Role of mitochondrial DNA variants and copy number in  diabetic atherogenesis.
Hyperglycemia-induced reactive oxygen species production can cause diabetes and its complications, including atherosclerosis. The role of mitochondrial DNA variants and mitochondrial copy number in the pathogenesis of diabetic atherogenesis is not well understood. We examined 36 diabetic patients who had undergone amputation for diabetic foot and seven non-diabetic patients who had undergone amputation after traumatic injury. Mitochondrial DNA was extracted and used for sequencing. Single nucleotide polymorphisms (SNPs) relative to the Cambridge reference sequence were analyzed. Mitochondrial DNA copy number was quantified by real-time PCR. Twenty-one novel variants were detected in 29 diabetic patients with arterial stenosis; six of the variants were heteroplasmic, and most occurred in highly evolutionarily conserved residues. These variants were more prevalent in patients with arterial stenosis than in those without stenosis. The novel variants included four in complex I (ND1: C3477A/C, A3523A/G; ND5: C13028A/C, C13060A/C), one in complex IV (COX1: T6090A/T), and one in rRNA (12srRNA: G857G/T). Compared with non-diabetic patients, the diabetic patients had significantly less mitochondrial DNA. Furthermore, among diabetic patients with arterial stenosis, there was a significant positive correlation between mitochondrial DNA copy number and the number of total SNPs. In conclusion, we identified six novel heteroplasmic mitochondrial DNA variants among diabetic patients with arterial stenosis, and we found that diabetic atherogenesis is associated with decreased amounts of mitochondrial DNA.
Mitochondrial Research Unit, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
M C
MC
Chien
W T
WT
Huang
P W
PW
Wang
C W
CW
Liou
T K
TK
Lin
C J
CJ
Hsieh
S W
SW
Weng
D000595:Amino Acid Sequence; D050197:Atherosclerosis / Q000235:genetics*; D001483:Base Sequence; D017124:Conserved Sequence / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D048909:Diabetes Complications / Q000235:genetics*; D042967:Electron Transport Complex I / Q000737:chemistry / Q000235:genetics; D003576:Electron Transport Complex IV / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000235:genetics; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; C481838:MT-ND5 protein, human; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I