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Enhanced Mitochondrial DNA Repair Confers Protection Against Obesity and Metabolic Syndrome by Altering White Adipose Tissue Energetics
Author(s) -
Komakula Sai Santosh Babu,
Tumova Jana,
Ye Hong,
Vartanian Vladimir,
Lloyd R Stephen,
Akal Tasleen,
Sampath Harini
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.670.44
Subject(s) - mitochondrial dna , nuclear dna , mitochondrion , adipose tissue , biology , white adipose tissue , oxidative phosphorylation , dna repair , dna damage , dna glycosylase , endocrinology , dna , microbiology and biotechnology , biochemistry , gene
Oxidative DNA damage is characterized by oxidative modifications of nuclear and mitochondrial DNA. Unrepaired DNA lesions can cause mutations. Mitochondrial DNA is more prone to oxidative damage when compared to nuclear DNA. 8‐oxo‐Guanine (8‐oxoG) is the most abundant oxidative DNA lesion, which is primarily repaired by the base excision repair (BER) pathway. BER is initiated by DNA glycosyslases such as 8‐oxo‐Guanine DNA glycosylase (OGG1) that recognizes and cleaves 8‐oxoG from nuclear and mitochondrial DNA. Previously, we reported that mice lacking OGG1 both in the nucleus and mitochondria are more prone to obesity and metabolic dysfunction compared to wild type controls. However, the contribution of mitochondrial vs. nuclear OGG1 to this metabolic phenotype have not been reported. We report here that transgenic mice over expressing human OGG1 only in the mitochondria ( Ogg1 Tg mice) are protected from high fat diet induced obesity, insulin resistance, fatty liver, and other features of metabolic syndrome, relative to diet‐matched wild type counterparts. The observed phenotype is a consequence of altered energy metabolism in white adipose tissue. Our results indicate that white adipose tissue of Ogg1 Tg mice have increased respiration due to mitochondrial uncoupling and increased expression of Pgc‐1α , Sirtuin‐1 , and uncoupling protein‐3. Plasma adiponectin levels are also elevated in Ogg1 Tg mice. Electron microscopy results indicate that, Ogg1 Tg mice on high fat diet have elongated and more electron dense mitochondria. These results confirm a novel and critical role for the mitochondrial DNA repair and structure on whole body energy homeostasis. These findings also indicate an important role for white adipose tissue mitochondrial metabolism on whole body energy balance. Support or Funding Information The Sampath lab is supported by the NJ Institute for Food Nutrition and Health, NIH grant R00DK100640 (Sampath PI) and a Euro Bio4Med grant (Sampath Co‐PI) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .