Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress

Abstract

Sirtuin 3 (Sirt3), a major mitochondrial NAD+-dependent deacetylase, targets various mitochondrial proteins for lysine deacetylation and regulates important cellular functions such as energy metabolism, aging, and stress response. In this study, we identified the human 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA repair enzyme that excises 7,8-dihydro-8-oxoguanine (8-oxoG) from damaged genome, as a new target protein for Sirt3. We found that Sirt3 physically associated with OGG1 and deacetylated this DNA glycosylase and that deacetylation by Sirt3 prevented the degradation of the OGG1 protein and controlled its incision activity. We further showed that regulation of the acetylation and turnover of OGG1 by Sirt3 played a critical role in repairing mitochondrial DNA (mtDNA) damage, protecting mitochondrial integrity, and preventing apoptotic cell death under oxidative stress. We observed that following ionizing radiation, human tumor cells with silencing of Sirt3 expression exhibited deteriorated oxidative damage of mtDNA, as measured by the accumulation of 8-oxoG and 4977 common deletion, and showed more severe mitochondrial dysfunction and underwent greater apoptosis in comparison with the cells without silencing of Sirt3 expression. The results reported here not only reveal a new function and mechanism for Sirt3 in defending the mitochondrial genome against oxidative damage and protecting from the genotoxic stress-induced apoptotic cell death but also provide evidence supporting a new mtDNA repair pathway.

SIRT6 rescues the age related decline in base excision repair in a PARP1-dependent manner

“…3A). SIRT3 has been implicated in regulating the BER pathway by deacetylating OGG1, 25 and we observed a significant stimulatory effect on BER by SIRT3 overexpression, suggesting that our reactivation assay is an appropriate tool for measuring BER efficiency. SIRT6 overexpression increases BER efficiency by »2 fold (Fig.…”

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

“…In the lung, SIRT3 deficiency augmented pulmonary fibrosis after asbestos and bleomycin exposure (88,89), and SIRT3 expression is attenuated in skin and lung of systemic sclerosis patients (90). It is also proposed that SIRT3 modulates mtDNA damage by regulating 8-oxoguanine-DNA glycosylase-1 (OGG1) acetylation (91,92). OGG1 is a DNA repair differently (Table 3).…”

Targeting aberrant cancer metabolism – The role of sirtuins

“…Among the 41 alternative theories which may reframe the classical paradigm of 42 carcinogenesis, those which take into consideration the formation 43 of cancer stem cells and the involvement of the cell microenviron-44 ment are the most promising [2,3]. Irrespective of the explanatory 45 utility of these theories, one of the most intriguing features of 46 cancer cells is the appearance of aerobic glycolysis, known as the 47 Warburg effect. 48 This phenomenon, which was first observed by Otto Warburg in 49 the 1920s, was initially thought to be adaptation to hypoxic 50 conditions, but later studies showed that the mutations that lead to 51 tumorigenesis also cause aerobic glycolysis by up-regulating the 52 expression of glycolytic genes at the transcriptional level [4].…”

“…Moreover, SIRT3 275 may protect mitochondrial DNA from oxidative damage because of 276 deacetylation of 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA 277 repair enzyme. Through this mechanism it can improve mito-278 chondrial oxidative phosphorylation and help cells to avoid 279 apoptotic death [47]. The mitochondria play a major role in 280 energetic metabolism, and the mitochondrial pyruvate dehydro-281 genase complex is crucial for glucose homeostasis in mammalian 282 cells.…”