Mitochondrial DNA Damage Level Determines Neural Stem Cell Differentiation Fate

Abstract

The mitochondrial DNA (mtDNA) of neural stem cells (NSCs) is vulnerable to oxidation damage. Subtle manipulations of the cellular redox state affect mtDNA integrity in addition to regulating the NSC differentiation lineage, suggesting a molecular link between mtDNA integrity and regulation of differentiation. Here we show that 8-oxoguanine DNA glycosylase (OGG1) is essential for repair of mtDNA damage and NSC viability during mitochondrial oxidative stress. Differentiating neural cells from ogg1 Ϫ/Ϫ knock-out mice spontaneously accumulate mtDNA damage and concomitantly shift their differentiation direction toward an astrocytic lineage, similar to wt NSCs subjected to mtDNA damaging insults. Antioxidant treatments reversed mtDNA damage accumulation and separately increased neurogenesis in ogg1 Ϫ/Ϫ cells. NSCs from a transgenic ogg1 Ϫ/Ϫ mouse expressing mitochondrially targeted human OGG1 were protected from mtDNA damage during differentiation, and displayed elevated neurogenesis. The underlying mechanisms for this shift in differentiation direction involve the astrogenesis promoting Sirt1 via an increased NAD/NADH ratio in ogg1 Ϫ/Ϫ cells. Redox manipulations to alter mtDNA damage level correspondingly activated Sirt1 in both cell types. Our results demonstrate for the first time the interdependence between mtDNA integrity and NSC differentiation fate, suggesting that mtDNA damage is the primary signal for the elevated astrogliosis and lack of neurogenesis seen during repair of neuronal injury.

Neuroprotective effects of Tualang honey against oxidative stress and memory decline in young and aged rats exposed to noise stress

“…Significant difference between stress control and stress treated with honey ( ♣ P < .05). both glucocorticoid exposure and oxidative stress may induce neuronal oxidative stress through enhanced mitochondrial respiration and oxidative phosphorylation [50], and promote gliogenesis over neurogenesis in hippocampal neural stem cell progenitors [51,52]. Correspondingly, we demonstrated that the stressed rats possessed a lower number of pyramidal neurons in the hippocampus as well as in the mPFC compared to the nonstressed rats.…”

Mitochondria-targeted Ogg1 and Aconitase-2 Prevent Oxidant-induced Mitochondrial DNA Damage in Alveolar Epithelial Cells

“…Loss of Ogg1 protein function predisposes mice to lung tumorigenesis (57). As compared with wild-type neuronal stem cells, loss of plasticity toward a terminally differentiated astrocytic lineage occurs in Ogg1-deficient neuronal stem cells that accumulate mtDNA damage (58). Ogg1 also has an emerging important role in linking DNA repair to Rac1 and Ras cellular signaling pathways (59,60).…”

Modifiers of Neural Stem Cells and Aging: Pulling the Trigger of a Neurogenic Decline

“…It is therefore not surprising that a higher incidence of mtDNA mutations has been shown to be associated with the aging brain as well as several age-related disorders such as AD and PD [36]. Wang and collaborators have demonstrated that mtDNA integrity is essential for aNSC function as alteration in the mtDNA repair machinery, through a knockout of 8-oxoguanine DNA glycosylase (Ogg1), can hamper neuronal differentiation to the benefit of astrogliosis [37]. This is of particular interest as increased astrogliosis and decreased neurogenesis have been described in the aging brain [4].…”