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.

Genomic heterogeneity meets cellular energetics: crosstalk between the mitochondria and the cell cycle

“…These phenotypes have started to reveal a profound level of cross-talk between these two processes of the DNA-damage kinases ATM and ATR [90] . A similar G2 delay accompanied by DNA damage is also observed after disruption of the Drp1 adaptor Fis1 [93] . Disruption of other mitochondria functions, such as in a Drosophila knockout of the mitochondria-specific form of RNaseZ [94] and in human cells depleted of mtDNA (rho0 cells) [95] also cause a G2 delay.…”

“…Disruption of other mitochondria functions, such as in a Drosophila knockout of the mitochondria-specific form of RNaseZ [94] and in human cells depleted of mtDNA (rho0 cells) [95] also cause a G2 delay. Furthermore the G2 delay after Fis1 depletion correlates with low expression of the cell cycle transcription factor FoxM1 and its downstream mitotic genes, including Cyclin B1, suggesting that defects in mitochondria dynamics/function can lead to transcriptional inhibition of the G2/M transition [93] . The link between mitochondria dynamics and cell cycle gene expression is further strengthened by observations of a correlation between Drp1 expression levels and expression of cell cycle genes in different cancers, particularly genes expressed in G2/M [96] .…”

Dysfunctional mitochondrial fission impairs cell reprogramming

“…Interference with mitochondrial fission in cancer cells by knocking down FIS1 induced a G2/M cell cycle arrest associated with DNA damage. 33 However, we did not observe differences in the induction of DNA damage between both genotypes after expressing the OSKM factors for 4 days, by either gH2AX-or p53BP1-stainings using High-Content Analysis ( Fig. 4E and Supplementary Fig.…”

Regulation of Mitochondrial Dynamics and Cell Fate

“…12 Furthermore, depletion of Fis1 impaired normal cell cycle progression, resulting in G2/M arrest. 43 Concordant with Fis1's role in mitochondrial OMM fission, reperfusion injury in the heart induced mitochondrial defects, including fission, impaired bioenergetics, and decline in cardiac function, that were completely reversed by the fission inhibitor P110. 24 Though Fis1 was initially identified as the primary OMM receptor for Drp1, recent advances in the field have suggested that Fis 1 may not be indispensable for mitochondrial fission.…”