Mitochondrial dysfunction, UPRmt signaling, and targeted therapy in metastasis tumor

Rajendiran Keerthiga; De-Sheng Pei; Ailing Fu

doi:10.1186/s13578-021-00696-0

Mitochondrial dysfunction, UPR^mt signaling, and targeted therapy in metastasis tumor

Cell Biosci. 2021 Oct 30;11(1):186. doi: 10.1186/s13578-021-00696-0.

Authors

Rajendiran Keerthiga¹, De-Sheng Pei², Ailing Fu³

Affiliations

¹ College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
² School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China. peids@cqmu.edu.cn.
³ College of Pharmaceutical Sciences, Southwest University, Chongqing, China. fal@swu.edu.cn.

Abstract

In modern research, mitochondria are considered a more crucial energy plant in cells. Mitochondrial dysfunction, including mitochondrial DNA (mtDNA) mutation and denatured protein accumulation, is a common feature of tumors. The dysfunctional mitochondria reprogram molecular metabolism and allow tumor cells to proliferate in the hostile microenvironment. One of the crucial signaling pathways of the mitochondrial dysfunction activation in the tumor cells is the retrograde signaling of mitochondria-nucleus interaction, mitochondrial unfolded protein response (UPR^mt), which is initiated by accumulation of denatured protein and excess ROS production. In the process of UPR^mt, various components are activitated to enhance the mitochondria-nucleus retrograde signaling to promote carcinoma progression, including hypoxia-inducible factor (HIF), activating transcription factor ATF-4, ATF-5, CHOP, AKT, AMPK. The retrograde signaling molecules of overexpression ATF-5, SIRT3, CREB, SOD1, SOD2, early growth response protein 1 (EGR1), ATF2, CCAAT/enhancer-binding protein-d, and CHOP also involved in the process. Targeted blockage of the UPR^mt pathway could obviously inhibit tumor proliferation and metastasis. This review indicates the UPR^mt pathways and its crucial role in targeted therapy of metastasis tumors.

Keywords: Cytosolic heat shock response (HSR); Hypoxia-inducible factor (HIF); Integrated stress response (ISR); Mitochondrial unfolded protein response UPRmt; Mitohormesis; Retrograde signaling.

Publication types

Review