Abstract 1696: Mitochondria-nuclear cross talk regulate cancer properties by activating oncogenic pathways.
Authors: Kumar Santosh , Gupta Vineet , Vithayathil Sajna , Park Junhyoung , Donti Taraka R. , Creighton Chad J. , Lewis Michael T. , Sreekumar Arun , Wong Lee-Jun , Kaipparettu Benny A. 
Published: August 2014

Abstract
Mitochondria are semiautonomous organelles within cells that play an important role in cellular energy metabolism, free radical generation, and apoptosis. Mitochondria contain their own genome (mtDNA), which encodes a number of proteins critical for energy metabolism, particularly in oxidative phosphorylation. They are also the major source of generating reactive oxygen species (ROS). So far, only limited studies (mostly focused on specific mtDNA mutations) analyzed the significance of mitochondria in cancer progression. However, it is not clear whether mitochondrial genomic status or functional defects affect nuclear genome stability and whether proteins involved in inter-genomic cross talk are involved in tumorigenesis. Transmitochondrial cybrids (cybrids) are a great utility for the study of the functional effects of mitochondria in a defined nuclear background. Cybrids are constructed by fusing enucleated cells harboring mitochondria of interest with ρ0 cells (mtDNA-depleted cells). In our cybrid model, we used ρ0 cells from moderately metastatic breast cancer cell line SUM159 as the common nuclear background. Cybrids were generated using mitochondria from benign breast epithelium (A1N4 & MCF10A), moderate (SUM159) and highly metastatic (MDA-MB231) breast cancer cells. Mitochondrial functional studies suggest that cybrids maintain the mitochondria characteristics of the mitochondria donor cells with decreased electron transport chain (ETC) function and increased ROS production in cybrids containing cancer mitochondria. In vitro tumorigenic studies suggest that even under the common moderate cancerous nuclear background, mitochondria from benign cells decreased and metastatic cell increased oncogenic properties. Metastatic mitochondria increased the expression of metastatic and EMT marker proteins and decreased the epithelial cell markers. Cybrids with mitochondria from benign breast cells showed an opposite protein expression pattern. Interestingly autophosphorylation of tyrosine residue (Tyr416) which results in Src activation was markedly increased in cybrids with metastatic mitochondria. Further analysis suggested that Src kinase phosphorylation depends on the mitochondrial characteristics and phosphorylated Src located in mitochondria. Treatment with inhibitors of Src kinases could abolish the oncogenic property of cybrids with metastatic mitochondria. Our results demonstrated that mitochondria can initiate cross-talk by regulation of nuclear gene expression or by post-translational modification of regulatory proteins such that some cellular properties of the origin of the mitochondria can be carried on to next generation.
Citation Format: Santosh Kumar, Vineet Gupta, Sajna Vithayathil, Junhyoung Park, Taraka R. Donti, Chad J. Creighton, Michael T. Lewis, Arun Sreekumar, Lee-Jun Wong, Benny A. Kaipparettu. Mitochondria-nuclear cross talk regulate cancer properties by activating oncogenic pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1696. doi:10.1158/1538-7445.AM2013-1696