Energy metabolic failure drives the selective degeneration of dopaminergic neurons in Parkinson's disease.

Parkinson's disease (PD) is the fastest growing neurodegenerative disorder worldwide. A critical barrier to therapeutic development is the incomplete understanding of mechanisms driving the selective degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons (DaNs), the pathological hallmark of PD. Increasing evidence from preclinical and clinical studies now identifies metabolic instability as a central, early driver of this selective neurodegeneration, preceding both motor symptom onset and canonical structural pathology. These neurons face constant energetic pressure due to their autonomous pacemaking and complex axonal structures. This is compounded by their limited capacity for mitochondrial maintenance and calcium regulation. When these intrinsic constraints intersect with genetic susceptibility, dopamine-derived toxic metabolites, and disturbances in redox balance, metabolic resilience declines and vulnerability increases long before clinical symptoms emerge. In this review, we examine current insights into the metabolic foundations of PD across mitochondrial function, glucose and lipid utilization, amino acid pathways, and neuron-glia metabolic support. We highlight evidence suggesting that bioenergetic impairment precedes overt neurodegeneration and contributes to the variability in disease onset, progression, and therapeutic response. We also discuss emerging approaches aimed at strengthening metabolic capacity, including strategies to enhance nicotinamide adenine dinucleotide (NAD+) availability, support glycolysis and fatty acid oxidation, reduce oxidative stress, and modulate trophic signaling. Understanding how metabolic crisis shapes the trajectory of PD may offer new opportunities for earlier diagnosis and the development of targeted, disease-modifying interventions. Future work comparing metabolic phenotypes across patient subgroups will be essential for advancing precision treatment and clarifying the role of energy dysregulation in disease heterogeneity.