Abstract 1491: Mitochondrial dysfunction from defective Cytochrome oxidase complex induces tumorigenic phenotype

Abstract Mitochondrial defects that affect activity of the electron transport chain (ETC) complexes are associated with several diseases including cancer. Dysfunctional mitochondria resulting from mitochondrial DNA (mtDNA) alterations or exposure to xenobiotics have been shown to initiate retrograde signaling pathway characterized by disrupted membrane potential, elevated cytosolic calcium and activation of Calcineurin, a calcium dependent phosphatase. In some cell types these events form the basis for triggering transcriptional reprogramming that converts non tumorigenic cells to tumorigenic phenotype. Cytochrome oxidase (CcO) is the terminal enzyme of the ETC that catalyzes the transfer of electrons from reduced cytochrome C to oxygen. All the mutations of CcO subunits identified as prevalent in various cancers like prostrate, pancreatic, colon and ovarian cancers have been found in mtDNA encoded subunits. Effect of loss of nuclear subunits leading to reduced Cytochrome oxidase activity on tumor progression are not well studied. Nuclear subunits IVi1 and Vb of CcO are susceptible to various stress conditions like exposure to long term hypoxia, ischemia-reperfusion and treatment with ethanol resulting in selective degradation and loss of activity. Here we report the activation of retrograde signaling by loss of these subunits. Genetic silencing of the subunits IVi1 and Vb, and loss of activity resulted in metabolic shift to glycolysis and was accompanied by increased glucose utilization. Disruption of the CcO complex activated many of the hallmark factors of Ca2+/Calcineurin mediated retrograde signaling. Importantly, rescue of the CcO deficiency by overexpressing CcO subunits or by inhibitors of retrograde signaling pathway attenuated the phenotypic changes such as anchorage independent growth and increased invasive potential. Further, esophageal tumor sections from human patients revealed reduced CcO subunits IVi1 and Vb in the center of the tumor mass suggesting a pathological significance of these findings. Our results show that mitochondrial ETC defect initiates a retrograde signaling and induces genes with major roles in tumor development. (Supported by NIH grants CA-22762 and GM-34883) Note: This abstract was not presented at the meeting. Citation Format: Satish Srinivasan, Manti Guha, Gordon Ruthel, Hiroshi Nakagawa, Narayan Avadhani. Mitochondrial dysfunction from defective Cytochrome oxidase complex induces tumorigenic phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1491. doi:10.1158/1538-7445.AM2017-1491