**Increased Mitochondrial Fragmentation Mediated by Dynamin-Related Protein 1 Contributes to Hexavalent Chromium-Induced Mitochondrial Respiratory Chain Complex I-Dependent Cytotoxicity**

#### **Yu Ma, Yujing Zhang, Yuanyuan Xiao and Fang Xiao \***

Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, China; 196901002@csu.edu.cn (Y.M.); zhangyujing@hunnu.edu.cn (Y.Z.); xiaoyuanyuan@csu.edu.cn (Y.X.) **\***

 Correspondence: fangxiao@csu.edu.cn

Received: 26 March 2020; Accepted: 23 July 2020; Published: 29 July 2020

**Abstract:** Hexavalent chromium (Cr(VI)) pollution is a severe public health problem in the world. Although it is believed that mitochondrial fragmentation is a common phenomenon in apoptosis, whether excessive fission is crucial for apoptosis remains controversial. We previously confirmed that Cr(VI) mainly targeted mitochondrial respiratory chain complex I (MRCC I) to induce reactive oxygen species (ROS)-mediated apoptosis, but the related mechanism was unclear. In this study, we found Cr(VI) targeted MRCC I to induce ROS accumulation and triggered mitochondria-related cytotoxicity. Cr(VI)-induced cytotoxicity was alleviated by pretreatment of Glutamate/malate (Glu/Mal; MRCC I substrates), and was aggravated by cotreatment of rotenone (ROT; MRCC I inhibitor). Cr(VI) induced excessive mitochondrial fragmentation and mitochondrial dynamin-related protein 1 (Drp1) translocation, the application of Drp1-siRNA alleviated Cr(VI)-induced apoptosis. The cytotoxicity in the Drp1-si plus Cr(VI) treatment group was alleviated by the application of Glu/Mal, and was aggravated by the application of ROT. Drp1 siRNA promoted the inhibition of Glu/Mal on Cr(VI)-induced cytotoxicity, and alleviated the aggravation of ROT on Cr(VI)-induced cytotoxicity. Taken together, Cr(VI)-induced Drp1 modulation was dependent on MRCC I inhibition-mediated ROS production, and Drp1-mediated mitochondrial fragmentation contributed to Cr(VI)-induced MRCC I-dependent cytotoxicity, which provided the experimental basis for further elucidating Cr(VI)-induced cytotoxicity.

**Keywords:** hexavalent chromium [Cr(VI)]; mitochondrial fragmentation; dynamin-related protein 1 (Drp1); mitochondrial respiratory chain complex I (MRCC I); reactive oxygen species (ROS)
