Editors' ChoiceCell Biology

Giving Mitochondria a Boost

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Science Signaling  06 May 2014:
Vol. 7, Issue 324, pp. ec120
DOI: 10.1126/scisignal.2005447

During division, cellular energy requirements increase, and conditions that compromise energy production activate cell cycle checkpoints to delay cell division until energy requirements can be met. Wang et al. found that cyclin B1 and its associated kinase cyclin-dependent kinase 1 (Cdk1), which form the complex cyclin B1/Cdk1, were present at mitochondria and enhanced mitochondrial function. Cyclin B1/Cdk1 was detected at mitochondria by immunoblotting of fractionated cells, immunogold-labeled electron microscopy, and immunofluorescence and was determined to reside in the matrix by protease accessibility assays. Analysis of synchronized cells showed that the abundance of cyclin B1/Cdk1 was greatest at the mitochondria at the time of the G2 and M phases of the cell cycle (G2/M). Profiling of mitochondrial proteins phosphorylated in vitro by commercially available Cdk1 or comparing the profiles of phosphorylated mitochondrial proteins from control cells with cells overexpressing a mitochondrially targeted, dominant-negative Cdk1 (MTS-Cdk1-dn) identified multiple components of the oxidative phosphorylation machinery, including eight subunits of complex 1 (CI). In vitro kinase assays confirmed that five of the C1 subunits were directly phosphorylated by Cdk1; furthermore, the phosphorylation of these subunits was greater in cells at G2/M than in cells at G0 or G1. When C1 subunits were knocked down, only phosphorylation-mimetic mutants or wild-type versions of these subunits restored C1 activity, confirming the importance of phosphorylation for maximal C1 activity. Expression of mitochondrially targeted cyclin B1 (MTS-cyclin B1) or mitochondrially targeted Cdk1 (MTS-Cdk1) enhanced C1 activity and mitochondrial respiration in unsynchronized cells, whereas expression of MTS-Cdk1-dn prevented the enhanced activity of C1 and mitochondrial respiration associated with G2/M. Cell-cycle analysis of MCF-10A cells indicated that overexpression of MTS-cyclinB1 reduced the duration of G1 by ~5 hours and that of S and G2/M phases by ~2 hours, resulting in the accumulation of cells in S and G2/M phases. Thus, cyclin B1/Cdk1 at mitochondria synchronizes energy production with the increased needs of dividing cells, thereby influencing the rate of cell division.

Z. Wang, M. Fan, D. Candas, T.-Q. Zhang, L. Qin, A. Eldridge, S. Wachsmann-Hogiu, K. M. Ahmed, B. A. Chromy, D. Nantajit, N. Duru, F. He, M. Chen, T. Finkel, L. S. Weinstein, J. J. Li, Cyclin B1/Cdk1 coordinates mitochondrial respiration for cell-cycle G2/M progression. Dev. Cell 29, 217–232 (2014). [PubMed]

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