# Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson’s disease

## TL;DR

This paper explores how cardiolipin in mitochondria interacts with α-synuclein to contribute to Parkinson’s disease, offering new insights into potential therapeutic targets.

## Contribution

The paper introduces a novel perspective on cardiolipin as a molecular switch linking mitochondrial dysfunction and α-synuclein toxicity in Parkinson’s disease.

## Key findings

- Cardiolipin binds α-synuclein and influences its aggregation and phase separation.
- Disruption of mitochondrial membranes by α-synuclein impairs respiratory function and mitophagy.
- Cardiolipin's role in determining α-synuclein's functional or toxic state is critical for neuronal survival.

## 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.