| 2003 |
NMR solution structure of human Fis1 revealed a TPR-like helix bundle composed of six alpha-helices forming a slightly twisted slab; the structure suggests Fis1 acts as a molecular adaptor on the mitochondrial outer membrane, with a concave hydrophobic surface predicted to mediate protein-protein interactions, and a C-terminal transmembrane segment for membrane anchoring. |
NMR spectroscopy |
Journal of molecular biology |
High |
14623186
|
| 2004 |
Human Fis1 inserts into the mitochondrial outer membrane via a C-terminal transmembrane domain; this transmembrane domain together with a short basic segment is essential for mitochondrial targeting. Overexpression causes mitochondrial fragmentation suppressible by dominant-negative Drp1(K38A), and RNAi knockdown causes elongation of mitochondrial tubules, establishing hFis1 as a regulator of mitochondrial fission acting upstream of or in concert with Drp1. |
Deletion mutagenesis, dominant-negative Drp1 rescue, RNAi knockdown with fluorescence microscopy |
Journal of cell science |
High |
14996942
|
| 2004 |
Down-regulation of hFis1 by shRNA inhibits apoptosis more potently than down-regulation of Drp1, and at a distinct stage. Cells depleted of Opa1 die spontaneously by a process requiring hFis1 expression, indicating Fis1 has a pro-apoptotic function that Opa1 normally counteracts. |
shRNA knockdown, apoptosis assays (flow cytometry, cell death quantification) |
Molecular biology of the cell |
Medium |
15356267
|
| 2005 |
Human Fis1 localizes to peroxisomes in addition to mitochondria; the transmembrane domain and short C-terminal tail are necessary and sufficient for targeting to both organelles, whereas the N-terminal region is required for organelle fission. Fis1 overexpression promotes peroxisome division and siRNA silencing causes peroxisome tubulation, establishing a role for Fis1 in peroxisomal fission. |
Differential tagging, deletion mutagenesis, siRNA, fluorescence microscopy |
Molecular biology of the cell |
High |
16107562
|
| 2005 |
Analysis of rat Fis1 by BN-PAGE revealed it forms an ~200 kDa complex at the outer mitochondrial membrane. Domain analysis showed the N-terminal and C-terminal segments are both essential for oligomeric rFis1 interaction, and the middle TPR-like domains regulate proper oligomer assembly; disruption of oligomeric assembly abolishes mitochondrial division-stimulating activity. |
Blue-native PAGE, deletion mutagenesis, RNAi, fluorescence microscopy |
Biochemical and biophysical research communications |
Medium |
15979461
|
| 2005 |
NMR structure of yeast Fis1 revealed that, unlike the flexible unstructured N-terminus of human Fis1, the longer N-terminus of yeast Fis1 is fixed to the concave face of the TPR domain in an intramolecular fashion. This N-terminal segment is required for Mdv1 recruitment to mitochondria and for rescuing mitochondrial fission in fis1Δ yeast, indicating intramolecular autoinhibitory regulation of Fis1 bioactivity. |
NMR spectroscopy, yeast complementation assay, fluorescence microscopy |
The Journal of biological chemistry |
High |
15809300
|
| 2007 |
Crystal structures of yeast Fis1 in complex with adaptor proteins Mdv1 and Caf4 showed these adaptors use two helices to bind both the concave and convex surfaces of the Fis1 TPR domain — a novel binding mode for TPR domains. Genetic and biochemical studies confirmed both interfaces are important for Mdv1/Caf4 binding and for mitochondrial fission in vivo. |
X-ray crystallography, biochemical binding assays, yeast genetics |
Proceedings of the National Academy of Sciences of the United States of America |
High |
17998537
|
| 2007 |
Yeast Fis1 directly binds Dnm1 (the Drp1 ortholog) in a manner negatively regulated by the Fis1 N-terminal arm; the concave surface of the Fis1 TPR domain mediates Dnm1 binding; removal of the arm increases Dnm1 binding >100-fold, indicating the arm acts in an autoinhibitory manner to restrict access to the Dnm1-binding site. |
In vitro binding assays, mutagenesis, fluorescence microscopy |
The Journal of biological chemistry |
High |
17884824
|
| 2007 |
Fis1 localizes to peroxisomes as well as mitochondria in mammalian cells (confirmed by subcellular fractionation). Fis1 directly interacts with the peroxisomal membrane protein Pex11pβ (co-IP and binding studies), and ternary complexes of Fis1–Pex11pβ–DLP1 were detected by chemical crosslinking; Fis1 overexpression induces peroxisome proliferation while Fis1 RNAi causes peroxisome tubulation. |
Subcellular fractionation, co-immunoprecipitation, chemical crosslinking, RNAi, fluorescence microscopy |
Experimental cell research |
High |
17408615
|
| 2008 |
In yeast, deletion of FIS1 consistently selects for a secondary mutation in WHI2, which rescues the mitochondrial respiratory defect (petite formation) caused by FIS1 deficiency but causes defective growth control. The long-term survival function of Fis1 in this context appears independent of Dnm1 and Mdv1 but may be mediated through the Caf4 adaptor. |
Yeast genetics, tiling arrays, genomic sequencing, growth assays |
Cell death and differentiation |
Medium |
18756280
|
| 2008 |
High-level Fis1 overexpression triggers autophagy (mitophagy) correlating with mitochondrial dysfunction rather than fragmentation per se, as demonstrated by Fis1 mutants with dissociated effects on organelle shape versus function. |
Fis1 overexpression/mutagenesis, autophagosome formation assays, fluorescence microscopy |
Biochimica et biophysica acta |
Medium |
18515060
|
| 2010 |
Fis1 bridges the mitochondria–ER interface by interacting with the ER protein Bap31, facilitating Bap31 cleavage into pro-apoptotic p20Bap31; the Fis1–Bap31 complex (ARCosome) recruits procaspase-8 via the variant death effector domain (vDED) of Bap31, activating procaspase-8 and releasing ER Ca²⁺ to amplify mitochondrial apoptosis in a feedback loop. |
Co-immunoprecipitation, subcellular fractionation, apoptosis assays, Ca²⁺ measurements, domain deletion analysis |
The EMBO journal |
High |
21183955
|
| 2011 |
AKAP121 inhibits Drp1–Fis1 interaction in a PKA-independent manner; reduced AKAP121 availability (via ubiquitin ligase Siah2) relieves inhibition and increases Drp1–Fis1 interaction, resulting in mitochondrial fission under hypoxia. This defines Siah2 as a key upstream regulator of Fis1/Drp1-mediated fission. |
Co-immunoprecipitation, genetic knockout (Siah2−/− mice), cardiac ischemia models, C. elegans lifespan assays |
Molecular cell |
High |
22099302
|
| 2011 |
The cytosolic domain of Fis1 alone binds lipid vesicles (enhanced by protonation and anionic phospholipids), undergoes a membrane-induced conformational change burying two tryptophan residues, and promotes reversible lipid vesicle clustering, suggesting Fis1 can directly interact with membranes to facilitate fission. |
Fluorescence spectroscopy, circular dichroism, light scattering, electron microscopy |
PloS one |
Medium |
21738650
|
| 2011 |
Crystal structure of yeast Fis1 at 1.75 Å resolution confirmed the TPR fold creates a concave surface important for fission that is sterically occluded by the N-terminal arm, providing a structural basis for autoinhibition. |
X-ray crystallography |
Acta crystallographica. Section F |
High |
22102223
|
| 2012 |
Fis1 directly and efficiently interacts with the Rab-GAP protein TBC1D15 (but not with Drp1) at mitochondria; bacterially expressed Fis1 and TBC1D15 form a direct stable complex in vitro; TBC1D15 localizes to mitochondria only when co-expressed with Fis1, and TBC1D15 knockdown induces mitochondrial network development similar to Fis1 knockdown, indicating Fis1 recruits TBC1D15 to mitochondria to regulate morphology independently of Drp1. |
Co-immunoprecipitation from HeLa extracts, bacterial protein reconstitution, RNAi, fluorescence microscopy |
Journal of cell science |
High |
23077178
|
| 2012 |
A designed point mutation A72P in Fis1 disrupts dimerization and abolishes fission activity, while two nonfunctional Fis1 variants (L80P or E78D/I85T/Y88H) are unexpectedly dimeric; these data support a model in which Fis1 activity depends on its ability to interconvert between monomer and dimer species. |
Analytical ultracentrifugation, mutagenesis, yeast fission assays |
Journal of molecular biology |
Medium |
22789569
|
| 2012 |
DJ-1 promotes proteasomal degradation of Fis1 via the DJ-1/Akt/RNF5 signaling pathway: Akt1 enhances mitochondrial translocation and E3-ligase activity of RNF5, leading to Fis1 ubiquitination and degradation; DJ-1 loss increases Fis1 levels and neuronal vulnerability in an MPTP mouse model. |
Western blotting, co-immunoprecipitation, MPTP mouse model, RNF5 E3 ligase activity assay |
The Biochemical journal |
Medium |
22871147
|
| 2012 |
miR-484 suppresses translation of Fis1 by binding to the amino acid coding sequence of Fis1 mRNA, inhibiting Fis1-mediated mitochondrial fission and apoptosis; Foxo3a transactivates miR-484 expression, establishing a Foxo3a–miR-484–Fis1 axis regulating mitochondrial fission. |
Luciferase reporter assay, miRNA overexpression/knockout mice, Western blot, apoptosis assays |
Nature communications |
Medium |
22510686
|
| 2013 |
Both Fis1 and Mff independently contribute to mitochondrial fission and are important for the number and size of Drp1 puncta on mitochondria; either MiD49 or MiD51 can mediate Drp1 recruitment and fission in the absence of both Fis1 and Mff, demonstrating that multiple independent receptors recruit Drp1. |
Fis1-null, Mff-null, and Fis1/Mff double-null cell lines, immunofluorescence, Drp1 localization analysis |
Molecular biology of the cell |
High |
23283981
|
| 2013 |
During the fission cycle, Drp1 first binds Mff, then enters a complex including Fis1 and ER proteins at the ER–mitochondrial interface; Fis1 mutations do not affect fission per se but disrupt downstream degradation events when mitochondrial toxins are used, leading to accumulation of large LC3 aggregates, indicating Fis1 acts after Mff to couple stress-induced fission with downstream mitophagy/degradation. |
Co-immunoprecipitation, Fis1 point mutations, mitochondrial toxin treatment, LC3 aggregation assays, ER-mitochondria interface imaging |
Molecular biology of the cell |
Medium |
24196833
|
| 2013 |
hFis1 depletion causes a severe cell cycle progression defect through G2/M phase (~3-fold reduction in mitotic index); reintroduction of hFis1 restores the cell cycle; G2/M regulators including cyclin B1, Cdk1, Plk1, Aurora kinase A, and Mad2 are suppressed in hFis1-knockdown cells; Plk1 or FoxM1 expression (but not cyclin B1/Cdk1 complex reconstitution) restores mitotic entry, placing hFis1 upstream of Plk1/FoxM1 in G2/M regulation. |
shRNA knockdown, flow cytometry, Western blotting, rescue overexpression experiments |
Cellular and molecular life sciences |
Medium |
23907611
|
| 2016 |
Deep mutational scanning of the Fis1p tail anchor in yeast showed: (1) the positively charged patch at the C-terminus is required for both membrane insertion and organelle specificity; (2) positively charged residues are more acceptable within the membrane-associated domain than negatively charged residues, providing in vivo evidence for lysine/arginine 'snorkeling'; (3) TA length changes of ±3 amino acids do not inhibit mitochondrial targeting. |
Next-generation sequencing-based deep mutational scanning, Gal4 reporter assay, fluorescence microscopy of individual mutants |
Genetics |
High |
28007883
|
| 2016 |
Fis1 E78A mutation weakens interaction with Mdv1 (identified by NMR-guided pKa analysis), alters mitochondrial morphology, abolishes fission in growth assays, and causes uniform Dnm1 coating of mitochondria rather than puncta formation at low expression, supporting a post-recruitment role for Fis1 in organizing Dnm1 puncta. |
NMR pKa measurements, mutagenesis, yeast fission growth assay, fluorescence microscopy |
The Journal of biological chemistry |
Medium |
27496949
|
| 2018 |
AMPK is intrinsically activated in AML leukemia stem cells and is upstream of FIS1; FIS1 mediates mitophagy activity essential for LSC self-renewal; FIS1 depletion attenuates mitophagy, inactivates GSK3, induces myeloid differentiation, cell cycle arrest, and loss of LSC self-renewal potential, establishing an AMPK→FIS1→mitophagy axis in LSC maintenance. |
shRNA knockdown, AMPK inhibition, mitophagy assays, colony-forming/self-renewal assays, xenograft models |
Cell stem cell |
Medium |
29910151
|
| 2019 |
Fis1 depletion from the outer mitochondrial membrane causes aberrant STX17 (Syntaxin 17) accumulation on mitochondria; STX17–Fis1 interaction (identified by proteomics) controls dynamic shuttling of STX17 between ER and mitochondria; Fis1 loss exposes the STX17 N-terminus, promotes STX17 self-oligomerization, triggering PINK1/Parkin-independent mitophagy via ATG14 recruitment and Rab7-dependent lysosome fusion. |
Super-resolution microscopy (SR-SIM), proteomics, Co-IP, STX17 oligomerization assays, mitophagy flux assays, Rab7 interaction experiments |
Nature communications |
High |
31053718
|
| 2021 |
Met receptor tyrosine kinase directly phosphorylates Fis1 at Tyr38 (Fis1 pY38); Fis1 pY38 promotes mitochondrial fission by recruiting Drp1 to mitochondria; fragmented mitochondria fuel actin remodeling and lamellipodia/invadopodia formation to facilitate HCC cell metastasis in vitro and in vivo. |
Structured illumination microscopy, live-cell imaging, in vitro kinase assay, phospho-specific antibody, Drp1 recruitment assays, invasion/migration assays, xenograft models |
Signal transduction and targeted therapy |
High |
34848680
|
| 2022 |
DNA-PKcs translocates to the cytoplasm during AKI, directly interacts with Fis1, and phosphorylates Fis1 at Thr34 (TQ motif); Fis1 pThr34 increases affinity of Fis1 for Drp1, inducing mitochondrial fragmentation and tubular cell death; knock-in T34A mice are protected from AKI and show reduced mitochondrial fragmentation. |
Co-immunoprecipitation, in vitro kinase assay, phospho-specific detection, T34A knockin mice, kidney function assays, electron microscopy |
Science signaling |
High |
35290083
|
| 2022 |
Fis1 is SUMOylated at K149, an amino acid residue critical for its mitochondrial localization; SENP3 (stabilized by CHIP downregulation upon DFP treatment) deSUMOylates Fis1, enhancing Fis1 mitochondrial localization; SENP3 depletion abolishes DFP-induced mitophagy; a K149R mutation (preventing SUMOylation) enhances mitochondrial Fis1 localization and restores DFP-induced mitophagy in SENP3-depleted cells. |
SUMOylation assays, site-directed mutagenesis (K149R), SENP3 depletion, mitophagy flux assays, fractionation |
EMBO reports |
High |
34994490
|
| 2022 |
NMR and X-ray structural studies showed the human Fis1 arm can adopt an intramolecular conformation akin to yeast Fis1; removal of the Fis1 arm reduces Drp1 recruitment and mitochondrial fission in cells similar to yeast; TBC1D15 expression partially rescues arm-less Fis1 function, reminiscent of Mdv1 in yeast, supporting conserved arm-dependent regulation across eukaryotes. |
Molecular dynamics simulations, NMR, intrinsic tryptophan fluorescence, cellular DRP1 recruitment assays, TBC1D15 rescue experiments |
The Journal of biological chemistry |
High |
36272645
|
| 2023 |
Human Fis1 directly binds human Drp1 (KD = 12–68 μM) as measured by NMR, differential scanning fluorimetry, and microscale thermophoresis; similar to yeast, interaction is governed by the Fis1 N-terminal arm and a conserved surface; alanine scanning of the arm identified loss-of-function (N6A → elongated mitochondria) and gain-of-function (E7A → fragmented mitochondria) alleles; Y76A substitution also caused fragmented mitochondria, supporting intramolecular arm–surface interactions regulating Drp1-mediated fission. |
NMR, differential scanning fluorimetry, microscale thermophoresis, alanine scanning mutagenesis, mitochondrial morphology assays in human cells |
The Journal of biological chemistry |
High |
37866629
|
| 2023 |
A switch I-adjacent groove (SWAG) on Drp1 is the binding site for the Fis1-derived peptide inhibitor P110; small molecules binding SWAG (e.g., SC9) mimic P110's benefit by selectively inhibiting pathological Drp1–Fis1-mediated fission without blocking physiological Drp1–Mff-mediated fission in cells and in a mouse endotoxemia model. |
Peptide mapping, structural modeling, small molecule screening, cellular Drp1–Fis1 interaction assays, mouse endotoxemia model |
Nature communications |
Medium |
37468472
|
| 2023 |
Crystal structure of human Fis1 bound to the C-terminal Bap31_vDED region showed that the Bap31 vDED region engages the convex surface of Fis1's TPR domain; one Fis1 conformation features the N-terminal arm (suggestive of autoinhibition); this provides structural basis for Fis1–Bap31 interaction at ER–mitochondria contact sites. |
X-ray crystallography (co-crystal structure), structural analysis |
Communications biology |
High |
40770055
|
| 2023 |
A conserved three-residue SKY insert (S45, K46, Y47) in FIS1's first TPR repeat is required for TBC1D15 and DRP1 recruitment to mitochondria; deletion of the SKY insert elongates mitochondrial networks with reduced mitochondrial DRP1 despite enriched DRP1 co-immunoprecipitates; the SKY insert mediates intramolecular interactions with the regulatory Fis1 arm to govern FIS1 activity. |
Site-directed mutagenesis/deletion, co-immunoprecipitation, fluorescence microscopy, YFP-TBC1D15 recruitment assays |
The Journal of biological chemistry |
Medium |
37777154
|
| 2023 |
SENP1 translocates to endothelial mitochondria under short-term hypoxia and deSUMOylates FIS1; deSUMOylated FIS1 assembles with MFN2 and VDAC1, enhancing MFN2 oligomerization and membrane tethering activity, thereby maintaining mitochondrial integrity and ER–mitochondria Ca²⁺ communication; prolonged hypoxia reduces SENP1 availability via miR-138 induction, causing SUMOylated FIS1 accumulation and mitochondrial dysfunction leading to pulmonary hypertension. |
Co-immunoprecipitation, MFN2 oligomerization assay, viral-packaged FIS1 mutant knock-in mice, Ca²⁺ communication assays, hypoxia/Sugen rat PH models |
Circulation research |
High |
37589160
|
| 2023 |
Lactylation of Fis1 at lysine 20 (Fis1 K20la), driven by excess lactate produced via SIRT3-mediated PDHA1 hyperacetylation/inactivation, promotes excessive mitochondrial fission leading to ATP depletion, mtROS overproduction, and mitochondrial apoptosis in sepsis-induced AKI; reducing lactate (via DCA or SIRT3 overexpression) decreases Fis1 K20la and alleviates AKI. |
Lactylation site identification, PDHA1 acetylation assays, in vitro and in vivo AKI models, mitochondrial morphology assays |
Cell death & disease |
Medium |
37479690
|
| 2024 |
Under oxidative stress, Fis1 undergoes a conformational change exposing its only cysteine Cys41 (in the α1 helix); exposed Cys41 forms disulfide-bridged Fis1 homodimers that increase Drp1 recruitment to mitochondria and excessive fission; a small molecule SP11 binds specifically to activated (Cys41-exposed) Fis1, blocking homodimerization and preserving mitochondrial integrity; cells lacking Cys41 (C41A) show reduced stress-induced fission. |
Structural analysis (activated Fis1–SP11 crystal structure), disulfide crosslinking, C41A knockin cell lines, Drp1 recruitment assays, mitochondrial morphology under oxidative stress |
Nature communications |
High |
40328741
|
| 2024 |
FIS1 deSUMOylation by SENP3 interacts with TBC1D17 (a Rab-GAP) in a SUMOylation-dependent manner under hypoxia; hypoxia promotes FIS1 SUMO2/3-ylation, triggering FIS1–TBC1D17 interaction that suppresses hypoxia-induced mitophagy; SENP3-mediated deSUMOylation of FIS1 promotes hypoxia-induced mitophagy and protects against hypoxic cell death. |
Co-immunoprecipitation, SUMOylation assays, SENP3 depletion, mitophagy flux assays, glioma patient-derived stem cells |
Cell death & disease |
Medium |
39638786
|