{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMitochondrial fission factor (MFF) is a pivotal outer‐mitochondrial membrane protein that orchestrates the division of both mitochondria and peroxisomes. Acting as a receptor for the dynamin‐related GTPase Drp1, MFF recruits and facilitates the assembly of the fission machinery in response to both constitutive signals and stress‐induced stimuli. Its ability to oligomerize and interact with other fission adaptors—distinct from proteins such as Fis1 and the MiD family—as well as to shape membrane curvature is essential for proper mitochondrial and peroxisomal fragmentation. This fundamental role of MFF in organelle division is underscored by studies showing that its depletion leads to elongated, interconnected organelle networks and delays in apoptosis progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMFF function is tightly regulated by cellular signaling pathways that modulate its expression, post‐translational modification, and downstream effects on organelle dynamics. Under conditions of oxidative stress and metabolic reprogramming, such as those observed in cancer-associated fibroblasts or in diabetic nephropathy, kinases like AMPK and JNK phosphorylate MFF to activate fission, leading to mitochondrial fragmentation, reduced ATP production, and the promotion of apoptosis. Genetic defects in MFF further highlight its clinical relevance, with mutations linked to neurodevelopmental disorders and impaired peroxisomal dynamics, while alterations in its expression serve as potential diagnostic markers in hepatocellular carcinoma and other malignancies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in organelle division, MFF is a critical mediator of cell death and survival pathways. Modifications in Drp1 that facilitate its binding to MFF—such as deSUMOylation—trigger cytochrome c release and apoptosis, a process that can be modulated by targeting the MFF–Drp1 interaction with inhibitory peptides. Moreover, MFF expression is subject to fine-tuning by microRNAs (for example, miR-27 and miR-593-5p) and interacts with additional regulators including VDAC1, Parkin, and even Mcl-1, thereby influencing mitochondrial permeability, mitophagy, and chemotherapeutic sensitivity in various cancers. These multifunctional roles position MFF as a promising diagnostic marker and therapeutic target in conditions ranging from drug-resistant tumors to mitochondrial disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shilpa Gandre-Babbe, Alexander M van der Bliek "}, {"type": "b", "children": [{"type": "t", "text": "The novel tail-anchored membrane protein Mff controls mitochondrial and peroxisomal fission in mammalian cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e07-12-1287"}], "href": "https://doi.org/10.1091/mbc.e07-12-1287"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18353969"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18353969"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Catherine S Palmer, Kirstin D Elgass, Robert G Parton, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.479873"}], "href": "https://doi.org/10.1074/jbc.M113.479873"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23921378"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23921378"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Patrick J Macdonald, Christopher A Francy, Natalia Stepanyants, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct Splice Variants of Dynamin-related Protein 1 Differentially Utilize Mitochondrial Fission Factor as an Effector of Cooperative GTPase Activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.680181"}], "href": "https://doi.org/10.1074/jbc.M115.680181"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26578513"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26578513"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Johannes Koch, Cécile Brocard "}, {"type": "b", "children": [{"type": "t", "text": "PEX11 proteins attract Mff and human Fis1 to coordinate peroxisomal fission."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.102178"}], "href": "https://doi.org/10.1242/jcs.102178"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22595523"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22595523"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Rong Yu, Tong Liu, Chenfei Ning, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The phosphorylation status of Ser-637 in dynamin-related protein 1 (Drp1) does not determine Drp1 recruitment to mitochondria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA119.008202"}], "href": "https://doi.org/10.1074/jbc.RA119.008202"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31533986"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31533986"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ao Liu, Frieda Kage, Henry N Higgs "}, {"type": "b", "children": [{"type": "t", "text": "Mff oligomerization is required for Drp1 activation and synergy with actin filaments during mitochondrial division."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.E21-04-0224"}], "href": "https://doi.org/10.1091/mbc.E21-04-0224"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34347505"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34347505"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Carmela Guido, Diana Whitaker-Menezes, Zhao Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.574"}], "href": "https://doi.org/10.18632/oncotarget.574"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22878233"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22878233"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Johannes Koch, René G Feichtinger, Peter Freisinger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Disturbed mitochondrial and peroxisomal dynamics due to loss of MFF causes Leigh-like encephalopathy, optic atrophy and peripheral neuropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmedgenet-2015-103500"}], "href": "https://doi.org/10.1136/jmedgenet-2015-103500"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26783368"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26783368"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Qingqing Zheng, Youshan Zhao, Juan Guo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Iron overload promotes mitochondrial fragmentation in mesenchymal stromal cells from myelodysplastic syndrome patients through activation of the AMPK/MFF/Drp1 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-018-0552-7"}], "href": "https://doi.org/10.1038/s41419-018-0552-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29725013"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29725013"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Junqin Sheng, Hongyan Li, Qin Dai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DUSP1 recuses diabetic nephropathy via repressing JNK-Mff-mitochondrial fission pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.27124"}], "href": "https://doi.org/10.1002/jcp.27124"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30191967"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30191967"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Hironori Takamura, Yoshihisa Koyama, Shinsuke Matsuzaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRAP1 controls mitochondrial fusion/fission balance through Drp1 and Mff expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0051912"}], "href": "https://doi.org/10.1371/journal.pone.0051912"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23284813"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23284813"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Kun Wu, Yuan-Yuan Mao, Qi Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hypoxia-induced ROS promotes mitochondrial fission and cisplatin chemosensitivity via HIF-1α/Mff regulation in head and neck squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Oncol (Dordr) (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13402-021-00629-6"}], "href": "https://doi.org/10.1007/s13402-021-00629-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34460078"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34460078"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Hyosun Tak, Hoin Kang, Eunbyul Ji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Potential use of TIA-1, MFF, microRNA-200a-3p, and microRNA-27 as a novel marker for hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2018.02.189"}], "href": "https://doi.org/10.1016/j.bbrc.2018.02.189"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29496454"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29496454"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Chun Guo, Kevin A Wilkinson, Ashley J Evans, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SENP3-mediated deSUMOylation of Drp1 facilitates interaction with Mff to promote cell death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep43811"}], "href": "https://doi.org/10.1038/srep43811"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28262828"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28262828"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Opher S Kornfeld, Nir Qvit, Bereketeab Haileselassie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-018-32228-1"}], "href": "https://doi.org/10.1038/s41598-018-32228-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30232469"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30232469"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Song Fan, Bodu Liu, Lijuan Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1-miR-593-5p-MFF axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.3659"}], "href": "https://doi.org/10.18632/oncotarget.3659"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25912308"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25912308"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Jae Ho Seo, Young Chan Chae, Andrew V Kossenkov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MFF Regulation of Mitochondrial Cell Death Is a Therapeutic Target in Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-19-1982"}], "href": "https://doi.org/10.1158/0008-5472.CAN-19-1982"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31582380"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31582380"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Hyosun Tak, Jihye Kim, Aravinth Kumar Jayabalan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-27 regulates mitochondrial networks by directly targeting the mitochondrial fission factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Mol Med (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emm.2014.73"}], "href": "https://doi.org/10.1038/emm.2014.73"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25431021"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25431021"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Yusuf Ziya Igci, Ahmet Arslan, Ersin Akarsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential expression of a set of genes in follicular and classic variants of papillary thyroid carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocr Pathol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12022-011-9157-8"}], "href": "https://doi.org/10.1007/s12022-011-9157-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21509594"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21509594"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Ju Gao, Siyue Qin, Chang'an Jiang "}, {"type": "b", "children": [{"type": "t", "text": "Parkin-induced ubiquitination of Mff promotes its association with p62/SQSTM1 during mitochondrial depolarization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Biochim Biophys Sin (Shanghai) (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/abbs/gmv044"}], "href": "https://doi.org/10.1093/abbs/gmv044"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26008206"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26008206"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Isha Panda, Istaq Ahmad, Shakti Sagar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Encephalopathy due to defective mitochondrial and peroxisomal fission 2 caused by a novel MFF gene mutation in a young child."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cge.13740"}], "href": "https://doi.org/10.1111/cge.13740"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32181496"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32181496"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Yangpei Liu, Yunyun Ma, Zhuang Tu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mcl-1 inhibits Mff-mediated mitochondrial fragmentation and apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2019.12.104"}], "href": "https://doi.org/10.1016/j.bbrc.2019.12.104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31941601"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31941601"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Hanan E Shamseldin, Amal Alhashem, Brahim Tabarki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial \"dysmorphology\" in variant classification."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-021-02378-w"}], "href": "https://doi.org/10.1007/s00439-021-02378-w"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34750646"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34750646"}]}]}]}