-mediated ferroptosis. Metabolism: clinical and experimental 136 34331963
2016 Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy. Protein & cell 135 27757847
2023 Neutrophil extracellular traps drive intestinal microvascular endothelial ferroptosis by impairing Fundc1-dependent mitophagy. Redox biology 131 37812880
2022 FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM. Cell death & disease 126 36470869
2014 MicroRNA-137 is a novel hypoxia-responsive microRNA that inhibits mitophagy via regulation of two mitophagy receptors FUNDC1 and NIX. The Journal of biological chemistry 125 24573672
2019 Dynamic PGAM5 multimers dephosphorylate BCL-xL or FUNDC1 to regulate mitochondrial and cellular fate. Cell death and differentiation 122 31367011
2020 FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity. Science advances 118 32938669
2022 FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia. Cell death & disease 112 35864106
2021 FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes are involved in angiogenesis and neoangiogenesis. Nature communications 107 33972548
2018 Mst1 promotes cardiac ischemia-reperfusion injury by inhibiting the ERK-CREB pathway and repressing FUNDC1-mediated mitophagy. The journal of physiological sciences : JPS 104 29961191
2018 A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity. The EMBO journal 97 30591555
2021 NLRX1/FUNDC1/NIPSNAP1-2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury. Cell proliferation 84 33432610
2020 Alpha-lipoic acid protects against pressure overload-induced heart failure via ALDH2-dependent Nrf1-FUNDC1 signaling. Cell death & disease 78 32732978
2020 Electroacupuncture preconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting mitophagy mediated by the mTORC1-ULK1-FUNDC1 pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 72 32344255
2023 Artesunate Sensitizes human hepatocellular carcinoma to sorafenib via exacerbating AFAP1L2-SRC-FUNDC1 axis-dependent mitophagy. Autophagy 69 37733919
2021 The role of FUNDC1 in mitophagy, mitochondrial dynamics and human diseases. Biochemical pharmacology 68 34968482
2020 The mitophagy effector FUNDC1 controls mitochondrial reprogramming and cellular plasticity in cancer cells. Science signaling 67 32723812
2020 The mitophagy receptor FUN14 domain-containing 1 (FUNDC1): A promising biomarker and potential therapeutic target of human diseases. Genes & diseases 65 34291135
2021 FUNDC1: A Promising Mitophagy Regulator at the Mitochondria-Associated Membrane for Cardiovascular Diseases. Frontiers in cell and developmental biology 63 35096821
2017 MARCH5-FUNDC1 axis fine-tunes hypoxia-induced mitophagy. Autophagy 59 28486049
2021 USP19 promotes hypoxia-induced mitochondrial division via FUNDC1 at ER-mitochondria contact sites. The Journal of cell biology 52 33978709
2024 FUNDC1 alleviates doxorubicin-induced cardiotoxicity by restoring mitochondrial-endoplasmic reticulum contacts and blocked autophagic flux. Theranostics 51 38948070
2019 Hydrogen gas inhalation attenuates sepsis-induced liver injury in a FUNDC1-dependent manner. International immunopharmacology 51 30877875
2023 Exercise protects aged mice against coronary endothelial senescence via FUNDC1-dependent mitophagy. Redox biology 48 37030149
2018 Ulk1/FUNDC1 Prevents Nerve Cells from Hypoxia-Induced Apoptosis by Promoting Cell Autophagy. Neurochemical research 44 29923038
2018 Hydrogen peroxide-induced mitophagy contributes to laryngeal cancer cells survival via the upregulation of FUNDC1. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 44 30284230
2022 Src Activation Aggravates Podocyte Injury in Diabetic Nephropathy via Suppression of FUNDC1-Mediated Mitophagy. Frontiers in pharmacology 43 35614934
2022 Puerarin inhibits FUNDC1-mediated mitochondrial autophagy and CSE-induced apoptosis of human bronchial epithelial cells by activating the PI3K/AKT/mTOR signaling pathway. Aging 42 35134750
2022 IL-6/STAT3 Signaling Promotes Cardiac Dysfunction by Upregulating FUNDC1-Dependent Mitochondria-Associated Endoplasmic Reticulum Membranes Formation in Sepsis Mice. Frontiers in cardiovascular medicine 40 35118141
2021 Overexpression of PLK1 relieved the myocardial ischemia-reperfusion injury of rats through inducing the mitophagy and regulating the p-AMPK/FUNDC1 axis. Bioengineered 39 34115550
2022 Ablation of FUNDC1-dependent mitophagy renders myocardium resistant to paraquat-induced ferroptosis and contractile dysfunction. Biochimica et biophysica acta. Molecular basis of disease 38 35598771
2021 FUNDC1 inhibits NLRP3-mediated inflammation after intracerebral hemorrhage by promoting mitophagy in mice. Neuroscience letters 38 34022268
2023 Neutrophil extracellular traps aggravate intestinal epithelial necroptosis in ischaemia-reperfusion by regulating TLR4/RIPK3/FUNDC1-required mitophagy. Cell proliferation 37 37691112
2018 PEDF protects cardiomyocytes by promoting FUNDC1‑mediated mitophagy via PEDF-R under hypoxic condition. International journal of molecular medicine 37 29512692
2023 Hypoxic mesenchymal stem cell-derived exosomes promote the survival of skin flaps after ischaemia-reperfusion injury via mTOR/ULK1/FUNDC1 pathways. Journal of nanobiotechnology 36 37735391
2023 Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface. Cell death & disease 34 36927870
2023 NTRK1 knockdown induces mouse cognitive impairment and hippocampal neuronal damage through mitophagy suppression via inactivating the AMPK/ULK1/FUNDC1 pathway. Cell death discovery 34 37907480
2021 LncRNA MEG3 Alleviates Diabetic Cognitive Impairments by Reducing Mitochondrial-Derived Apoptosis through Promotion of FUNDC1-Related Mitophagy via Rac1-ROS Axis. ACS chemical neuroscience 34 33843209
2022 Selenium alleviates cadmium-induced mitophagy through FUNDC1-mediated mitochondrial quality control pathway in the lungs of sheep. Environmental pollution (Barking, Essex : 1987) 32 36581240
2023 Saturated fatty acids increase LPI to reduce FUNDC1 dimerization and stability and mitochondrial function. EMBO reports 31 36847607
2022 FUNDC1 Induces Apoptosis and Autophagy Under Oxidative Stress via PI3K/Akt/mTOR Pathway in Cataract Lens Cells. Current eye research 31 35179404
2021 Melatonin inhibits triple-negative breast cancer progression through the Lnc049808-FUNDC1 pathway. Cell death & disease 31 34272359
2024 Src inhibition rescues FUNDC1-mediated neuronal mitophagy in ischaemic stroke. Stroke and vascular neurology 30 37793899
2023 FUNDC1: An Emerging Mitochondrial and MAMs Protein for Mitochondrial Quality Control in Heart Diseases. International journal of molecular sciences 30 37298100
2023 SGLT2 inhibitor empagliflozin alleviates cardiac remodeling and contractile anomalies in a FUNDC1-dependent manner in experimental Parkinson's disease. Acta pharmacologica Sinica 30 37679644
2019 Silencing FUNDC1 alleviates chronic obstructive pulmonary disease by inhibiting mitochondrial autophagy and bronchial epithelium cell apoptosis under hypoxic environment. Journal of cellular biochemistry 30 31237014
2022 FUNDC1 activates the mitochondrial unfolded protein response to preserve mitochondrial quality control in cardiac ischemia/reperfusion injury. Cellular signalling 29 35051611
2024 Multiple roles of mitochondrial autophagy receptor FUNDC1 in mitochondrial events and kidney disease. Frontiers in cell and developmental biology 28 39445333
2022 Empagliflozin activates Wnt/β-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance against type-3 cardiorenal syndrome. Molecular metabolism 28 35863636
2022 Ferulic acid attenuates high glucose-induced MAM alterations via PACS2/IP3R2/FUNDC1/VDAC1 pathway activating proapoptotic proteins and ameliorates cardiomyopathy in diabetic rats. International journal of cardiology 27 36481261
2024 AP39 through AMPK-ULK1-FUNDC1 pathway regulates mitophagy, inhibits pyroptosis, and improves doxorubicin-induced myocardial fibrosis. iScience 26 38558936
2023 Activation of ULK1 to trigger FUNDC1-mediated mitophagy in heart failure: Effect of Ginsenoside Rg3 intervention. Phytomedicine : international journal of phytotherapy and phytopharmacology 26 37659296
2023 MiR-130a-3p regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial ischemia/reperfusion injury. Cell death discovery 25 36841811
2022 Hypoxia Acclimation Protects against Heart Failure Postacute Myocardial Infarction via Fundc1-Mediated Mitophagy. Oxidative medicine and cellular longevity 25 35422895
2021 The Emerging Role of FUNDC1-Mediated Mitophagy in Cardiovascular Diseases. Frontiers in physiology 25 34975548
2024 FUNDC1-induced mitophagy protects spinal cord neurons against ischemic injury. Cell death discovery 24 38177127
2024 Ablation of mitophagy receptor FUNDC1 accentuates septic cardiomyopathy through ACSL4-dependent regulation of ferroptosis and mitochondrial integrity. Free radical biology & medicine 24 39326685
2024 Endothelial FUNDC1 Deficiency Drives Pulmonary Hypertension. Circulation research 24 39655444
2021 BI-1 ameliorates myocardial injury by activating the mitochondrial unfolded protein response and FUNDC1-related mitophagy in cardiorenal syndrome type 3. Cellular signalling 24 34921980
2019 Ginkgolic Acids Impair Mitochondrial Function by Decreasing Mitochondrial Biogenesis and Promoting FUNDC1-Dependent Mitophagy. Journal of agricultural and food chemistry 24 31418272
2024 Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury. Renal failure 23 38584135
2022 FUN14 Domain Containing 1 (FUNDC1): A Promising Mitophagy Receptor Regulating Mitochondrial Homeostasis in Cardiovascular Diseases. Frontiers in pharmacology 23 35645834
2022 N-acetyl-L-cysteine alleviates FUNDC1-mediated mitophagy by regulating mitochondrial dynamics in type 1 diabetic nephropathy canine. Life sciences 23 36521547
2020 FUNDC1 regulates receptor-mediated mitophagy independently of the PINK1/Parkin-dependent pathway in rotenone-treated SH-SY5Y cells. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 23 32001317
2023 Poricoic acid A induces mitophagy to ameliorate podocyte injury in diabetic kidney disease via downregulating FUNDC1. Journal of biochemical and molecular toxicology 22 37706594
2021 Electroacupuncture Pretreatment Alleviates Cerebral Ischemia-Reperfusion Injury by Regulating Mitophagy via mTOR-ULK1/FUNDC1 Axis in Rats. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 22 34775182
2024 PHLDA1 contributes to hypoxic ischemic brain injury in neonatal rats via inhibiting FUNDC1-mediated mitophagy. Acta pharmacologica Sinica 20 38750074
2020 Circular RNA FUNDC1 improves prediction of stroke associated infection in acute ischemic stroke patients with high risk. Bioscience reports 20 32537657
2019 Fundc1 is necessary for proper body axis formation during embryogenesis in zebrafish. Scientific reports 19 31827208
2022 Molybdenum and Cadmium Co-induce Mitochondrial Quality Control Disorder via FUNDC1-Mediated Mitophagy in Sheep Kidney. Frontiers in veterinary science 18 35155662
2022 Melatonin Improved the Survival of Multi-Territory Perforator Flaps by Promoting Angiogenesis and Inhibiting Apoptosis via the NRF2/FUNDC1 Axis. Frontiers in pharmacology 18 35685624
2023 Dapagliflozin protects heart function against type-4 cardiorenal syndrome through activation of PKM2/PP1/FUNDC1-dependent mitophagy. International journal of biological macromolecules 17 37541471
2021 FUNDC1 Regulates Autophagy by Inhibiting ROS-NLRP3 Signaling to Avoid Apoptosis in the Lung in a Lipopolysaccharide-Induced Mouse Model. Shock (Augusta, Ga.) 17 34238903
2020 Induction of mitophagy in C2C12 cells by electrical pulse stimulation involves increasing the level of the mitochondrial receptor FUNDC1 through the AMPK-ULK1 pathway. American journal of translational research 17 33194079
2022 Increased FUN14 domain containing 1 (FUNDC1) ubiquitination level inhibits mitophagy and alleviates the injury in hypoxia-induced trophoblast cells. Bioengineered 16 34699308
2019 FUNDC1-mediated mitophagy in bovine papillomavirus-infected urothelial cells. Veterinary microbiology 15 31213272
2025 Emodin Inhibits NLRP3 Inflammasome Activation and Protects Against Sepsis via Promoting FUNDC1-Mediated Mitophagy. International journal of biological sciences 14 40520006
2023 Effects of honokiol protects against chronic kidney disease via BNIP3/NIX and FUNDC1-mediated mitophagy and AMPK pathways. Molecular biology reports 14 37338733
2023 Integration of FUNDC1-associated mitochondrial protein import and mitochondrial quality control contributes to TDP-43 degradation. Cell death & disease 14 37951930
2022 The multi-faced role of FUNDC1 in mitochondrial events and human diseases. Frontiers in cell and developmental biology 14 35959490
2022 FUNDC1 Mediated Mitophagy in Epileptic Hippocampal Neuronal Injury Induced by Magnesium-Free Fluid. Neurochemical research 14 36094682

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