Sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1α signaling pathway: Molecular mechanisms from mitochondrial function regulation to the treatment of neurodegenerative diseases

Abstract

Mitochondrial dysfunction is considered a central factor in the onset and progression of various neurodegenerative diseases. Sirtuin 1 is a nicotinamide adenine dinucleotide-dependent deacetylase that senses changes in the nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide ratio and activates the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1α through deacetylation. Activated peroxisome proliferator-activated receptor gamma coactivator 1α subsequently interacts with multiple transcription factors to regulate mitochondrial biogenesis, mitochondrial dynamics, autophagy, energy metabolism, and antioxidant defense, thereby playing a critical role in maintaining mitochondrial functional homeostasis. Preclinical studies have shown that neurodegenerative diseases are frequently accompanied by downregulation of the expression or activity of key components of the Sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1α pathway, whereas activation of this pathway can ameliorate associated mitochondrial dysfunction and exert neuroprotective effects. This article systematically elucidates the pivotal role of the Sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1α pathway in neurodegenerative diseases from the perspectives of molecular structure, interaction mechanisms, and regulation of mitochondrial function, aiming to provide a theoretical foundation for the development of novel multi-target drugs and intervention strategies.