Affinage

FUNDC2

FUN14 domain-containing protein 2 · UniProt Q9BWH2

Length
189 aa
Mass
20.7 kDa
Annotated
2026-06-09
18 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FUNDC2 is a conserved mitochondrial outer membrane protein that integrates mitochondrial redox homeostasis, membrane dynamics, and lipid-dependent survival signaling across multiple cell types (PMID:36037337, PMID:35710796, PMID:29786068). At the outer membrane it interacts with the mitochondrial glutathione transporter SLC25A11 and influences the stability of both SLC25A11 and GPX4, thereby sustaining mitochondrial glutathione pools; its loss lowers mitochondrial GSH and protects against ferroptosis and doxorubicin-induced cardiomyopathy (PMID:36037337). FUNDC2 also restrains mitochondrial fusion by binding directly to the GTPase domain of MFN1 through its amino-terminal region, driving mitochondrial fragmentation and metabolic reprogramming in liver cancer cells (PMID:35710796). Through a conserved N-terminal motif, FUNDC2 binds the lipid PIP3 at the outer membrane to support AKT phosphorylation, downstream BAD phosphorylation, and BCL-xL maintenance, a pathway required for platelet survival under hypoxia and, via an AKT/GSK-3β/cGMP axis, for platelet activation, aggregation, hemostasis, and thrombosis in vivo (PMID:29786068, PMID:30576423). A parallel body of work on the same gene (HCBP6) places it in hepatic and adipose lipid and glucose metabolism, where it regulates SREBP1c/FASN-driven triglyceride handling and AMPK-dependent lipolysis and thermogenesis (PMID:25855506, PMID:32535386, PMID:36195403).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2006 Low

    Establishing that the HCBP6/FUNDC2 locus carries an active promoter provided the first evidence that the gene is transcriptionally regulated, setting the stage for later transcription-factor and metabolic studies.

    Evidence Promoter-reporter (pCAT3/CAT ELISA) assays in HepG2 and NIH3T3 cells

    PMID:16494772

    Open questions at the time
    • single promoter-reporter method with no follow-up on transcription factor identity
    • no link to protein function or localization
    • no in vivo validation
  2. 2015 Medium

    Linked FUNDC2/HCBP6 to hepatic lipid handling, answering whether the gene influences triglyceride metabolism and identifying miR-122 as an upstream post-transcriptional regulator.

    Evidence Knockdown/overexpression with TG measurement, SREBP1c/FASN expression, and miR-122 3'-UTR luciferase reporter in hepatocytes

    PMID:25855506

    Open questions at the time
    • no reconstitution or structural validation
    • direction of SREBP1c regulation reported here as suppression, in tension with later promoter-binding work
    • mechanism connecting a mitochondrial protein to SREBP1c not resolved
  3. 2018 High

    Defined the molecular basis for FUNDC2-dependent platelet survival by showing direct PIP3 binding through its N-terminal motif drives AKT/BAD/BCL-xL signaling.

    Evidence PIP3 lipid-binding assay, FUNDC2 KO mice with hypoxic thrombocytopenia, AKT/BAD phosphorylation readouts

    PMID:29786068

    Open questions at the time
    • structural basis of the PIP3-binding motif not solved
    • how a mitochondrial outer-membrane protein accesses PIP3 not fully explained
  4. 2018 Medium

    Provided a direct DNA-binding mechanism for HCBP6 in lipid metabolism, showing it binds the SREBP1c promoter to upregulate SREBP1c and raise triglycerides.

    Evidence ChIP, promoter-reporter, and DNA-binding assays at the C/EBPβ-binding site of the SREBP1c promoter

    PMID:29187281

    Open questions at the time
    • single lab with limited methodological detail
    • opposite directionality versus the 2015 suppression finding unresolved
    • nuclear DNA-binding role hard to reconcile with mitochondrial localization
  5. 2019 High

    Extended the platelet PIP3/AKT mechanism to platelet activation, establishing FUNDC2 as a positive regulator of aggregation, hemostasis, and thrombosis through an AKT/GSK-3β/cGMP axis.

    Evidence Multi-agonist platelet aggregation assays, KO mouse tail-bleeding and thrombosis models, AKT/GSK-3β phosphorylation and cGMP measurement

    PMID:30576423

    Open questions at the time
    • direct molecular link between FUNDC2 and cGMP generation not defined
    • no direct binding partners beyond the inferred PIP3/AKT module
  6. 2020 Medium

    Implicated HCBP6 in systemic lipid and glucose homeostasis via AMPK, showing KO mice develop aggravated fatty liver and impaired glucose handling and thermoregulation on high-fat diet.

    Evidence HCBP6 KO mice on HFD, glucose tolerance testing, AMPK pathway Western blots, histology

    PMID:32535386

    Open questions at the time
    • mechanism connecting FUNDC2 to AMPK activation not defined
    • single lab, limited mechanistic depth
  7. 2021 Medium

    Tested whether FUNDC2's PIP3-dependent pro-survival function operates in trans, showing platelet-mitochondria transfer activates Akt/FOXO3a and suppresses Bim in recipient neurons after hypoxia/reoxygenation.

    Evidence Platelet mitochondria transplantation into SH-SY5Y cells, PIP3 mitochondrial localization, Akt/FOXO3a/Bim measurements

    PMID:34105393

    Open questions at the time
    • no direct mutagenesis or reciprocal Co-IP
    • single lab
    • physiological relevance of inter-cellular mitochondrial transfer unestablished
  8. 2022 High

    Identified FUNDC2 as a regulator of mitochondrial glutathione and ferroptosis through interaction with SLC25A11, defining a redox-protective axis with cardiac relevance.

    Evidence Co-IP, FUNDC2 KO mouse model, GSH/lipid-peroxidation assays, SLC25A11 knockdown in KO cells

    PMID:36037337

    Open questions at the time
    • structural basis of the FUNDC2–SLC25A11 interaction not solved
    • mechanism of GPX4/SLC25A11 stabilization not defined
  9. 2022 High

    Established FUNDC2 as a brake on mitochondrial fusion by mapping its N-terminal binding to the MFN1 GTPase domain, linking mitochondrial fragmentation to cancer metabolic reprogramming.

    Evidence Domain-mapping Co-IP/pulldown, knockdown/overexpression, mitochondrial morphology imaging, metabolic profiling, mouse liver tumor model

    PMID:35710796

    Open questions at the time
    • structural details of the MFN1 GTPase interface not resolved
    • relationship between fusion control and the SLC25A11/ferroptosis role unexplored
  10. 2022 Medium

    Connected HCBP6 to thermogenic gene programs, showing KO reduces UCP1, PGC1α, Cidea, and OXPHOS expression and impairs thermogenesis in brown adipose tissue.

    Evidence HCBP6 KO mice under HFD/cold challenge, qRT-PCR/Western for thermogenic markers, BAT transcriptomics

    PMID:36195403

    Open questions at the time
    • direct mechanism between FUNDC2 and UCP1 not resolved
    • single lab
  11. 2023 Medium

    Extended FUNDC2's pro-survival signaling to oncogenesis, showing it promotes triple-negative breast cancer growth through AKT/GSK3β/GLI1 (Hedgehog) signaling.

    Evidence FUNDC2 siRNA in TNBC cells, proliferation/migration/invasion assays, xenograft model, pathway protein analysis

    PMID:37700593

    Open questions at the time
    • no direct binding or reconstitution
    • single lab
    • link to mitochondrial localization not addressed
  12. 2026 Low

    Probed FUNDC2 in adipocyte-vascular crosstalk under hypertension, linking its knockdown to altered mitochondrial dynamics, ferroptosis markers, adipokine secretion, and VSMC phenotype switching.

    Evidence FUNDC2 knockdown in 3T3-L1 adipocytes, Western blots, adipokine measurement, conditioned-medium VSMC assays, TEM

    PMID:41477710

    Open questions at the time
    • indirect conditioned-medium readouts with no direct mechanistic interaction demonstrated
    • single lab
    • causal molecular link to vascular phenotype unestablished

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FUNDC2's mitochondrial outer-membrane roles (SLC25A11/ferroptosis, MFN1/fusion, PIP3/AKT survival) mechanistically integrate with its reported nuclear/promoter and metabolic functions, and whether a single structural module underlies its multiple binding activities, remains unresolved.
  • no structural model of FUNDC2 or its binding interfaces
  • apparent contradiction between mitochondrial localization and direct SREBP1c promoter binding unreconciled
  • no unifying mechanism connecting redox, fusion, and lipid-signaling roles

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 2 GO:0098772 molecular function regulator activity 2
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-109582 Hemostasis 1
Partners
AKT1GPX4MFN1SLC25A11

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 FUNDC2 interacts with SLC25A11 (the mitochondrial glutathione transporter) at the mitochondrial outer membrane to regulate mitochondrial GSH (mitoGSH) levels; FUNDC2 also affects the stability of both SLC25A11 and GPX4. Loss of FUNDC2 reduces mitoGSH and protects against ferroptosis (and DOX-induced cardiomyopathy) in mice. Co-immunoprecipitation, FUNDC2 knockout mouse model, ferroptosis assays (GSH/LPO measurement), SLC25A11 knockdown in KO cells Proceedings of the National Academy of Sciences of the United States of America High 36037337
2022 FUNDC2 inhibits mitofusin 1 (MFN1)-mediated outer mitochondrial membrane fusion by directly binding to the GTPase domain of MFN1 via its amino-terminal region, promoting mitochondrial fragmentation and reprogrammed cellular metabolism in liver cancer cells. Co-immunoprecipitation/pulldown with domain-mapping, FUNDC2 knockdown/overexpression, mitochondrial morphology imaging, metabolic profiling, mouse liver tumor model Nature communications High 35710796
2018 FUNDC2 binds the lipid PIP3 via its conserved N-terminal motif at the mitochondrial outer membrane, enabling AKT phosphorylation and downstream BAD phosphorylation in a PI3K/PIP3-dependent manner to maintain BCL-xL levels and platelet survival; FUNDC2 KO mice exhibit thrombocytopenia under hypoxia. Lipid-binding assay (PIP3 binding), FUNDC2 knockout mouse model, phosphorylation assays (AKT/BAD), platelet survival/apoptosis assays under hypoxia Cell death and differentiation High 29786068
2019 FUNDC2 positively regulates platelet activation and aggregation through a PI3K-dependent AKT/GSK-3β/cGMP signaling axis; FUNDC2-knockout mice show impaired hemostasis and thrombosis in vivo. Platelet aggregation assays with multiple agonists (ADP, collagen, thrombin, ristocetin/VWF), FUNDC2 KO mouse tail bleeding and thrombosis models, AKT/GSK-3β phosphorylation assays, cGMP measurement Cardiovascular research High 30576423
2021 FUNDC2 in platelet-derived mitochondria induces mitochondrial translocation of PIP3 via its N-terminal domain, activating Akt/FOXO3a signaling and suppressing pro-apoptotic Bim accumulation at mitochondria in recipient neuronal cells after hypoxia/reoxygenation. Platelet mitochondria transplantation into SH-SY5Y cells, FUNDC2 expression analysis, PIP3 mitochondrial localization assay, Akt/FOXO3a/Bim pathway protein measurement Cell transplantation Medium 34105393
2015 FUNDC2/HCBP6 negatively regulates intracellular triglyceride levels in hepatocytes by suppressing SREBP1c-mediated FASN expression; miR-122 post-transcriptionally represses HCBP6 via its 3'-UTR. Knockdown/overexpression of HCBP6 with TG measurement, SREBP1c/FASN expression analysis, miR-122 overexpression with luciferase 3'-UTR reporter assay Journal of cellular biochemistry Medium 25855506
2018 FUNDC2/HCBP6 directly binds to the C/EBPβ-binding site in the SREBP1c promoter (−139 to +359 bp region) to upregulate SREBP1c transcription, thereby increasing intracellular TG levels. Chromatin immunoprecipitation (ChIP), promoter-reporter assays, EMSA or equivalent DNA-binding assay in vitro and in vivo BMB reports Medium 29187281
2020 FUNDC2/HCBP6 regulates lipolysis and fatty acid oxidation via AMPK activation in vivo; HCBP6-KO mice on a high-fat diet exhibit aggravated fatty liver, impaired glucose homeostasis, and inability to maintain body temperature under cold challenge. HCBP6 knockout mouse model on high-fat diet, glucose tolerance test, Western blot for AMPK pathway, histological staining Biomedicine & pharmacotherapy Medium 32535386
2022 FUNDC2/HCBP6 upregulates UCP1 expression and increases mitochondrial number in brown adipocytes; HCBP6-KO in mice reduces UCP1, PGC1α, Cidea, and OXPHOS gene expression in brown adipose tissue, impairing thermogenesis. HCBP6 knockout mouse model under HFD and cold challenge, UCP1/PGC1α/Cidea expression by qRT-PCR and Western blot, transcriptomic analysis of BAT Journal of thermal biology Medium 36195403
2023 FUNDC2 promotes triple-negative breast cancer cell proliferation, migration, and invasion via the AKT/GSK3β/GLI1 (Hedgehog) signaling pathway; FUNDC2 silencing inhibits tumor growth in vivo. FUNDC2 siRNA knockdown in TNBC cells, proliferation/migration/invasion assays, subcutaneous xenograft mouse model, AKT/GSK3β/GLI1 pathway protein analysis Acta biochimica et biophysica Sinica Medium 37700593
2026 FUNDC2 knockdown in 3T3-L1 adipocytes reverses hypertension-associated changes in mitochondrial dynamics and ferroptosis markers, and alters adipokine secretion; conditioned medium from FUNDC2-KD adipocytes changes VSMC phenotypic switching and migration. FUNDC2 knockdown in 3T3-L1 adipocytes, Western blot for mitochondrial dynamics/ferroptosis proteins, adipokine measurement, VSMC phenotype/migration assays with conditioned medium, TEM Clinical and experimental hypertension Low 41477710
2006 The HCBP6 (FUNDC2) promoter contains functional transcriptional elements; two promoter constructs (−1066 bp and −240 bp upstream) drive reporter gene expression at 3.1× and 6.4× above baseline in HepG2 and NIH3T3 cells. Promoter-reporter (pCAT3) transfection assay in HepG2 and NIH3T3 cells, CAT ELISA Zhonghua gan zang bing za zhi Low 16494772

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 130 36037337
2022 FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion. Nature communications 66 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 17 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

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