Mitochondrial Sirtuins in Skin and Skin Cancers

Abstract

Mammalian sirtuins (SIRTs 1‐7) are a family of NAD+‐dependent deacetylases with distinct subcellular localization and biological functions that regulate various important cellular processes. Among these, SIRTs ‐3, ‐4 and ‐5 are located in the mitochondria and have been implicated in caloric restriction, oxidative stress, aging and various human diseases. Emerging evidence has found dysregulation of mitochondrial sirtuins in multiple dermatological conditions, including responses to ultraviolet radiation (UVR), suggesting their importance in maintaining skin health. In this review, we discuss the roles and implications of mitochondrial sirtuins in cutaneous cellular processes, and their emerging potential as a target for the management of skin diseases, including skin cancer. Among mitochondrial sirtuins, SIRT3 is the most studied and linked to multiple skin conditions and diseases (keratinocyte differentiation, wound healing, chronological aging, UVR and ozone response, systemic sclerosis, melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)). SIRT4 has been connected to keratinocyte differentiation, chronological aging, UVR response, alopecia, BCC and SCC. Further, SIRT5 has been associated with keratinocyte differentiation, melanoma, BCC and SCC. Overall, while there is compelling evidence for the involvement of mitochondrial sirtuins in skin, additional detailed studies are needed to understand their exact roles in skin and skin cancers.

Combined Inhibition of Specific Sirtuins as a Potential Strategy to Inhibit Melanoma Growth

“…SIRT3 also plays a key role in the regulation of several cellular processes, including transcription, insulin secretion, and programmed cell death (30). The ability of SIRT3 to regulate numerous cellular processes that are critical in cancer cell proliferation suggests it as a valid therapeutic target in the management of cancers, including cutaneous neoplasm (28,31). A study from our laboratory demonstrated that SIRT3 is overexpressed in human melanoma tissues and cell lines.…”

“…Similarly, the mitochondrial sirtuin SIRT3 also appears to be involved in melanoma progression. Based on numerous studies, SIRT3 has emerged as a metabolic regulator, and its potential role in cancer is being intensively investigated (1,3,28). SIRT3 is known to affect most of the mitochondrial dynamics, including nutrient oxidation, generation of ATP, and detoxification of reactive oxygen species (ROS) (29).…”

Insights on the role of l-lactate as a signaling molecule in skin aging

“…During aging, skin undergoes a complex plethora of biochemical and structural changes. For example, the role of NAD + -dependent deacetylases, known as sirtuins (SIRT 1–7), is fundamental to comprehend skin aging, particularly for photoaging, and the involvement of mitochondria biology (Su et al 2020 ). Sirtuins 3 (SIRT3), 4 (SIRT4) and 5 (SIRT5), which are localized in mitochondria, are implicated in aging, besides to oxidative stress response and caloric restrictions (Gambini et al 2011 ).…”

Genetic Manipulation of Sirtuin 3 Causes Alterations of Key Metabolic Regulators in Melanoma

“…It also plays important roles in the regulation of a variety of cellular processes, including transcription, insulin secretion, apoptosis and redox signaling (6). SIRT3 has also been implicated in multiple cutaneous functions including skin renewal, and response to environmental stressors (7,8).…”