title: Mitochondrial genome instability and ROS enhance intestinal tumorigenesis in APC(Min/+) 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.
authors: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520-8023, USA.
authors: Dong Kyun
authors: DK
authors: Woo
authors: Paula D
authors: PD
authors: Green
authors: Janine H
authors: JH
authors: Santos
authors: Anthony D
authors: AD
authors: D'Souza
authors: Zenta
authors: Z
authors: Walther
authors: W David
authors: WD
authors: Martin
authors: Brooke E
authors: BE
authors: Christian
authors: Navdeep S
authors: NS
authors: Chandel
authors: Gerald S
authors: GS
authors: Shadel
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000209:etiology* / Q000378:metabolism; D000818:Animals; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage / Q000502:physiology; D004272:DNA, Mitochondrial / Q000502:physiology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D054629:Genome, Mitochondrial / Q000502:physiology*; D042822:Genomic Instability / Q000502:physiology*; D006609:High Mobility Group Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D017382:Reactive Oxygen Species; C081930:Tfam protein, mouse