Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.
Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Warsaw, PL · Author affiliation
Department of Cellular Signalling, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland. evadaniela.ruiz@unison.mx.Location evidence
Hermosillo, MX · Author affiliation
Department of Chemical Engineering and Metallurgy, University of Sonora, 83000, Hermosillo, Mexico. evadaniela.ruiz@unison.mx.Location evidence
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Original abstract
Parkinson's disease (PD) is defined by the progressive loss of dopaminergic neurons and the accumulation of misfolded α-synuclein (α-syn), yet the molecular determinants of selective neuronal vulnerability remain unresolved. Increasing evidence implicates mitochondria-and particularly their membranes-as critical platforms where α-syn is toxic. This review highlights how α-syn engages mitochondrial membranes through two interconnected processes: classical aggregation and liquid‒liquid phase separation. Both pathways disrupt membrane architecture, compromise respiratory chain function, and impair mitophagy. A pivotal mediator of these events is cardiolipin (CL), a mitochondria-specific phospholipid essential for cristae organization and quality control pathways. Despite extensive progress, the precise mechanistic contributions of CL to α-syn aggregation, phase transitions, and neuronal degeneration remain poorly defined. Clarifying this interplay is crucial, as CL not only binds α-syn with high affinity but also determines whether it remains in a functional state or progresses toward toxic assemblies. By integrating recent advances, we propose a unifying perspective on CL as a molecular switch at the crossroads of mitochondrial biology, protein aggregation, and phase behavior. Beyond mechanistic insight, this view underscores the potential of CL as a target for the development of mitochondria-directed therapies in PD.