1. Academic Validation
  2. Disrupted mitochondrial homeostasis coupled with mitotic arrest generates antineoplastic oxidative stress

Disrupted mitochondrial homeostasis coupled with mitotic arrest generates antineoplastic oxidative stress

  • Oncogene. 2022 Jan;41(3):427-443. doi: 10.1038/s41388-021-02105-9.
Xiaohe Hao 1 Wenqing Bu 2 Guosheng Lv 1 Limei Xu 1 Dong Hou 1 Jing Wang 1 Xiaojie Liu 2 Tingting Yang 2 Xiyu Zhang 1 Qiao Liu 1 Yaoqin Gong 1 Changshun Shao 3 4
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Experimental Teratology, Department of Genetics, Shandong University School of Basic Medical Sciences, Jinan, Shandong, 250012, China.
  • 2 State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, 215123, China.
  • 3 MOE Key Laboratory of Experimental Teratology, Department of Genetics, Shandong University School of Basic Medical Sciences, Jinan, Shandong, 250012, China. shaoc@suda.edu.cn.
  • 4 State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, 215123, China. shaoc@suda.edu.cn.
Abstract

Reactive Oxygen Species (ROS) serve as critical signals in various cellular processes. Excessive ROS cause cell death or senescence and mediates the therapeutic effect of many Cancer drugs. Recent studies showed that ROS increasingly accumulate during G2/M arrest, the underlying mechanism, however, has not been fully elucidated. Here, we show that in Cancer cells treated with Anticancer agent TH287 or paclitaxel that causes M arrest, mitochondria accumulate robustly and produce excessive mitochondrial superoxide, which causes oxidative DNA damage and undermines cell survival and proliferation. While mitochondrial mass is greatly increased in cells arrested at M phase, the mitochondrial function is compromised, as reflected by reduced mitochondrial membrane potential, increased SUMOylation and acetylation of mitochondrial proteins, as well as an increased metabolic reliance on glycolysis. Chk1 functional disruption decelerates cell cycle, spares the M arrest and attenuates mitochondrial oxidative stress. Induction of Mitophagy and blockade of mitochondrial biogenesis, measures that reduce mitochondrial accumulation, also decelerate cell cycle and abrogate M arrest-coupled mitochondrial oxidative stress. These results suggest that cell cycle progression and mitochondrial homeostasis are interdependent and coordinated, and that impairment of mitochondrial homeostasis and the associated redox signaling may mediate the antineoplastic effect of the M arrest-inducing chemotherapeutics. Our findings provide insights into the fate of cells arrested at M phase and have implications in Cancer therapy.

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