Reference SummaryWoo DK, Am J Pathol 2012 Jan;180(1):24-31
Title |
Mitochondrial genome instability and ROS enhance intestinal tumorigenesis in APC(Min/+) mice. |
Authors |
Woo DK; Green PD; Santos JH; D'Souza AD; Walther Z; Martin WD; Christian BE; Chandel NS; Shadel GS |
Journal |
Am J Pathol |
Volume |
180 |
Issue |
1 |
Year |
2012 |
Pages |
24-31 |
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/beta-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. |
Links |
J:180188 – MGI References 22056359 – National Library of Medicine/PubMed |
| Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
|---|---|---|---|---|---|
| C57BL/6J-ApcMin/+ | Intestine - Large Intestine - Colon adenoma | Intestine - Large Intestine - Colon |
91.67 - 100 |
||
| C57BL/6J-ApcMin/+ Tfamtm1.1Lrsn/+ | Intestine - Large Intestine - Colon adenoma | Intestine - Large Intestine - Colon |
100 |
||
| [not specified]-ApcMin/+ Tg(CAG-OTC/CAT)#Wcl | Intestine - Large Intestine - Colon adenoma | Intestine - Large Intestine - Colon |
100 |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine adenoma | Intestine - Small Intestine |
100 |
||
| C57BL/6J-ApcMin/+ Tfamtm1.1Lrsn/+ | Intestine - Small Intestine adenoma | Intestine - Small Intestine |
100 |
||
| [not specified]-ApcMin/+ Tg(CAG-OTC/CAT)#Wcl | Intestine - Small Intestine adenoma | Intestine - Small Intestine |
100 |