Serotonin-mediated regulation of mitophagy in Alzheimer's disease: Mechanistic insights and therapeutic potential

Abstract

This review delves into the intricate relationship between serotonin signaling, mitophagy and mitochondrial dysfunction in Alzheimer's disease (AD), with a focus on the mechanistic pathways that link these processes and their potential therapeutic implications. A neurodegenerative condition called Alzheimer's disease is marked by cognitive deterioration. It is increasingly recognized as being influenced by impaired mitochondrial function and mitophagy, the selective degradation of damaged mitochondria. Serotonin, a neurotransmitter traditionally known for its role in mood regulation, has emerged as a critical modulator of mitochondrial dynamics and quality control through its interaction with key pathways such as the PINK1-Parkin and cAMP/PKA signaling pathways. In AD, alterations in serotonin levels and receptor function are associated with disruptions in mitophagy, leading to the accumulation of dysfunctional mitochondria, increased oxidative stress, and subsequent neuronal damage. This review synthesizes current evidence that links serotonin dysregulation to mitochondrial pathology in AD, exploring how impaired serotonin signaling exacerbates mitochondrial dysfunction and contributes to amyloid-beta (Aβ), phosphorylation of Tau (p-Tau) accumulations, and increased neuroinflammation. Additionally, we assessed the therapeutic potential of serotonin-targeting agents, particularly selective serotonin reuptake inhibitors (SSRIs), in restoring mitophagy, enhancing mitochondrial integrity, and attenuating neurodegeneration. By highlighting existing knowledge gaps and key controversies, this review underscores the promise of serotonin-mitochondria pathways as novel therapeutic targets and advocates for focused investigation into receptor-specific, mitophagy-centered interventions for AD.