Functional Difference of Mitochondrial Genome and Its Association with Traits of Common Complex Diseases in Humans

Abstract

Recent evidence suggests that mitochondrial genomes harboring common mitochondrial DNA polymorphisms might have functional difference and could be associated with common complex human diseases such as metabolic syndrome and cancer that are related to mitochondrial dysfunction. However, there has been no report examining the functional difference of mitochondrial genome in the pathogenesis of such diseases at the cellular or molecular level. In order to examine the effect of mitochondrial genome on metabolic syndrome or cancer without interference from nuclear genes, we analyzed trans-mitochondrial cytoplasmic hybrid cells (cybrids) with common Asian mtDNA haplogroups A, B, D, and F from healthy volunteers. The mitochondrial oxygen consumption rates of cybrids were associated with multiple components of metabolic syndrome such as body mass index, waist circumference, serum triglyceride levels and high-density lipoprotein cholesterol levels. In addition, the cybrids showed varying degree of tumorigenicity both in vitro and in vivo. Especially, the cybrids harboring mtDNA haplogroup D had a significantly slower growth rate. These findings suggest that the phenotypes of common complex diseases in humans can be determined by their mitochondrial genomes. Therefore, not only nuclear genome but also mitochondrial genome should be considered in explaining the genetic pathogenesis of common complex human diseases.