J Cancer 2020; 11(4):962-973. doi:10.7150/jca.34330

Research Paper

Pyruvate dehydrogenase kinase 1 interferes with glucose metabolism reprogramming and mitochondrial quality control to aggravate stress damage in cancer

Xinyue Deng1, Quan Wang2, Meiyu Cheng1, Yingying Chen1, Xiaoyu Yan1, Rui Guo1, Liankun Sun1, Yang Li1✉, Yanan Liu1✉

1. Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
2. Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.

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Citation:
Deng X, Wang Q, Cheng M, Chen Y, Yan X, Guo R, Sun L, Li Y, Liu Y. Pyruvate dehydrogenase kinase 1 interferes with glucose metabolism reprogramming and mitochondrial quality control to aggravate stress damage in cancer. J Cancer 2020; 11(4):962-973. doi:10.7150/jca.34330. Available from http://www.jcancer.org/v11p0962.htm

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Abstract

Pyruvate dehydrogenase kinase 1 (PDK1) is a key factor in the connection between glycolysis and the tricarboxylic acid cycle. Restoring the mitochondrial OXPHOS function by inhibiting glycolysis through targeting PDK1 has become a hot spot for tumor therapy. However, the specific mechanism by which metabolic changes affect mitochondrial function remains unclear. Recent studies have found that mitochondrial quality control such as mitochondrial protein homeostasis plays an important role in maintaining mitochondrial function. Here, we focused on PDK1 and explored the specific mechanism by which metabolic changes affect mitochondrial OXPHOS function. We showed that glucose metabolism in HepG2 and HepG3B cells switched from anaerobic glycolysis to the mitochondrial tricarboxylic acid cycle under different concentrations of dichloroacetate (DCA) or short hairpin PDK1. After DCA treatment or knockdown of PDK1, the mitochondrial morphology was gradually condensed and exhibited shorter and more fragmented filaments. Additionally, expression of the mitochondrial autophagy proteins parkin and PTEN-induced kinase was down-regulated, and the biosynthetic protein peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) and its regulated complex I, III, IV, and V protein were down-regulated. This indicated that PDK1 inhibition affected the level of mitochondrial quality control. Analysis of mitochondrial function revealed significantly increased mitochondrial reactive oxygen species and decreased membrane potential. Therefore, glucose metabolism reprogramming by PDK1 inhibition could induce mitochondrial quality control disorders to aggravate mitochondrial stress damage.

Keywords: DCA, glucose metabolic reprogramming, mitochondiral quality control, oxidative phosphorylation, PDK1.