Mitochondrial-Synaptic Crosstalk : The Missing Link in Early Neurodegenerative Disease Detection - A Perspective

Abstract

Synaptic dysfunction is increasingly recognized as one of the earliest detectable pathophysiological events in many neurodegenerative disorders, often preceding overt neuronal loss. Separately, mitochondrial impairment—deficits in bioenergetics, dynamics, and quality control—is a recurring, early feature across diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Mounting evidence supports the concept that mitochondrial–synaptic crosstalk is not merely correlative but causally relevant to early synaptic failure; exploiting this axis could yield sensitive, disease-agnostic biomarkers for preclinical or prodromal detection. In this Perspective we synthesize mechanistic links between mitochondria and synapses, review emerging in-vivo and fluid biomarkers that capture this interface, and propose an integrated translational roadmap — combining synaptic imaging, mitochondrial molecular signatures, and functional assays — for earlier and more specific detection of neurodegenerative disease. (1)(2)(3).