title: Human mitochondrial Fis1 links to cell cycle regulators at G2/M transition.
abstract: We have previously shown that prolonged mitochondrial elongation triggers cellular senescence. Here, we report that enforced mitochondrial elongation by hFis1 depletion caused a severe defect in cell cycle progression through G2/M phase (~3-fold reduction in mitotic index; p < 0.01). Reintroduction of Myc-hFis1 to these cells induced mitochondrial fragmentation and restored the cell cycle, indicating that morphodynamic changes of mitochondria closely link to the cell cycle. In hFis1-knockdown cells, cell cycle regulators governing the G2/M phase, including cyclin A, cyclin B1, cyclin-dependent kinase1 (Cdk1), polo-like kinase1 (Plk1), aurora kinase A and Mad2, were significantly suppressed (2- to 10-fold). Notably, however, when mitochondrial fragmentation was induced by double knockdown of hFis1 and Opa1, the cells regained their ability to enter mitosis, and cell cycle regulators were rebounded. Reconstitution of the cyclin B1/Cdk1 complex, a major regulator of the G2/M transition, failed to restore mitotic entry in hFis1-depleted cells. In contrast, expression of Plk1, an upstream regulator of the cyclin B1/Cdk1 complex, or FoxM1 (forkhead box M1), a master transcriptional factor for the cell cycle regulators of G2/M phase, restored the cell cycle in these cells. Our findings suggest that mitochondrial fission molecule hFis1 ensures the proper cell division by interplay with the cell cycle machinery.
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, 5 Wonchon-dong, Yeongtong-gu, Suwon, 443-721, Korea.
authors.forename: Seungmin
authors.initials: S
authors.lastname: Lee
authors.forename: Yong-Yea
authors.initials: YY
authors.lastname: Park
authors.forename: Song-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Oanh T Kim
authors.initials: OT
authors.lastname: Nguyen
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Yoo
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Chan
authors.forename: Xuejun
authors.initials: X
authors.lastname: Sun
authors.forename: Hyeseong
authors.initials: H
authors.lastname: Cho
mesh_terms: D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D002522:Chlorocebus aethiops; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D016195:G2 Phase; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C476525:FIS1 protein, human; C107585:FOXM1 protein, human; C415198:OPA1 protein, human
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