The DOI matches its Crossref record; 17 of the 17 references it cites were found in a registry or an index.
Mitochondrial hyperfusion induced by loss of the fission protein Drp1 causes ATM-dependent G2/M arrest and aneuploidy through DNA replication stress
Open accessAbstract
Summary: Mitochondrial fission and fusion cycles are integrated with cell cycle progression. In this paper, we demonstrate that the inhibition of mitochondrial fission protein Drp1 causes an unexpected delay in G2/M cell cycle progression and aneuploidy. In investigating the underlying molecular mechanism, we revealed that inhibiting Drp1 triggers replication stress, which is mediated by a hyperfused mitochondrial structure and unscheduled expression of cyclin E in the G2 phase. This persistent replication stress then induces an ATM-dependent activation of the G2 to M transition cell cycle checkpoint. Knockdown of ATR, an essential kinase in preventing replication stress, significantly enhanced DNA damage and cell death of Drp1-deficienct cells. Persistent mitochondrial hyperfusion also induces centrosomal overamplification and chromosomal instability, which are causes of aneuploidy. Analysis using cells depleted of mitochondrial DNA revealed that these events are not mediated by the defects in mitochondrial ATP production and reactive oxygen species (ROS) generation. Thus dysfunctional mitochondrial fission directly induces genome instability by replication stress, which then initiates the DNA damage response. Our findings provide a novel mechanism that contributes to the cellular dysfunction and diseases associated with altered mitochondrial dynamics.
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Citations
Cites
Fission and selective fusion govern mitochondrial segregation and elimination by autophagy
Twig, G., Elorza, A., Molina, A. J. A., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., et al. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601963 · Cited by 3,082 · cited 1×
“Drp1 deficiency is generally thought to cause mitochondrial dysfunction due to a failure of a Drp1-dependent mechanism of mitophagy that removes damaged mitochondria within the cell (Twig et al., 2008).”
BackgroundCell-cycle checkpoints and cancer
Kastan, M. B., & Bartek, J. (2004) · Nature · doi:10.1038/nature03097 · Cited by 2,836
Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions
Gorgoulis, V. G., Vassiliou, L.-V. F., Karakaidos, P., Zacharatos, P., Kotsinas, A., Liloglou, T., Venere, M., DiTullio, R. A., Kastrinakis, N. G., Levy, B., et al. (2005) · Nature · doi:10.1038/nature03485 · Cited by 2,009
Mitochondrial fusion and fission in cell life and death
Westermann, B. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3013 · Cited by 2,002 · cited 2×
“Mitochondrial fission is required for inheritance and partitioning of mitochondria during cell division (Westermann, 2010).”
BackgroundATR: an essential regulator of genome integrity
Cimprich, K. A., & Cortez, D. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2450 · Cited by 1,798
Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
Weinberg, F., Hamanaka, R., Wheaton, W. W., Weinberg, S., Joseph, J., Lopez, M., Kalyanaraman, B., Mutlu, G. M., Budinger, G. R. S., & Chandel, N. S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003428107 · Cited by 1,742
OPA1 requires mitofusin 1 to promote mitochondrial fusion
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Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission.
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S-Nitrosylation of Drp1 Mediates β-Amyloid-Related Mitochondrial Fission and Neuronal Injury
Cho, D.-H., Nakamura, T., Fang, J., Cieplak, P., Godzik, A., Gu, Z., & Lipton, S. A. (2009) · Science · doi:10.1126/science.1171091 · Cited by 1,092
Cited by
Mitochondrial dynamics in health and disease: mechanisms and potential targets
Chen, W., Zhao, H., & Li, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01547-9 · Cited by 1,306
Erk2 Phosphorylation of Drp1 Promotes Mitochondrial Fission and MAPK-Driven Tumor Growth
Kashatus, J. A., Nascimento, A., Myers, L. J., Sher, A., Byrne, F. L., Hoehn, K. L., Counter, C. M., & Kashatus, D. F. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.01.002 · Cited by 698
Quality control of the mitochondrion
Ng, M. Y. W., Wai, T., & Simonsen, A. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.02.009 · Cited by 445
Mitochondrial allostatic load puts the 'gluc' back in glucocorticoids
Picard, M., Juster, R.-P., & McEwen, B. S. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2014.22 · Cited by 405
Huang, Q., Zhan, L., Cao, H., Li, J., Lyu, Y., Guo, X., Zhang, J., Ji, L., Ren, T., An, J., et al. (2016) · Autophagy · doi:10.1080/15548627.2016.1166318 · Cited by 396
Metadata
- Authors
- Qian, W., Choi, S., Gibson, G. A., Watkins, S. C., Bakkenist, C. J., & Van Houten, B.
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2012-12-01
- Volume
- 125
- Issue
- 23
- Pages
- 5745-5757
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2139131640
- Cited by
- 200
- References
- 17
- FWCI
- 4.65
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: Mitochondrial hyperfusion induced by loss of the fission protein Drp1 causes ATM-dependent G2/M arrest and aneuploidy through DNA replication stress. https://app.cochat.ai/papers/10.1242/jcs.109769
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- Qian, W., Choi, S., Gibson, G. A., Watkins, S. C., Bakkenist, C. J., & Van Houten, B. (2012). Mitochondrial hyperfusion induced by loss of the fission protein Drp1 causes ATM-dependent G2/M arrest and aneuploidy through DNA replication stress. Journal of Cell Science. https://doi.org/10.1242/jcs.109769
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