Endogenous mitochondrial oxidative stress in MnSOD-deficient mouse embryonic fibroblasts promotes mitochondrial DNA glycation

Abstract

The accumulation of somatic mutations in mitochondrial DNA (mtDNA) induced by reactive oxidative species (ROS) is regarded as a major contributor of aging and age-related degenerative diseases. ROS has also been shown to facilitate the formation of certain advanced glycation end-products in proteins and DNAs, and N2-carboxyethyl-2′-deoxyguanosine (CEdG) has been identified as a major DNA-bound AGE. Therefore, the influence of mitochondrial ROS on the glycation of mtDNA was investigated in primary embryonic fibroblasts derived from mutant mice (Sod2−/+) deficient in the mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD). In Sod2−/+ fibroblasts vs. wildtype fibroblasts, the CEdG content of mtDNA was increased from 1.90±1.39 pg/μg DNA to 17.14±6.60 pg/μg DNA (p<0.001). On the other hand, the CEdG content of nuclear DNA did not differ between Sod2+/+ and −/+ cells. Similarly, cytosolic proteins did not show any difference in the advanced glycation end-products or protein carbonyl contents between Sod2+/+ and −/+. Taken together, the data suggest that mitochondrial oxidative stress specifically promotes glycation of mtDNA and does not affect nuclear DNA or cytosolic proteins. Because DNA glycation can change DNA integrity and gene functions, glycation of mtDNA may play an important role in the decline of mitochondrial functions.

AGEs in human lens capsule promote the TGFβ2‐mediated EMT of lens epithelial cells: implications for age‐associated fibrosis

“…The AGE formation in tissue proteins is enhanced by transition metal ions, oxidative stress, phosphate, and neighboring positively charged amino acids (Chace et al ., 1991; Breyer et al ., 2012). Whether any of these factors contributed to the higher level of capsule AGEs in cataractous lenses is not known and needs further investigation.…”

The Interplay Between Respiratory Supercomplexes and ROS in Aging

“…In mutant mice deficient in SOD2, mitochondrial oxidative stress specifically promotes glycation of mtDNA and does not affect nuclear DNA or cytosolic proteins (40). A generally negative correlation has been consistently found between endogenous tissue antioxidants and longevity in animals (313,295).…”

Glycation damage to organelles and their DNA increases during maize seedling development

“…de Bari et al 24 concluded that oxidative stress and MGO are interconnected and in equilibrium with each other and that high levels of mitochondrially generated ROS can lead to an increase in MGO, AGEs, and cell death. In cultured mouse cells deficient in superoxide dismutase, glycation of mtDNA (but not nuclear DNA) indicated to Breyer et al 25 that oxidative stress promotes glycation of mtDNA. They proposed that H 2 O 2 degrades deoxyribose, creating reactive carbonyl species that react with guanine (G) to yield CEdG, a DNA-bound AGE that they measured by competitive ELISA.…”