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

Sep 30, 2026

Parkinson’s disease is characterized by progressive loss of dopaminergic neurons and accumulation of misfolded α-synuclein, yet the molecular basis of selective vulnerability remains unclear. This review explains how α-syn damages mitochondrial membranes through aggregation and liquid–liquid phase separation, leading to impaired membrane architecture, respiratory chain dysfunction, and defective mitophagy. Cardiolipin, a mitochondria-specific phospholipid, is highlighted as a key mediator, binding α-syn and influencing whether it stays functional or advances toward toxic assemblies. The synthesis supports cardiolipin as a molecular switch for CL-directed therapeutic strategies.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages21

Reading Time53 min

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Abstract

Introduction

Ruiz-Ortega et al. Acta Neuropathologica Communications (2026) 14:11 [https://doi.org/10.1186/s40478-025-02190-x](https://doi.org/10.1186/s40478-025-02190-x) Acta Neuropathologica Communications REVIEW Open Access Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson’s disease Eva D. Ruiz-Ortega 1,3*†, Anna Wil kaniec 1†, Josué Juárez2 and Agata Adamczyk 1* 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. Keywords Parkinson’s disease, Alpha-synuclein, Mitochondrial dysfunction, Cardiolipin, Liquid‒liquid phase separation †Eva D. Ruiz-Ortega and Anna Wil kaniec have contributed equally to this work and share first authorship. *Correspondence: Eva D. Ruiz-Ortega [evadaniela.ruiz@unison. mx](evadaniela.ruiz@unison. mx)[ ](evadaniela.ruiz@unison. mx)Agata Adamczyk[aadamczyk@imdik.pan.pl](aadamczyk@imdik.pan.pl) 1Department of Cellular Signalling, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland 2Department of Physics, University of Sonora, 83000 Hermosillo, Mexico 3Department of Chemical Engineering and Metallurgy, University of Sonora, 83000 Hermosillo, Mexico Introduction The pathological accumulation of misfolded proteins into insoluble, amyloid-like fibrils is a unifying hallmark of several major neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple system atrophy (MSA), and amyotrophic lateral sclerosis (ALS). Each disorder arises from the misfolding and aggregation of distinct proteins within the central nervous system (CNS), resulting in distinctive molecular signatures and neuropathological features that enable their classification [39, 82, 223, 282]. Among these conditions, PD stands out as the second most common neurodegenerative disorder worldwide [51, 125, 211], and a major health challenge in aging populations [150], with © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by

FAQs

What is the central focus of this review on Parkinson’s disease?

It analyzes how α-synuclein interacts with mitochondrial membranes and how this contributes to neuronal vulnerability and neurodegeneration in Parkinson’s disease.

How does α-synuclein affect mitochondria according to the review?

Through two interconnected mechanisms—classical aggregation and liquid–liquid phase separation—that disrupt membrane architecture, impair respiratory chain function, and compromise mitophagy.

Why is cardiolipin emphasized as a mediator in these processes?

Cardiolipin is identified as an essential mitochondria-specific phospholipid that organizes cristae and quality control pathways, binds α-syn with high affinity, and influences whether α-syn remains functional or becomes toxic.

Sep 30, 2026

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