Mitochondrial Genome Instability and ROS Enhance Intestinal Tumorigenesis in APC Mice

Abstract

Alterations in mitochondrial oxidative phosphorylation have long been documented in tumors. Other types of mitochondrial dysfunction, including altered reactive oxygen species (ROS) production and apoptosis, also can contribute to tumorigenesis and cancer phenotypes. Furthermore, mutation and altered amounts of mitochondrial DNA (mtDNA) have been observed in cancer cells. However, how mtDNA instability per se contributes to cancer remains largely undetermined. Mitochondrial transcription factor A (TFAM) is required for expression and maintenance of mtDNA. Tfam heterozygous knock-out (Tfam(+/-)) mice show mild mtDNA depletion, but have no overt phenotypes. We show that Tfam(+/-) mouse cells and tissues not only possess less mtDNA but also increased oxidative mtDNA damage. Crossing Tfam(+/-) mice to the adenomatous polyposis coli multiple intestinal neoplasia (APC(Min/+)) mouse cancer model revealed that mtDNA instability increases tumor number and growth in the small intestine. This was not a result of enhancement of Wnt/β-catenin signaling, but rather appears to involve a propensity for increased mitochondrial ROS production. Direct involvement of mitochondrial ROS in intestinal tumorigenesis was shown by crossing APC(Min/+) mice to those that have catalase targeted to mitochondria, which resulted in a significant reduction in tumorigenesis in the colon. Thus, mitochondrial genome instability and ROS enhance intestinal tumorigenesis and Tfam(+/-) mice are a relevant model to address the role of mtDNA instability in disease states in which mitochondrial dysfunction is implicated, such as cancer, neurodegeneration, and aging.

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

“…TFAM mutations associated with a lowered TFAM protein and a decreased mitochondrial copy number were found in colorectal cancers with microsatellite instability while no TFAM mutations were observed in colorectal cancers with microsatellite stability. Additionally TFAM mutated cells (TFAM frame-shift mutation) were able to grow larger tumors in vivo [93] and lowered mtDNA copy number and more oxidative mtDNA damage was observed in TFAM +/ À mice [94,162]. When this model was crossbred with the adenomatous polyposis coli multiple intestinal neoplasia (APC À/+ ) mouse cancer model, mtDNA instability enhanced tumorigenesis [162].…”

Endothelial NO synthase and reactive oxygen species mediated effect of simvastatin on vessel structure and function: Pleiotropic and dose-dependent effect on tumor vascular stabilization

“…Oxidative stress and elevated ROS generation have been incriminated in many pathological conditions, including diabetes and cancer (14,15). Hypoxia and other adverse stimuli inducing high levels of ROS contribute to endothelium dysfunction and apoptosis in both diabetic retina and tumor microenvironment (16)(17)(18).…”

A Novel MitoTimer Reporter Gene for Mitochondrial Content, Structure, Stress, and Damage in Vivo

“…reduced respiratory function and increased production of reactive oxygen species (ROS), 3 features prominently in cardiovascular, metabolic, and neurodegenerative diseases, and other pathological conditions (1)(2)(3)(4)(5)(6)(7)(8)(9). Despite the importance of mitochondrial dysfunction in a myriad of pathological conditions, very few effective drugs and interventions are available for their prevention and treatment.…”