The Impact of Mitochondrial Genetic Background on Development of Complex Multifactorial Diseases.

摘要

Complex multifactorial diseases such as cardiovascular disease (CVD) and cancer are a pervasive and inescapable component of modern society. However, the genetic elements that modulate individual susceptibility to these diseases remain poorly defined. Excessive mitochondrial oxidant production has been implicated in the initiation and progression of both CVD and cancer. Moreover, polymorphisms inherited on the mitochondria genome appear to influence mammalian mitochondrial function and oxidant generation. In the present study, mitochondrial-nuclear-eXchange (MNX) mice were used to directly assess the contribution of mitochondrial DNA (mtDNA) polymorphisms to atherosclerosis in the apoE deficient (apoE --/--) mouse model of hypercholesterolemia induced atherogenesis. ApoE--/-- mice are maintained on a C57BL/6 (C57) strain genetic background, and replacement of their C57 mtDNA with C3H/HeN (C3H) mtDNA resulted in metabolic alterations to their endothelial cells. Specifically, MNX apoE (C57n:C3Hmt apoE --/--) endothelial cells displayed reduced intracellular ATP and an age-related decline in mtDNA copy number that did not occur in cells isolated from C57 apoE (C57n:C57mt apoE --/--) animals. In addition, aortic root sections from 8-week old MNX apoE mice displayed reduced monocyte infiltration relative to sections from C57 apoE animals. However, these metabolic and inflammatory discrepancies were ultimately not associated with any differences in atherosclerotic plaque burden, suggesting that disease phenotype in this model may be too severe to be significantly impacted by mitochondrial gene variation.;Previous studies have also used MNX mice to demonstrate that mtDNA polymorphisms influence progression of mammary adenocarcinoma in mice harboring an oncogenic MMTV-PyMT transgene. However, this study did not address the degree to which mitochondrial genetic background exerted its influence through modulation of tumor-host interactions. Non-transformed cells present in the tumor microenvironment such as fibroblasts, macrophages, and endothelial cells are known to foster tumor growth and malignant behavior. The present study examined the ability of mtDNA polymorphisms to modify the behavior of these cells and thereby alter tumor progression by comparing the growth of B16F10 melanoma tumors implanted in C57n:C57mt WT and C57n:C3Hmt MNX animals. However, tumor growth did not differ in these animals, suggesting that mtDNA mutations exert their cancer-specific effects in a manner intrinsic to tumor cells themselves.