Affinage

FUNDC2

FUN14 domain-containing protein 2 · UniProt Q9BWH2

Length
189 aa
Mass
20.7 kDa
Annotated
2026-04-28
18 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FUNDC2 is a conserved mitochondrial outer membrane protein that integrates lipid signaling, mitochondrial dynamics, ferroptosis regulation, and transcriptional control of lipid metabolism. It binds PIP3 via its N-terminal motif to activate AKT signaling, sustaining BAD/BCL-xL-mediated cell survival and GSK-3β/cGMP-dependent platelet activation, such that FUNDC2 knockout mice exhibit thrombocytopenia and deficient hemostasis (PMID:29786068, PMID:30576423). FUNDC2 interacts with the GTPase domain of MFN1 through its N-terminal region to suppress MFN1 GTPase activity and inhibit mitochondrial fusion, and separately interacts with the mitochondrial glutathione transporter SLC25A11 to maintain mitochondrial GSH levels and GPX4 stability, thereby modulating ferroptosis sensitivity (PMID:35710796, PMID:36037337). In the nucleus, FUNDC2 directly binds the C/EBPβ site in the SREBP1c promoter to upregulate SREBP1c transcription and regulate triglyceride metabolism, and its deficiency in mice exacerbates NAFLD through impaired AMPK-dependent lipolysis and fatty acid oxidation (PMID:29187281, PMID:32535386).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2015 Medium

    The first functional link between FUNDC2 and intracellular lipid metabolism was established, showing it negatively regulates triglyceride accumulation via the SREBP1c/FASN pathway in hepatocytes, moving the gene beyond its initial identification as a hepatitis C-binding protein.

    Evidence Bidirectional knockdown/overexpression in hepatocytes with TG quantification and SREBP1c/FASN expression analysis

    PMID:25855506

    Open questions at the time
    • No direct DNA- or protein-binding mechanism identified
    • Single lab, no independent replication
    • Relationship between mitochondrial localization and nuclear transcriptional role unexplained
  2. 2018 High

    Two key mechanisms were simultaneously resolved: FUNDC2 was shown to bind PIP3 via its conserved N-terminal motif on the outer mitochondrial membrane to activate AKT/BAD/BCL-xL survival signaling in platelets, and separately to directly bind the C/EBPβ site in the SREBP1c promoter to activate transcription — establishing FUNDC2 as both a lipid-binding signaling scaffold and a transcriptional regulator.

    Evidence PIP3 lipid-binding assays, FUNDC2-KO mice with platelet phenotyping under hypoxia, AKT/BAD phosphorylation analysis; ChIP and in vitro DNA-protein binding assays at the SREBP1c promoter

    PMID:29187281 PMID:29786068

    Open questions at the time
    • Structural basis of PIP3 binding by the N-terminal motif unresolved
    • How FUNDC2, a mitochondrial membrane protein, accesses nuclear chromatin is unexplained
    • Whether PIP3 binding and transcriptional functions are coordinated or independent is unknown
  3. 2019 High

    The AKT signaling role of FUNDC2 was extended downstream to GSK-3β and cGMP in platelets, establishing FUNDC2 as a positive regulator of platelet activation and hemostasis in vivo.

    Evidence FUNDC2-KO mice with multi-agonist platelet aggregation assays, tail bleeding and thrombus formation models, AKT/GSK-3β phosphorylation and cGMP measurement

    PMID:30576423

    Open questions at the time
    • Whether FUNDC2 directly scaffolds AKT or acts indirectly via PIP3 presentation is unresolved
    • Mechanism connecting mitochondrial FUNDC2 to cytoplasmic cGMP regulation not defined
  4. 2020 Medium

    FUNDC2 deficiency was shown to exacerbate NAFLD in mice through impaired AMPK activation, establishing an in vivo metabolic role that complements the earlier hepatocyte lipid findings and positioning FUNDC2 as a regulator of lipolysis and fatty acid oxidation.

    Evidence FUNDC2-KO mice on high-fat diet with metabolic phenotyping (GTT, lipids) and AMPK activation assays

    PMID:32535386

    Open questions at the time
    • Direct mechanism linking FUNDC2 to AMPK activation not identified
    • Relationship between SREBP1c transcriptional activity and AMPK pathway not resolved
    • Single lab finding
  5. 2022 High

    Two new molecular interaction partners were identified — MFN1 and SLC25A11 — revealing that FUNDC2 controls mitochondrial dynamics by inhibiting MFN1 GTPase-mediated fusion and regulates ferroptosis by maintaining mitochondrial GSH through SLC25A11 and GPX4 stability.

    Evidence Co-IP with domain mapping (FUNDC2 N-terminus to MFN1 GTPase domain), FUNDC2-KD liver tumor model with mitochondrial morphology and metabolic readouts; Co-IP of FUNDC2–SLC25A11, FUNDC2-KO mice with doxorubicin cardiac injury, mitoGSH quantification, ferroptosis assays

    PMID:35710796 PMID:36037337

    Open questions at the time
    • Whether MFN1 inhibition and SLC25A11 interaction occur simultaneously or are regulated independently is unknown
    • Structural basis for N-terminal domain interaction with MFN1 GTPase domain unresolved
    • Whether ferroptosis regulation is relevant in tissues beyond the heart not tested
  6. 2022 Medium

    FUNDC2 was found to promote brown adipose tissue thermogenesis by upregulating UCP1, extending its metabolic roles beyond hepatic lipid metabolism to energy expenditure.

    Evidence FUNDC2-KO mice on high-fat diet with BAT transcriptomics, UCP1/PGC1α expression, and mitochondrial quantification

    PMID:36195403

    Open questions at the time
    • No direct mechanism linking FUNDC2 to UCP1 transcription identified
    • Whether the effect is through AMPK, SREBP1c, or a distinct pathway is unknown
    • Single lab
  7. 2023 Medium

    FUNDC2's AKT/GSK-3β signaling role was linked to cancer biology, as FUNDC2 silencing suppressed triple-negative breast cancer proliferation and invasion via inactivation of AKT/GSK-3β and the Hedgehog effector GLI1.

    Evidence FUNDC2 siRNA in TNBC cells with proliferation/invasion assays and xenograft model, Western blot for AKT/GSK-3β/GLI1

    PMID:37700593

    Open questions at the time
    • Whether FUNDC2 directly regulates GLI1 or acts solely through GSK-3β is unknown
    • No direct binding assay for FUNDC2–GLI1 axis
    • Generalizability to other cancer types not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FUNDC2 coordinates its multiple functions — mitochondrial membrane PIP3-binding/AKT activation, MFN1-mediated fusion inhibition, SLC25A11-dependent ferroptosis regulation, and nuclear transcriptional activity at the SREBP1c promoter — remains unresolved, and no structural model exists for any of these interactions.
  • No structural model of FUNDC2 or any of its interaction interfaces
  • Mechanism by which a mitochondrial outer membrane protein accesses chromatin is completely unknown
  • Whether different functions are tissue-specific or co-occur within single cells is not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 2 GO:0098772 molecular function regulator activity 2 GO:0003677 DNA binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005739 mitochondrion 4 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
AKTGPX4MFN1SLC25A11

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 FUNDC2, a mitochondrial outer membrane protein, interacts with SLC25A11 (the mitochondrial glutathione transporter) to regulate mitochondrial GSH (mitoGSH) levels, and also affects the stability of SLC25A11 and GPX4, thereby modulating ferroptotic stress; knockout of FUNDC2 protected mice from doxorubicin-induced cardiac injury by preventing ferroptosis. Co-immunoprecipitation, FUNDC2 knockout mice, siRNA knockdown of SLC25A11 in FUNDC2-KO cells, ferroptosis assays (erastin-induced), mitoGSH measurement Proceedings of the National Academy of Sciences of the United States of America High 36037337
2022 FUNDC2 inhibits mitochondrial fusion by interacting with the GTPase domain of MFN1 (mitofusin 1) via its amino-terminal region, suppressing MFN1 GTPase activity and promoting mitochondrial fragmentation; loss of FUNDC2 leads to mitochondrial elongation, decreased mitochondrial respiration, and reprogrammed cellular metabolism. Co-immunoprecipitation, domain mapping (N-terminal region of FUNDC2 with GTPase domain of MFN1), FUNDC2 knockdown in mouse liver tumor model, mitochondrial morphology imaging, metabolic assays Nature communications High 35710796
2018 FUNDC2 binds the lipid PIP3 via its unique, highly conserved N-terminal motif on the outer mitochondrial membrane; FUNDC2 deficiency abrogates phosphorylation of AKT and its substrate BAD in a PIP3/PI3K-dependent manner, suppressing BCL-xL and shortening platelet lifespan under stress (hypoxia), leading to thrombocytopenia in FUNDC2 knockout mice. Lipid-binding assays (PIP3 binding), FUNDC2 knockout mice, phosphorylation assays (AKT, BAD), platelet apoptosis and lifespan assays, hypoxia model Cell death and differentiation High 29786068
2019 FUNDC2 positively regulates platelet activation and aggregation via the AKT/GSK-3β/cGMP signaling axis; FUNDC2 deficiency impairs AKT and GSK-3β phosphorylation in a PI3K-dependent manner, reducing platelet aggregation in response to ADP, collagen, ristocetin/VWF, and thrombin, and causing deficient hemostasis and thrombosis in vivo. FUNDC2 knockout mice, platelet aggregation assays with multiple agonists, tail bleeding and thrombus formation in vivo, phosphorylation assays (AKT, GSK-3β), cGMP measurement, clot retraction assay Cardiovascular research High 30576423
2021 FUNDC2 mediates mitochondrial translocation of PIP3 via its N-terminal domain, activating the AKT/FOXO3a pathway and inhibiting mitochondrial accumulation of pro-apoptotic Bim, thereby protecting neuronal cells from hypoxia/reoxygenation injury after platelet mitochondria transplantation. Platelet mitochondria transplantation into SH-SY5Y cells, FUNDC2 expression analysis, PIP3 mitochondrial localization assay, AKT/FOXO3a/Bim pathway assessment Cell transplantation Medium 34105393
2015 HCBP6 (FUNDC2) negatively regulates intracellular triglyceride levels in hepatocytes via the SREBP1c/FASN pathway; bidirectional manipulation (knockdown or overexpression) alters TG accumulation, and miR-122 represses HCBP6 expression via its 3'-UTR. HCBP6 knockdown and overexpression in hepatocytes, TG measurement, SREBP1c/FASN expression analysis, luciferase reporter assay with HCBP6 3'-UTR and miR-122 Journal of cellular biochemistry Medium 25855506
2018 HCBP6 (FUNDC2) upregulates SREBP1c transcription by directly binding to the C/EBPβ-binding site in the SREBP1c promoter (−139 to +359 bp region), increasing intracellular TG levels. Promoter-reporter assay, chromatin immunoprecipitation (ChIP), in vitro and in vivo DNA-protein binding assay for HCBP6 at SREBP1c promoter C/EBPβ site BMB reports Medium 29187281
2020 HCBP6 (FUNDC2) deficiency in mice exacerbates NAFLD-associated metabolic disorders; mechanistically, HCBP6 regulates lipolysis and fatty acid oxidation via activation of AMPK in vivo. HCBP6 knockout mice on high-fat diet, metabolic phenotyping (GTT, lipid measurements), AMPK activation assays, Western blot Biomedicine & pharmacotherapy Medium 32535386
2023 FUNDC2 promotes triple-negative breast cancer progression; FUNDC2 silencing reduces cell proliferation, migration, invasion, and in vivo tumor growth, with the mechanism involving inactivation of AKT/GSK3β signaling and GLI1 (a Hedgehog pathway effector). FUNDC2 siRNA knockdown in TNBC cells, cell proliferation/migration/invasion assays, subcutaneous xenograft mouse model, Western blot for AKT/GSK3β/GLI1 Acta biochimica et biophysica Sinica Medium 37700593
2022 HCBP6 (FUNDC2) activates brown adipose tissue thermogenesis by upregulating UCP1 expression and increasing mitochondrial number in brown adipocytes; HCBP6-KO mice show reduced UCP1, PGC1α, Cidea, and OXPHOS gene expression in BAT under high-fat diet. HCBP6 knockout mice, high-fat diet model, gene expression analysis (qRT-PCR, Western blot), transcriptomics, UCP1 and mitochondria quantification in brown adipocytes Journal of thermal biology Medium 36195403
2026 FUNDC2 knockdown in adipocytes reverses changes in proteins related to mitochondrial dynamics and ferroptosis, and alters adipokine secretion; conditioned medium from FUNDC2-knockdown adipocytes changes vascular smooth muscle cell phenotype and migration, linking FUNDC2 to PVAT dysfunction and hypertensive vascular remodeling. Proteomics of PVAT from hypertensive rats, FUNDC2 knockdown in 3T3-L1 adipocytes, Western blot for mitochondrial dynamics/ferroptosis proteins, adipokine measurement, VSMC co-culture/conditioned medium experiments Clinical and experimental hypertension Low 41477710

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America 128 36037337
2022 FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion. Nature communications 62 35710796
2007 Double complex mutations involving F8 and FUNDC2 caused by distinct break-induced replication. Human mutation 50 17683067
2018 Mitochondrial PIP3-binding protein FUNDC2 supports platelet survival via AKT signaling pathway. Cell death and differentiation 39 29786068
2021 Platelet Mitochondria Transplantation Rescues Hypoxia/Reoxygenation-Induced Mitochondrial Dysfunction and Neuronal Cell Death Involving the FUNDC2/PIP3/Akt/FOXO3a Axis. Cell transplantation 31 34105393
2019 FUNDC2 regulates platelet activation through AKT/GSK-3β/cGMP axis. Cardiovascular research 16 30576423
2015 HCBP6 Modulates Triglyceride Homeostasis in Hepatocytes Via the SREBP1c/FASN Pathway. Journal of cellular biochemistry 16 25855506
2020 HCBP6 deficiency exacerbates glucose and lipid metabolism disorders in non-alcoholic fatty liver mice. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 15 32535386
2020 Deletion of FUNDC2 and CMC4 on Chromosome Xq28 Is Sufficient to Cause Hypergonadotropic Hypogonadism in Men. Frontiers in genetics 9 33193636
2018 HCBP6 Is Involved in the Development of Hepatic Steatosis Induced by High-Fat Diet and CCL4 in Rats. Annals of hepatology 8 29735802
2006 [Identification and evaluation promoter sequence and the transcription activation of Hcbp6 interaction with core protein of hepatitis C virus]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 5 16494772
2023 FUNDC2, a mitochondrial outer membrane protein, mediates triple-negative breast cancer progression via the AKT/GSK3β/GLI1 pathway. Acta biochimica et biophysica Sinica 4 37700593
2018 HCBP6 upregulates human SREBP1c expression by binding to C/EBPβ-binding site in the SREBP1c promoter. BMB reports 4 29187281
2026 FUNDC2 contributes to hypertensive vascular remodeling by regulating mitochondrial dynamics and ferroptosis in perivascular adipose tissue. Clinical and experimental hypertension (New York, N.Y. : 1993) 0 41477710
2025 Expression and immunological role of FUNDC2 in pan-cancer. PloS one 0 40294153
2023 [Regulatory effect of eight Chinese herbal medicines on glucose and lipid metabolism and their potential active components based on HCBP6 target]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 0 37005851
2022 Methylation of the HCBP6 promoter is associated with primary biliary cholangitis pathogenesis. Biochemical and biophysical research communications 0 35468421
2022 HCBP6-induced activation of brown adipose tissue and upregulated of BAT cytokines genes. Journal of thermal biology 0 36195403