Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder characterised by dopaminergic neuron loss and pathological accumulation of alpha-synuclein. Emerging evidence highlights a crucial interplay between mitochondrial dysfunction and disrupted lipid homeostasis as central mechanisms driving PD pathogenesis. This scoping review synthesises current evidence on the relationship between mitochondrial dysfunction and neuronal lipid dysregulation in PD and identifies potential therapeutic targets within these intersecting pathways. Following the PRISMA-ScR guidelines, a comprehensive literature search was conducted across PubMed, Embase, and Web of Science for studies published between 2015 and 2025. Two independent reviewers screened and selected eligible studies based on predefined inclusion criteria. Analysis revealed four central interconnected pathological mechanisms: ferroptosis, alpha-synuclein-lipid interactions, mitochondrial dysfunction, and impaired autophagy/mitophagy. These mechanisms collectively contribute to oxidative stress, membrane destabilisation, and bioenergetic collapse, driving dopaminergic neuronal vulnerability. The findings underscore a complex, bidirectional relationship between mitochondrial dysfunction and lipid dysregulation in PD. Therapeutic strategies targeting iron accumulation, lipid peroxidation, and alpha-synuclein aggregation are promising. However, further mechanistic studies are required to clarify these interactions and advance the development of effective disease-modifying interventions. Summary of the mechanism underlying mitochondrial dysfunction and dysregulated lipid metabolism in Parkinson’s disease. • Mitochondrial dysfunction and lipid dysregulation interact bidirectionally in the pathogenesis of PD. • Ferroptosis, an iron-dependent lipid peroxidation form, contributes to PD's dopaminergic neuron loss. • Alpha-synuclein pathology is closely associated with lipid dysregulation, influencing aggregation and toxicity. • Impaired mitophagy and autophagy pathways exacerbate the buildup of damaged mitochondria and toxic protein aggregates. • Disrupted ER-mitochondria crosstalk contributes to mitochondrial stress and cellular dysfunction, emerging as a promising area for future therapeutic development. • Key gaps remain in Parkinson’s research, and integrating mitochondrial lipid biology could enable more effective multi-target therapies.
Quan et al. (Thu,) studied this question.