The mitophagy-inflammasome axis: a shared pathological hub in Alzheimer’s and Parkinson’s diseases

Abstract

Alzheimer’s disease (AD) and Parkinson’s disease (PD) represent the most prevalent chronic neurodegenerative disorders, characterized by progressive loss of neurons as a core pathological feature. Despite discrepancies in their clinical phenotypes and signature pathological proteins, accumulating evidence has validated a common molecular pathogenic mechanism: dysfunctional bidirectional crosstalk between mitophagy and inflammasomes. As the central hub of neuronal energy metabolism, mitochondrial impairment triggers the release of damage-associated molecular patterns such as reactive oxygen species and mitochondrial DNA, which in turn activate inflammasomes (e.g., NLRP3) to elicit chronic neuroinflammation. Conversely, excessive inflammasome activation suppresses mitophagy, exacerbating the accumulation of damaged mitochondria and pathological protein aggregates, and forming a pathological mitochondrial damage—inflammatory activation—autophagy inhibition cycle. Microglia and astrocytes, key immunocompetent cells of the central nervous system, act as a hub within this regulatory network. Therapeutic strategies targeting the mitophagy-inflammasome axis have achieved remarkable advancements, including mitophagy agonists, inflammasome inhibitors, and dual-target modulators. This review summarizes recent findings regarding the pathogenic roles of β-amyloid and α-synuclein in AD and PD, as well as the protective effects offered by regulating mitophagy and inflammasome activity. Furthermore, the major directions and potential hurdles in the development of targeted therapeutics are discussed, in the aim of providing insights into the novel therapeutic avenues for the treatment of both disorders.