Affinage

BNIP3

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 · UniProt Q12983

Length
194 aa
Mass
21.5 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BNIP3 is a tail-anchored mitochondrial outer membrane protein that functions as a stress-induced, context-dependent switch between caspase-independent cell death and mitochondrial quality control (PMID:9396766, PMID:10891486). Its C-terminal transmembrane domain drives homodimerization and mitochondrial integration, both of which are obligatory for its activity (PMID:9396766, PMID:9867803). During death signaling, BNIP3 inserts fully into the outer membrane with an N-terminus-cytoplasmic/C-terminus-membrane topology, opens the mitochondrial permeability transition pore, and kills cells independently of Apaf-1, cytochrome c release, and caspase activation (PMID:10891486); this death requires the downstream effectors Bax and Bak, which act upstream of or parallel to pore opening (PMID:17447897). BNIP3 transcription is a major hypoxia-responsive node, driven directly by HIF-1α through a promoter HRE and additionally by FOXO3a, PLAGL2, and nitric-oxide signaling, while p53 and TAp73 directly repress it (PMID:10922063, PMID:11550088, PMID:21792176, PMID:27694219, PMID:11832486, PMID:15358175, PMID:25950386). In its survival role, BNIP3 acts as a mitophagy receptor: it directly binds LC3, an interaction enhanced by ULK1 phosphorylation at S17 and JNK1/2 phosphorylation at S60/T66, and initiates autophagosome biogenesis through both a WIPI-ATG13 and a FIP200/ULK1 pathway (PMID:34654847, PMID:36396625, PMID:40715440). BNIP3 and NIX are the principal receptors for this mitophagy, and their loss elevates mitochondrial ROS and sensitizes cells to ferroptosis (PMID:38519771). BNIP3 abundance is tightly restrained post-translationally by the SCF/CRL1-FBXL4 ubiquitin ligase—scaffolded by the phosphatase PPTC7—which degrades BNIP3 to suppress basal mitophagy, with pathogenic FBXL4 mutations causing BNIP3/NIX accumulation and a mitochondrial DNA depletion syndrome (PMID:36896912, PMID:37161784, PMID:38151018); PGAM5 opposes this by stabilizing BNIP3, and the protein is additionally cleared by constitutive autophagy-independent lysosomal delivery regulated by the ER membrane protein complex (PMID:38919131, PMID:38177312). Beyond mitophagy, BNIP3 binds PINK1 to suppress its cleavage and promote PINK1/Parkin mitophagy, interacts with the receptor CD47 to mediate ligand-triggered death, and binds ANXA2 to liberate TFEB for lysosomal biogenesis (PMID:27528605, PMID:12690108, PMID:38973294).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1997 High

    Established the structural basis of BNIP3 action by showing its transmembrane domain is required for the dimerization, mitochondrial targeting, and death-inducing activity that define the protein.

    Evidence Yeast two-hybrid and truncation-mutant transfection with cell death assays in Rat-1/MCF-7 cells

    PMID:9396766

    Open questions at the time
    • Did not resolve the death effector pathway downstream of mitochondrial integration
    • No atomic structure of the transmembrane dimer
  2. 2000 High

    Defined BNIP3-mediated death as a non-canonical pathway by showing membrane integration drives permeability transition pore opening independent of apoptosome/caspase machinery.

    Evidence Protease-protection topology, pharmacological mPTP inhibition, and dominant-negative Apaf-1 in transfected cells

    PMID:10891486

    Open questions at the time
    • Did not identify the direct mitochondrial target that opens the pore
    • Relationship to Bcl-2 family effectors unresolved at this stage
  3. 2000 High

    Identified BNIP3 as a direct hypoxia-responsive gene, linking it to HIF-1α signaling and explaining its induction in low-oxygen tissue.

    Evidence Promoter-reporter assays with HRE mutation and HIF-1α overexpression

    PMID:10922063

    Open questions at the time
    • Did not address non-hypoxic inducers or repressors
    • Transcriptional control under chronic versus acute hypoxia not distinguished
  4. 2007 High

    Placed Bax/Bak as essential downstream effectors of BNIP3, resolving how a transmembrane receptor couples to the core mitochondrial death machinery.

    Evidence Bax/Bak double-knockout MEFs with re-expression rescue, dominant-negative and RNAi approaches

    PMID:17447897

    Open questions at the time
    • Mechanism by which BNIP3 activates Bax/Bak not defined
    • Hierarchy of Bax/Bak activation versus mPTP opening only partially ordered
  5. 2011 High

    Showed BNIP3 transcription is bidirectionally controlled, with p53 acting as a direct repressor that tempers hypoxic death, complementing its HIF-1α activation.

    Evidence ChIP, promoter mutagenesis, and p53 knockdown in human cells and zebrafish

    PMID:21792176

    Open questions at the time
    • Interplay between HIF-1α activation and p53 repression at a single promoter not quantitatively resolved
    • Tissue specificity of repression unclear
  6. 2003 High

    Connected BNIP3 to surface receptor signaling by identifying CD47 as a binding partner whose ligation triggers BNIP3 mitochondrial translocation and death.

    Evidence Yeast two-hybrid, reciprocal co-IP, ligand-specificity, and antisense knockdown rescue

    PMID:12690108

    Open questions at the time
    • How CD47 ligation is transmitted to BNIP3 translocation not defined
    • Direct versus indirect nature of the interaction in cells not fully established
  7. 2016 High

    Revealed a pro-survival arm by showing BNIP3 binds PINK1 to block its cleavage and promote PINK1/Parkin mitophagy, distinguishing it from its death function.

    Evidence Co-IP, PINK1 cleavage and Parkin recruitment assays, and Drosophila genetic epistasis

    PMID:27528605

    Open questions at the time
    • Structural basis of BNIP3-PINK1 interaction unknown
    • How a single protein switches between death and mitophagy roles not resolved
  8. 2021 High

    Defined phospho-regulation of BNIP3-LC3 binding by showing ULK1 phosphorylates S17 adjacent to the LIR motif to enhance LC3 engagement and stabilize BNIP3.

    Evidence In vitro kinase assay, S17A mutagenesis, BNIP3-LC3 co-IP, and mitophagy flux

    PMID:34654847

    Open questions at the time
    • Upstream signals activating ULK1 toward BNIP3 not mapped
    • Role of the BH3 domain in turnover only preliminarily addressed
  9. 2022 High

    Extended phospho-control by identifying JNK1/2 phosphorylation at S60/T66 as a hypoxic signal that protects BNIP3 from degradation and drives LC3 binding, opposed by PP1/2A.

    Evidence In vitro kinase assay, S60A/T66A mutagenesis, phosphatase manipulation, and mitophagy flux

    PMID:36396625

    Open questions at the time
    • Integration of S17 and S60/T66 phosphorylation signals not resolved
    • Relative contribution of each kinase in vivo unknown
  10. 2023 High

    Established FBXL4-PPTC7 as the master post-translational brake on BNIP3, with SCF/CRL1-FBXL4 ubiquitinating BNIP3/NIX and PPTC7 scaffolding the degradative complex to suppress basal mitophagy.

    Evidence Co-IP, ubiquitination/reconstitution assays, genetic double-knockout rescue in mice, and patient-derived models

    PMID:36896912 PMID:37161784 PMID:37568009 PMID:38151018 PMID:38991726

    Open questions at the time
    • Trigger that relieves FBXL4-mediated degradation during physiologic mitophagy not defined
    • How PPTC7 phosphatase activity feeds into ligase scaffolding mechanistically incomplete
  11. 2024 High

    Showed opposing stabilization by PGAM5 and identified a parallel degradation route, expanding the network controlling BNIP3 abundance.

    Evidence Domain-mapped co-IP, ubiquitination assays, knockout mice (PGAM5), and a genome-wide CRISPR screen identifying EMC-dependent lysosomal flux

    PMID:38177312 PMID:38919131

    Open questions at the time
    • How PGAM5 stabilization is balanced against FBXL4 degradation not quantified
    • Cargo selectivity of the EMC-dependent constitutive lysosomal route unknown
  12. 2024 High

    Defined the physiological consequence of BNIP3/NIX mitophagy by showing the receptors are required to limit mitochondrial ROS and protect against ferroptosis.

    Evidence BNIP3/NIX double-knockout HeLa cells with WT versus mitophagy-dead mutant rescue and ferroptosis/Nrf2 readouts

    PMID:38519771

    Open questions at the time
    • Whether other cell types share this ferroptosis dependence not established
    • Quantitative threshold of mitophagy needed for protection unclear
  13. 2025 High

    Resolved the autophagy-initiation mechanism by reconstituting BNIP3/NIX-driven autophagosome biogenesis through a WIPI-ATG13 pathway in addition to the FIP200/ULK1 pathway, distinguishing it from other transmembrane mitophagy receptors.

    Evidence In vitro reconstitution with genetic perturbation of initiation complexes and comparison across receptors

    PMID:40715440

    Open questions at the time
    • What dictates pathway choice between WIPI-ATG13 and FIP200/ULK1 unknown
    • In-cell relevance of the dual-pathway flexibility under physiologic stress not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single BNIP3 protein is partitioned between its pro-death (mPTP/Bax-Bak) and pro-survival (mitophagy receptor) functions within the same cell.
  • No defined molecular determinant separating death-inducing from mitophagy-promoting BNIP3 pools
  • Structural mechanism of mPTP/Bax-Bak engagement versus LC3 engagement not co-resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2 GO:0140313 molecular sequestering activity 1
Localization
GO:0005739 mitochondrion 2 GO:0005634 nucleus 1
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 2
Partners
ANXA2CD47FBXL4LC3PGAM5PINK1PPTC7TMEM11
Complex memberships
PPTC7-SCF-FBXL4 degradation holocomplex (substrate)SCF/CRL1-FBXL4 ubiquitin ligase (substrate)TMEM11-BNIP3/BNIP3L complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 BNIP3 (Nip3) is a dimeric mitochondrial protein; the transmembrane domain and C-terminus are required for homodimerization, mitochondrial localization, and induction of apoptosis. A mutant lacking the transmembrane domain (Nip3-163) fails to dimerize, fails to localize to mitochondria, and is unable to induce cell death. Yeast two-hybrid homodimerization assay; transient transfection of epitope-tagged wild-type and truncation mutants in Rat-1 and MCF-7 cells; cell death assays The Journal of experimental medicine High 9396766
2000 BNIP3 integrates into the mitochondrial outer membrane (N terminus cytoplasmic, C terminus in membrane) during cell death induction, whereas under normal conditions it is loosely associated. BNIP3-mediated cell death is independent of Apaf-1, caspase activation, cytochrome c release, and AIF nuclear translocation, but requires mitochondrial permeability transition (PT) pore opening; PT pore inhibitors cyclosporin A and bongkrekic acid block BNIP3-mediated mitochondrial dysfunction and cell death. Subcellular fractionation; protease protection assay for membrane topology; co-transfection with dominant-negative Apaf-1, caspase inhibitors; cyclosporin A and bongkrekic acid pharmacological rescue; electron microscopy Molecular and cellular biology High 10891486
2000 Transcription of BNIP3 (Nip3) is strongly induced by hypoxia through HIF-1α; the BNIP3 promoter contains a functional HIF-1-responsive element (HRE) that is activated by both hypoxia and forced HIF-1α expression. Promoter-reporter (luciferase) assays with HRE mutation; HIF-1α overexpression; Western blot for Nip3 protein under hypoxia Proceedings of the National Academy of Sciences of the United States of America High 10922063
2001 HIF-1α (but not p53) induces BNIP3 expression under hypoxia; BNIP3 overexpression causes cell death without cytochrome c release and resistant to caspase inhibitors, consistent with a non-classical apoptotic pathway. HIF-1α and p53 overexpression constructs; Western blot; cytochrome c release assay; caspase inhibitor treatment; neonatal cardiomyocyte model Cell death and differentiation High 11550088
1999 BNIP3 and NIX (BNIP3L) form a subfamily of pro-apoptotic mitochondrial proteins; the transmembrane domain of each is required for mitochondrial localization and apoptosis induction; both can overcome Bcl-2 and Bcl-XL suppression, though high Bcl-XL levels can inhibit NIX-induced apoptosis. Sequence homology analysis; subcellular co-localization with HSP60; transmembrane domain deletion mutants; transient transfection apoptosis assays; Bcl-2/Bcl-XL co-transfection The Journal of biological chemistry High 9867803
2003 BNIP3 physically interacts with the surface receptor CD47; this interaction was identified by yeast two-hybrid with CD47 as bait and confirmed by co-immunoprecipitation. CD47 ligation by thrombospondin-1 C-terminal domain (but not SIRPα1) triggers BNIP3 translocation to mitochondria to induce caspase-independent apoptosis; antisense knockdown of BNIP3 inhibits CD47-induced cell death. Yeast two-hybrid; co-immunoprecipitation; immunofluorescence colocalization; antisense oligonucleotide knockdown; apoptosis assays The Journal of biological chemistry High 12690108
2007 Bnip3 mediates mitochondrial dysfunction and cell death through downstream effectors Bax and Bak; MEFs deficient in both Bax and Bak are completely resistant to hypoxia-induced cell death even with elevated Bnip3, and resistant to Bnip3 overexpression; re-expression of Bax or Bak restores susceptibility. mPTP inhibitors reduce cell death but do not prevent Bnip3-mediated Bax/Bak activation, placing Bax/Bak activation upstream of or parallel to mPTP opening downstream of Bnip3. Bax/Bak double-knockout MEFs; re-expression rescue; GFP-Bax translocation assay; dominant-negative Bnip3ΔTM; RNA interference; mPTP inhibitor pharmacology The Biochemical journal High 17447897
2011 p53 directly suppresses BNIP3 expression by binding a p53-response element motif in the BNIP3 promoter and recruiting the corepressor mSin3a; the DNA-binding domain of p53 is required for this repression. Loss of p53 enhances hypoxia-induced BNIP3 expression and cell death in human cell lines and in a zebrafish model. Chromatin immunoprecipitation (ChIP); promoter-reporter assays; p53 DNA-binding domain mutants; p53 knockdown in human cells and zebrafish; nip3a knockdown in zebrafish The EMBO journal High 21792176
2002 PLAGL2, a zinc-finger transcription factor, induces BNIP3 (Nip3) mRNA expression by activating the Nip3 promoter (containing an HRE) independently of HIF-1; antisense oligonucleotide knockdown of Nip3 mRNA reduces PLAGL2-induced apoptosis, placing BNIP3 downstream of PLAGL2 in an apoptotic pathway. cDNA transfection; promoter-reporter assay; RT-PCR; antisense oligonucleotide knockdown; apoptosis assays (TUNEL, annexin V) The Journal of biological chemistry Medium 11832486
2004 BNip3 is loosely bound to mitochondria under neutral hypoxia but becomes tightly associated at acidic pH, coinciding with mPTP opening; BNip3-mediated cell death under acidic hypoxia is blocked by antisense BNip3 oligonucleotides and mPTP inhibitors but not by caspase inhibitors. Subcellular fractionation under varying pH; mPTP opening assay; antisense oligonucleotide knockdown; caspase inhibitor pharmacology; microarray to identify BNip3 upregulation Journal of molecular and cellular cardiology Medium 15623420
2004 Nitric oxide (NO) induces BNIP3 expression in macrophages; LPS/IFN-γ-stimulated macrophages produce NO via NOS2, which drives BNIP3 expression; NOS2 inhibitor and NOS2-null macrophages fail to upregulate BNIP3 in response to LPS/IFN-γ. Overexpression of BNIP3 but not its ΔTM mutant (lacking transmembrane domain and C-terminal tail) causes macrophage apoptosis. Promoter analysis identified a −281 to −1 region sufficient for NO-dependent BNIP3 expression. cDNA microarray; NOS2 inhibitor; NOS2 knockout macrophages; BNIP3 and BNIP3ΔTM overexpression; promoter-reporter assay Biochemical and biophysical research communications Medium 15358175
2009 TNF-α upregulates BNIP3 expression in L929 fibrosarcoma cells via nitric oxide; dominant-negative BNIP3 lacking the C-terminal transmembrane domain (ΔTM-BNIP3) reduces TNF-induced mitochondrial membrane potential loss, ROS production, and lysosomal activation, without affecting cytochrome c, Smac/Diablo, or Omi/HtrA2 release. Stable transfection of L929-ΔTM-BNIP3; mitochondrial membrane potential assay; ROS measurement; NOS inhibitor; lysosomal activation assays; Western blot Biochimica et biophysica acta Medium 19321129
2012 Bnip3 is upregulated during embryoid body cavitation in a hypoxia/HIF-2α-dependent manner; shRNA silencing of Bnip3 inhibits core cell apoptosis and delays cavitation. Apoptosis-inducing factor (AIF) cooperates with Bnip3 — Bnip3 silencing in AIF-null embryoid bodies nearly blocks apoptosis and cavitation. AIF regulates Bnip3 expression via mitochondrial ROS and HIF-2α stabilization. shRNA knockdown; HIF-2α and HIF-1β knockout embryoid bodies; AIF-null cells; epistasis analysis; ROS measurement The Journal of cell biology High 22753893
2013 BNIP3 is degraded primarily by the proteasome under normoxia; under hypoxia combined with amino acid starvation, BNIP3 undergoes both proteasomal and autophagic degradation. Autophagic degradation of BNIP3 is dependent on ATG7, MAP1LC3, and specifically regulated by ULK1 via the mTOR-AMPK pathway. Proteasome and autophagy inhibitors; ATG7 and ULK1 knockdown; AMPK activation; mTOR inhibitor (Torin1); Western blot Autophagy Medium 23291726
2014 BNIP3 is required for melanoma cell migration and vasculogenic mimicry; BNIP3 shRNA knockdown abolishes tubular network formation on Matrigel, alters actin cytoskeleton remodeling (increased stress fibers, reduced lamellipodia/filopodia), and reduces protein levels of CD47, Rac1, and Cdc42. Loss of BNIP3 also increases phosphorylated focal adhesion kinase levels. shRNA lentiviral knockdown; Matrigel tube formation assay; immunofluorescence of actin cytoskeleton; Western blot for CD47, Rac1, Cdc42, pFAK; migration assays Cell death & disease Medium 24625986
2015 PDK2 (pyruvate dehydrogenase kinase 2) activity controls alternative splicing of Bnip3 pre-mRNA; a truncated splice variant lacking exon 3 (Bnip3Δex3) is preferentially expressed in adenocarcinomas and promotes cell survival, whereas full-length Bnip3 promotes death. PDK2 inhibition shifts the ratio toward full-length Bnip3, inducing mitochondrial perturbation and cell death. RT-PCR isoform analysis; PDK2 inhibitor treatment; exon-deletion construct expression; mitochondrial membrane potential assay; cell death assays The Journal of cell biology Medium 26416963
2015 Bnip3 binds and activates the histone acetyltransferase p300 in cardiac myocytes, increasing acetylation of histones and the transcription factor GATA4, leading to morphological changes and cardiomyopathy. This was demonstrated in cultured myocytes and confirmed in transgenic mice overexpressing Bnip3 in the heart; p300 inhibition with curcumin partially prevents ventricular dilation. Co-immunoprecipitation of Bnip3 and p300; histone acetylation assay; GATA4 acetylation assay; Bnip3 transgenic mice; curcumin pharmacological inhibition PloS one Medium 26317696
2016 BNIP3 interacts with PINK1 on the mitochondrial outer membrane to suppress PINK1 proteolytic cleavage and promote accumulation of full-length PINK1, thereby facilitating parkin recruitment and PINK1/parkin-mediated mitophagy. Inactivation of BNIP3 promotes PINK1 proteolytic processing and suppresses this pathway. In Drosophila, BNIP3 expression suppresses muscle degeneration caused by PINK1 inactivation. Co-immunoprecipitation; PINK1 cleavage assay; Parkin recruitment assay; BNIP3 siRNA knockdown; BNIP3 overexpression in Drosophila PINK1 mutants; mitophagy flux assay The Journal of biological chemistry High 27528605
2016 FOXO3a transcription factor upregulates BNIP3 expression in cardiac myocytes, leading to increased mitochondrial Ca2+, decreased mitochondrial membrane potential, mitochondrial fragmentation, and apoptosis. Dominant-negative FOXO3a attenuates BNIP3 expression and its consequences in stressed myocytes and improves cardiac function in a rat heart failure model. FOXO3a overexpression and dominant-negative construct; BNIP3 Western blot; mitochondrial Ca2+ measurement; membrane potential assay; AAV9-mediated gene delivery in HFpEF rat model; echocardiography American journal of physiology. Heart and circulatory physiology Medium 27694219
2021 ULK1 phosphorylates BNIP3 on serine 17 (S17) adjacent to its LIR motif; this phosphorylation promotes interaction between BNIP3 and LC3, enhancing mitophagy. ULK1 also stabilizes BNIP3 protein by limiting proteasomal turnover. Similarly, ULK1 phosphorylates BNIP3L on S35. Deletion of the BH3 domain reduces BNIP3 turnover and increases protein levels independently of ULK1. In vitro kinase assay; site-directed mutagenesis (S17A); Co-immunoprecipitation of BNIP3 with LC3; proteasome inhibitor; BNIP3 BH3-domain deletion; mitophagy flux assay Scientific reports High 34654847
2022 JNK1/2 phosphorylates BNIP3 at Ser60/Thr66 under hypoxia, which hampers proteasomal degradation of BNIP3 and drives mitophagy by facilitating BNIP3's direct binding to LC3. Protein phosphatase PP1/2A counteracts this by dephosphorylating BNIP3, triggering its proteasomal degradation and suppressing mitophagy. In vitro kinase assay with JNK1/2; phosphosite mutagenesis (S60A/T66A); PP1/2A inhibitor and activation; co-immunoprecipitation of BNIP3-LC3; mitophagy flux assay; proteasome inhibitor Cell death & disease High 36396625
2023 SCF-FBXL4 is a mitochondrial ubiquitin E3 ligase complex that ubiquitinates BNIP3 and NIX, targeting them for proteasomal degradation to restrain basal mitophagy. Pathogenic FBXL4 mutations disrupt SCF complex assembly and impair BNIP3/NIX degradation; Fbxl4-knockout mice show elevated BNIP3/NIX and perinatal lethality rescued by Bnip3 or Nix knockout. Genetic screen; co-immunoprecipitation; ubiquitination assay; Fbxl4 and Bnip3/Nix knockout mice; genetic rescue (double KO); mitophagy flux assay The EMBO journal High 36896912
2023 FBXL4 (CRL1^FBXL4 ubiquitin ligase) directly interacts with BNIP3 and BNIP3L and promotes their degradation via the ubiquitin-proteasome pathway; MTDPS13-associated FBXL4 mutations impair active CRL1^FBXL4 assembly, causing BNIP3/BNIP3L accumulation and excessive basal mitophagy. This was independently confirmed in Fbxl4 knock-in mice and in cortical neurons derived from patient iPSCs. Co-immunoprecipitation; ubiquitination assay; CRL1^FBXL4 assembly assay with patient-derived mutants; Fbxl4 knock-in mice; iPSC-derived patient neurons; mitophagy assay Cell death and differentiation High 37568009
2023 FBXL4 (SCFFBXL4) localizes to the mitochondrial outer membrane and mediates constitutive ubiquitylation and degradation of BNIP3 and NIX to suppress basal mitophagy; pathogenic FBXL4 variants associated with encephalopathic mtDNA depletion syndrome fail to interact with core SCF ubiquitin ligase machinery or mediate degradation. Co-immunoprecipitation; ubiquitylation assay; subcellular fractionation; patient-variant characterization; BNIP3/NIX protein turnover assay The EMBO journal High 37161784
2023 PPTC7, a mitochondrial matrix phosphatase, suppresses BNIP3/NIX-mediated mitophagy by scaffolding assembly of a substrate-PPTC7-SCF^FBXL4 holocomplex on the mitochondrial outer membrane to degrade BNIP3 and NIX. PPTC7 knockout causes perinatal lethality rescued by NIX knockout. Starvation upregulates PPTC7 to repress mitophagy, maintaining hepatic mitochondrial mass. PPTC7 knockout mice; NIX knockout rescue; co-immunoprecipitation; proximity labeling; subcellular fractionation; mitophagy flux assay; liver gluconeogenesis assay Molecular cell High 38151018
2023 TMEM11, a mitochondrial outer membrane protein, forms a complex with BNIP3 and BNIP3L and co-enriches at sites of mitophagosome formation. Loss of TMEM11 hyperactivates mitophagy by increasing the number of BNIP3/BNIP3L mitophagy sites, demonstrating that TMEM11 spatially restricts BNIP3/BNIP3L-dependent mitophagosome formation. Co-immunoprecipitation; live-cell imaging; TMEM11 knockout; mitophagy flux quantification under normoxia and hypoxia-mimetic conditions The Journal of cell biology High 36795401
2023 BNIP3 is constitutively delivered to lysosomes in an autophagy-independent manner via endolysosomal trafficking; the ER membrane protein complex (EMC) is identified as a regulator of this constitutive BNIP3 flux through a genome-wide CRISPR screen. The endolysosomal and ubiquitin-proteasome systems regulate BNIP3 independently, and perturbation of either modulates BNIP3-associated mitophagy. Genome-wide CRISPR screen; autophagy-independent lysosomal flux assay; EMC subunit knockdown; ubiquitin-proteasome inhibitor; mitophagy assay The EMBO journal High 38177312
2024 BNIP3 and NIX are the principal mitophagy receptors required for mitophagy under multiple conditions in HeLa cells; BNIP3/NIX double-knockout (DKO) cells show complete loss of mitophagy. DKO cells accumulate elevated mitochondrial ROS, activating Nrf2 antioxidant pathway, and are highly sensitive to ferroptosis when Nrf2-driven antioxidant enzymes are compromised; this sensitivity is fully rescued by wild-type BNIP3/NIX but not by mutant forms incapable of facilitating mitophagy. BNIP3/NIX double-knockout HeLa cells; mitophagy flux assay under multiple conditions; mitochondrial ROS measurement; Nrf2 pathway assay; ferroptosis sensitivity assay; rescue with WT vs. mutant BNIP3/NIX Cell death and differentiation High 38519771
2024 BNIP3 interacts with PGAM5 (mitochondrial serine/threonine phosphatase); the NH2-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to stabilize BNIP3 by dampening its ubiquitination and proteasomal degradation, thereby sustaining continuous mitophagy. S100A9-AGER signaling activates this PGAM5-BNIP3 interaction to drive cancer-associated muscle wasting. Co-immunoprecipitation; domain mapping (NH2-terminal PGAM5 vs. PEST motif of BNIP3); ubiquitination assay; Pgam5 and Bnip3 knockout mice; tumor-bearing mouse models; muscle mass measurement Autophagy High 38919131
2024 PPTC7, dual-localized to the mitochondrial matrix and outer mitochondrial membrane, promotes proteasomal turnover of BNIP3 and NIX. Its catalytic activity is required for this regulation; anchoring PPTC7 to the outer mitochondrial membrane is sufficient to suppress BNIP3/NIX accumulation. Proximity labeling and co-localization experiments show dynamic association of PPTC7 with BNIP3 and NIX. PPTC7 knockout; catalytic-mutant PPTC7 rescue; OMM-targeted PPTC7 construct; proximity labeling (BioID); fluorescence co-localization; proteasome inhibitor; protein half-life assay Life science alliance High 38991726
2025 Reconstitution of BNIP3/NIX-mediated mitophagy initiation shows that BNIP3/NIX transmembrane receptors can initiate autophagosome biogenesis via a WIPI-ATG13 complex pathway, distinct from and in addition to the FIP200/ULK1 complex pathway used by other mitophagy receptors (FUNDC1, BCL2L13). This reveals hierarchical flexibility in autophagy initiation machinery for receptor-mediated mitophagy. In vitro reconstitution of autophagosome biogenesis; BNIP3/NIX receptor constructs; genetic perturbation of FIP200/ULK1 vs. WIPI-ATG13 complex components; comparison with other mitophagy receptors Nature cell biology High 40715440
2024 Reconstitution of BNIP3/NIX-mediated autophagy (preprint version) confirms that BNIP3/NIX receptors initiate autophagosome biogenesis via a WIPI-ATG13 complex pathway in addition to the FIP200/ULK1 pathway; this is distinct from FUNDC1 and BCL2L13 which exclusively require FIP200/ULK1. In vitro reconstitution; genetic perturbation of autophagy initiation complex components; comparison across transmembrane mitophagy receptors bioRxivpreprint Medium 39253418
2009 In hepatocytes, BNIP3 localizes to the nucleus under normoxia, redistributes to the cytoplasm during hypoxia, and returns to the nucleus upon reoxygenation. This dynamic relocalization is distinct from the mitochondrial integration described in other cell types and is accompanied by p38 MAPK-dependent upregulation. BNIP3 knockdown reduces hypoxic hepatocyte injury. Immunofluorescence of BNIP3 localization at different oxygen tensions; p38 MAPK inhibitor; siRNA knockdown; subcellular fractionation; Western blot American journal of physiology. Gastrointestinal and liver physiology Medium 19147804
2015 TAp73 (p53 family member) directly binds the BNIP3 gene promoter to transcriptionally repress BNIP3 expression. Chromatin immunoprecipitation (ChIP); promoter-reporter assay; TAp73 knockout cell lines Cell cycle (Georgetown, Tex.) Medium 25950386
2019 FTO-mediated m6A demethylation in the 3'UTR of BNIP3 mRNA induces its degradation via an YTHDF2-independent mechanism, reducing BNIP3 protein levels in breast cancer cells. m6A-RNA immunoprecipitation sequencing (MeRIP-seq); FTO knockdown/overexpression; BNIP3 mRNA stability assay; YTHDF2 knockdown to test independence Molecular cancer Medium 30922314
2023 YTHDF2 recognizes methylated (m6A) BNIP3 mRNA and promotes its destabilization, reducing BNIP3 protein expression. Following FTO silencing, elevated m6A modification on BNIP3 transcripts leads to YTHDF2-mediated mRNA destabilization and decreased BNIP3 protein. RNA immunoprecipitation (RIP); m6A modification detection; YTHDF2 overexpression/knockdown; BNIP3 mRNA stability assay; Western blot Human cell Medium 37500815
2024 BNIP3 interacts with annexin A2 (ANXA2), enabling liberation of transcription factor EB (TFEB) from the ANXA2-TFEB complex, thereby promoting TFEB nuclear translocation and activating autophagy and lysosomal gene expression. Co-immunoprecipitation of BNIP3 with ANXA2; TFEB localization by immunofluorescence; BNIP3 overexpression and knockdown; TFEB target gene expression Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 38973294
2024 Mst1/2 (Hippo kinases) are required for BNIP3-dependent mitophagy induction under mitochondrial stress; Mst1/2 knockdown impairs mitophagy and reduces BNIP3 involvement, acting independently of both the PINK1-Parkin pathway and the canonical Hippo pathway. BNIP3 is identified as an essential downstream effector of Mst1/2-mediated mitophagy. Mst1/2 siRNA knockdown; pharmacological Mst1/2 inhibition (XMU-MP-1); mitophagy flux assay; BNIP3 involvement tested by epistasis; Mst1 AAV in MPTP Parkinson's disease mouse model Experimental & molecular medicine Medium 38443598

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell death and differentiation 851 19229244
2000 Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proceedings of the National Academy of Sciences of the United States of America 653 10922063
2000 BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Molecular and cellular biology 531 10891486
2019 RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Molecular cancer 481 30922314
2020 HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury. Redox biology 305 32829253
2001 Hypoxia induces the expression of the pro-apoptotic gene BNIP3. Cell death and differentiation 292 11550088
1997 The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis. The Journal of experimental medicine 287 9396766
2015 BNIP3- and BNIP3L-Mediated Mitophagy Promotes the Generation of Natural Killer Cell Memory. Immunity 265 26253785
1999 Nix and Nip3 form a subfamily of pro-apoptotic mitochondrial proteins. The Journal of biological chemistry 249 9867803
2016 BNIP3 Protein Suppresses PINK1 Kinase Proteolytic Cleavage to Promote Mitophagy. The Journal of biological chemistry 237 27528605
2019 HIF-1α/BNIP3 signaling pathway-induced-autophagy plays protective role during myocardial ischemia-reperfusion injury. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 201 31590128
2009 The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death. Cell death and differentiation 190 19136941
2008 BNIP3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions. Oncogene 184 19641497
2019 Activation of BNIP3-mediated mitophagy protects against renal ischemia-reperfusion injury. Cell death & disease 182 31515472
2010 Mitochondrial pruning by Nix and BNip3: an essential function for cardiac-expressed death factors. Journal of cardiovascular translational research 182 20559783
2007 Bnip3 mediates mitochondrial dysfunction and cell death through Bax and Bak. The Biochemical journal 181 17447897
2020 Bnip3 in mitophagy: Novel insights and potential therapeutic target for diseases of secondary mitochondrial dysfunction. Clinica chimica acta; international journal of clinical chemistry 133 32092316
2019 Bnip3 mediates doxorubicin-induced cardiomyocyte pyroptosis via caspase-3/GSDME. Life sciences 132 31862454
2014 BNIP3 supports melanoma cell migration and vasculogenic mimicry by orchestrating the actin cytoskeleton. Cell death & disease 117 24625986
2015 Tumor suppressor functions of BNIP3 and mitophagy. Autophagy 115 26315353
2007 The role of the hypoxia-inducible BH3-only proteins BNIP3 and BNIP3L in cancer. Cancer metastasis reviews 114 17805942
2024 Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species. Cell death and differentiation 111 38519771
2019 Baicalin relieves hypoxia-aroused H9c2 cell apoptosis by activating Nrf2/HO-1-mediated HIF1α/BNIP3 pathway. Artificial cells, nanomedicine, and biotechnology 104 31478766
2020 Lactate accelerates vascular calcification through NR4A1-regulated mitochondrial fission and BNIP3-related mitophagy. Apoptosis : an international journal on programmed cell death 101 31993850
1998 Isolation, mapping, and functional analysis of a novel human cDNA (BNIP3L) encoding a protein homologous to human NIP3. Genes, chromosomes & cancer 101 9523198
2023 A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease. The EMBO journal 98 36896912
2011 p53 directly suppresses BNIP3 expression to protect against hypoxia-induced cell death. The EMBO journal 94 21792176
2023 HIF1α-BNIP3-mediated mitophagy protects against renal fibrosis by decreasing ROS and inhibiting activation of the NLRP3 inflammasome. Cell death & disease 93 36928344
2017 Ellagic acid antagonizes Bnip3-mediated mitochondrial injury and necrotic cell death of cardiac myocytes. Free radical biology & medicine 91 28838842
2021 ULK1 promotes mitophagy via phosphorylation and stabilization of BNIP3. Scientific reports 90 34654847
2004 BNip3 and signal-specific programmed death in the heart. Journal of molecular and cellular cardiology 84 15623420
2016 FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress. American journal of physiology. Heart and circulatory physiology 83 27694219
2011 Bnip3 as a dual regulator of mitochondrial turnover and cell death in the myocardium. Pediatric cardiology 83 21210091
2022 BNIP3 phosphorylation by JNK1/2 promotes mitophagy via enhancing its stability under hypoxia. Cell death & disease 82 36396625
2003 CD47 and the 19 kDa interacting protein-3 (BNIP3) in T cell apoptosis. The Journal of biological chemistry 78 12690108
2020 IGF-1 Signalling Regulates Mitochondria Dynamics and Turnover through a Conserved GSK-3β-Nrf2-BNIP3 Pathway. Cells 74 31936236
2021 BNIP3 promotes HIF-1α-driven melanoma growth by curbing intracellular iron homeostasis. The EMBO journal 73 33932034
2023 FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors. The EMBO journal 68 37161784
2002 A zinc-finger protein, PLAGL2, induces the expression of a proapoptotic protein Nip3, leading to cellular apoptosis. The Journal of biological chemistry 68 11832486
2023 A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass. Molecular cell 67 38151018
2013 BNIP3 is degraded by ULK1-dependent autophagy via MTORC1 and AMPK. Autophagy 60 23291726
2007 Regulation of mitochondrial integrity, autophagy and cell survival by BNIP3. Autophagy 60 17786027
2006 Regulation of BNIP3 in normal and cancer cells. Molecules and cells 60 16511341
2020 Resveratrol Improves Bnip3-Related Mitophagy and Attenuates High-Fat-Induced Endothelial Dysfunction. Frontiers in cell and developmental biology 59 32923443
2024 Hypoxia-Preconditioned BMSC-Derived Exosomes Induce Mitophagy via the BNIP3-ANAX2 Axis to Alleviate Intervertebral Disc Degeneration. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 56 38973294
2022 BNIP3 and Nix: Atypical regulators of cell fate. Biochimica et biophysica acta. Molecular cell research 56 35863652
2022 Neuronal induction of BNIP3-mediated mitophagy slows systemic aging in Drosophila. Nature aging 54 36213625
2019 Involvement of autophagy in hypoxia-BNIP3 signaling to promote epidermal keratinocyte migration. Cell death & disease 53 30850584
2014 High expression of HIF-1α, BNIP3 and PI3KC3: hypoxia-induced autophagy predicts cholangiocarcinoma survival and metastasis. Asian Pacific journal of cancer prevention : APJCP 53 25081716
2022 Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy. Cell death & disease 50 35459212
2009 Role of BNIP3 in TNF-induced cell death--TNF upregulates BNIP3 expression. Biochimica et biophysica acta 50 19321129
2024 Semaglutide attenuates doxorubicin-induced cardiotoxicity by ameliorating BNIP3-Mediated mitochondrial dysfunction. Redox biology 47 38574433
2021 BNIP3-Dependent Mitophagy via PGC1α Promotes Cartilage Degradation. Cells 44 34360007
2022 BNIP3 (BCL2 interacting protein 3) regulates pluripotency by modulating mitochondrial homeostasis via mitophagy. Cell death & disease 43 35410319
2014 Structure, function, and epigenetic regulation of BNIP3: a pathophysiological relevance. Molecular biology reports 40 25096512
2004 Nitric oxide induces BNIP3 expression that causes cell death in macrophages. Biochemical and biophysical research communications 39 15358175
1999 A novel adenovirus E1B19K-binding protein B5 inhibits apoptosis induced by Nip3 by forming a heterodimer through the C-terminal hydrophobic region. Cell death and differentiation 39 10381623
2024 Hypoxia-induced BNIP3 facilitates the progression and metastasis of uveal melanoma by driving metabolic reprogramming. Autophagy 38 39265983
2023 The outer mitochondrial membrane protein TMEM11 demarcates spatially restricted BNIP3/BNIP3L-mediated mitophagy. The Journal of cell biology 37 36795401
2002 A mycobacterial iron chelator, desferri-exochelin, induces hypoxia-inducible factors 1 and 2, NIP3, and vascular endothelial growth factor in cancer cell lines. Cancer research 37 12460908
2023 FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome. Cell death and differentiation 36 37568009
2020 BNIP3 in Lung Cancer: To Kill or Rescue? Cancers 35 33207677
2019 Testosterone induces renal tubular epithelial cell death through the HIF-1α/BNIP3 pathway. Journal of translational medicine 33 30819186
2019 Ripk3 mediates cardiomyocyte necrosis through targeting mitochondria and the JNK-Bnip3 pathway under hypoxia-reoxygenation injury. Journal of receptor and signal transduction research 33 31658855
2009 Expression and subcellular localization of BNIP3 in hypoxic hepatocytes and liver stress. American journal of physiology. Gastrointestinal and liver physiology 33 19147804
2024 BNIP3-mediated mitophagy boosts the competitive growth of Lenvatinib-resistant cells via energy metabolism reprogramming in HCC. Cell death & disease 31 38969639
2015 PDK2-mediated alternative splicing switches Bnip3 from cell death to cell survival. The Journal of cell biology 31 26416963
2013 BNIP3 mediates pre-myelinating oligodendrocyte cell death in hypoxia and ischemia. Journal of neurochemistry 30 23692407
2012 Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis. The Journal of cell biology 27 22753893
2018 Expression and epigenetic regulatory mechanism of BNIP3 in clear cell renal cell carcinoma. International journal of oncology 23 30365137
2012 Autophagy and Bcl-2/BNIP3 death regulatory pathway in non-small cell lung carcinomas. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 23 23216071
2021 Inhibition of the HIF-1α/BNIP3 pathway has a retinal neuroprotective effect. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 34314069
2018 DNA methylation of the promoter region of bnip3 and bnip3l genes induced by metabolic programming. BMC genomics 22 30223788
2023 RNA methylation reading protein YTHDF2 relieves myocardial ischemia-reperfusion injury by downregulating BNIP3 via m6A modification. Human cell 21 37500815
2022 Soluble RAGE attenuates myocardial I/R injuries via FoxO3-Bnip3 pathway. Cellular and molecular life sciences : CMLS 21 35501612
2019 Bnip3 regulates airway smooth muscle cell focal adhesion and proliferation. American journal of physiology. Lung cellular and molecular physiology 21 31509440
2011 H-ras up-regulates expression of BNIP3. Anticancer research 19 21868531
2024 N6-methyladenosine demethyltransferase FTO alleviates sepsis by upregulating BNIP3 to induce mitophagy. Journal of cellular physiology 18 39308045
2024 Coordinating BNIP3/NIX-mediated mitophagy in space and time. Biochemical Society transactions 18 39377319
2023 Long Non-Coding RNA BNIP3 Inhibited the Proliferation of Bovine Intramuscular Preadipocytes via Cell Cycle. International journal of molecular sciences 18 36835645
2017 BNIP3 promotes the motility and migration of keratinocyte under hypoxia. Experimental dermatology 18 27783443
2017 Expression and Functional Characterization of the BNIP3 Protein in Renal Cell Carcinomas. Translational oncology 18 28918350
2016 Targeting BNIP3 in inflammation-mediated heart failure: a novel concept in heart failure therapy. Heart failure reviews 18 27112557
2015 Bnip3 Binds and Activates p300: Possible Role in Cardiac Transcription and Myocyte Morphology. PloS one 18 26317696
2020 BNIP3 contributes to cisplatin-induced apoptosis in ovarian cancer cells. FEBS open bio 17 32412667
2020 Hyperoxia exposure arrests alveolarization in neonatal rats via PTEN‑induced putative kinase 1‑Parkin and Nip3‑like protein X‑mediated mitophagy disorders. International journal of molecular medicine 17 33125104
2024 The Mst1/2-BNIP3 axis is required for mitophagy induction and neuronal viability under mitochondrial stress. Experimental & molecular medicine 16 38443598
2024 PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting. Autophagy 16 38919131
2023 The ER membrane protein complex restricts mitophagy by controlling BNIP3 turnover. The EMBO journal 16 38177312
2022 LncRNA HABON promoted liver cancer cells survival under hypoxia by inhibiting mPTP opening. Cell death discovery 16 35387966
2015 TAp73 transcriptionally represses BNIP3 expression. Cell cycle (Georgetown, Tex.) 16 25950386
2025 Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery. Nature cell biology 15 40715440
2024 RNF31 alleviates liver steatosis by promoting p53/BNIP3-related mitophagy in hepatocytes. Free radical biology & medicine 15 38615890
2024 Mitophagy and cancer: role of BNIP3/BNIP3L as energetic drivers of stemness features, ATP production, proliferation, and cell migration. Aging 15 38834039
2024 Reconstitution of BNIP3/NIX-mediated autophagy reveals two pathways and hierarchical flexibility of the initiation machinery. bioRxiv : the preprint server for biology 15 39253418
2025 Neutrophil extracellular traps aggravate placental injury in OAPS by facilitating activation of BNIP3 mediated mitophagy. Free radical biology & medicine 14 40286883
2023 Effects of honokiol protects against chronic kidney disease via BNIP3/NIX and FUNDC1-mediated mitophagy and AMPK pathways. Molecular biology reports 14 37338733
2022 BNIP3 Upregulation Characterizes Cancer Cell Subpopulation With Increased Fitness and Proliferation. Frontiers in oncology 14 35912211
2025 BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation. Autophagy 13 40195021
2024 Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX. Life science alliance 13 38991726

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