A Promising Strategy to Treat Neurodegenerative Diseases by SIRT3 Activation

SIRT3, the primary mitochondrial deacetylase, regulates the functions of mitochondrial proteins including metabolic enzymes and respiratory chain components. Although SIRT3's functions in peripheral tissues are well established, the significance of its downregulation in neurodegenerative diseases is beginning to emerge. SIRT3 plays a key role in brain energy metabolism and provides substrate flexibility to neurons. It also facilitates metabolic coupling between fuel substrate-producing tissues and fuel-consuming tissues. SIRT3 mediates the health benefits of lifestyle-based modifications such as calorie restriction and exercise. SIRT3 deficiency is associated with metabolic syndrome (MetS), a precondition for diseases including obesity, diabetes, and cardiovascular disease. The pure form of Alzheimer's disease (AD) is rare, and it has been reported to coexist with these diseases in aging populations. SIRT3 downregulation leads to mitochondrial dysfunction, neuroinflammation, and inflammation, potentially triggering factors of AD pathogenesis. Recent studies have also suggested that SIRT3 may act through multiple pathways to reduce plaque formation in the AD brain. In this review, we give an overview of SIRT3's roles in brain physiology and pathology and discuss several activators of SIRT3 that can be considered potential therapeutic agents for the treatment of dementia.

Automated summary

SIRT3 is a mitochondrial deacetylase that regulates the functions of mitochondrial proteins. Its downregulation in neurodegenerative diseases is starting to be understood. SIRT3 plays a crucial role in brain energy metabolism and metabolic coupling. It is involved in the health benefits of lifestyle modifications and its deficiency is associated with metabolic syndrome. SIRT3 downregulation leads to mitochondrial dysfunction and inflammation, potentially contributing to Alzheimer's disease pathogenesis. This review discusses the roles of SIRT3 in brain physiology and pathology, as well as potential therapeutic agents for dementia.