Abstract
Cancer cells have several hallmarks that define their neoplastic behavior. One is their unabated replicative potential that allows cells to continually proliferate, and thereby contribute to increasing tumor burden. The progression of a cell through the cell cycle is regulated by a series of checkpoints that ensures successful transmission of genetic information, as well as various cellular components, including organelles and protein complexes to the two resulting daughter cells. The mitochondrial reticulum undergoes coordinated changes in shape to correspond with specific stages of the cell cycle, the most dramatic being complete mitochondrial fragmentation prior to cytokinesis. To determine whether mitochondrial fission is a required step to ensure proper mitochondrial segregation into two daughter cells, we investigated the importance of mitochondrial dynamics to cell cycle progression. We found that mitochondrial hyperfusion promotes a defect in cell cycle progression characterized by an inability for cells to exit G2/M. Additionally, extended periods of persistent mitochondrial fusion led to robust caspase-dependent cell death. The cell death signals were coordinated through activation and cleavage of caspase-8, promoting a potent death response. These results demonstrate the importance of mitochondrial dynamics in cell cycle progression, and that inhibiting mitochondrial fission regulators may provide a therapeutic strategy to target the replicative potential of cancer cells.
Highlights
Mitochondria play critical roles in meeting the bioenergetics needs of the cell, which include the generation of cellular ATP through oxidative phosphorylation [1]
Mitochondria undergo architectural changes during progression through the cell cycle Mitochondria are in constant flux, the reticulum transitioning from states of heavily fused networks to individual punctate fragments spread throughout the cytosol
Given that mitochondrial morphology is altered in preparation for mitotic cell division [11], we proposed that mitochondrial fission and fusion are important regulatory processes in determining the success of a cell division event by ensuring segregation of the mitochondrial reticulum to the resulting daughter cells
Summary
Mitochondria play critical roles in meeting the bioenergetics needs of the cell, which include the generation of cellular ATP through oxidative phosphorylation [1]. A fourth GTPase, dynamin related protein 1 (Drp1) regulates mitochondrial fission and is recruited from the cytosol to the mitochondrial by a series of OMM proteins (mitochondrial fission factor, Mff; fission 1, Fis; mitochondrial elongation factor 49, MiD49; mitochondrial elongation factor, MiD51; or endophilin B1) [8,9]. Influenced by their surrounding cellular environment, mitochondrial morphology is important for maintaining mitochondrial function, but has recently been marked as an important cellular feature for the completion of biological processes, including cellular proliferation and apoptosis [10,11,12]
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