The Protein Deacetylase SIRT3 Prevents Oxidative Stress-induced Keratinocyte Differentiation

Background: SIRT3 plays a major role in protecting against mitochondrial oxidative stress. Results: Oxidative stress increases during keratinocyte differentiation, and SIRT3 can decrease differentiation by attenuating oxidative stress. Conclusion: SIRT3-induced down-regulation of mitochondrial oxidative stress attenuates keratinocyte differentiation. Significance: Understanding the regulation of keratinocyte differentiation is crucial for developing new therapies against dysregulated skin differentiation and aging. Keratinocyte differentiation is a key process in the formation and maintenance of the protective skin barrier. Dysregulation in the balance of reactive oxygen species homeostasis may play a role in keratinocyte differentiation. We have identified the mitochondrial deacetylase SIRT3 as a key regulator of mitochondrial reactive oxygen species in keratinocytes. Our studies demonstrate that SIRT3 expression is down-regulated during keratinocyte differentiation, consistent with an increase in mitochondrial superoxide levels. Importantly, loss of SIRT3 expression in keratinocytes increased superoxide levels and promoted the expression of differentiation markers, whereas overexpression decreased superoxide levels and reduced the expression of differentiation markers. These findings identify a new role for SIRT3 in the suppression of epidermal differentiation via lowering oxidative stress.