Aberrant S-nitrosylation in the TCA cycle contributes to mitochondrial dysfunction, energy compromise, and synapse loss in neurodegenerative diseases.

Abstract

Neuronal synaptic activity relies heavily on mitochondrial energy production, as synaptic transmission requires substantial ATP. Accordingly, mitochondrial dysfunction represents a key underlying factor in synaptic loss that strongly correlates with cognitive decline in Alzheimer's disease and other neurocognitive disorders. Increasing evidence suggests that elevated nitro-oxidative stress impairs mitochondrial bioenergetic function, leading to synaptic degeneration. In this review, we highlight the pathophysiological roles of nitric oxide (NO)-dependent posttranslational modifications (PTMs), particularly S-nitrosylation of cysteine residues, and their impact on mitochondrial metabolism. We focus on the pathological S-nitrosylation of tricarboxylic acid cycle enzymes, particularly α-ketoglutarate dehydrogenase, as well as electron transport chain proteins. This aberrant PTM disrupts mitochondrial energy production. Additionally, we discuss the consequences of aberrant protein S-nitrosylation on mitochondrial dynamics and mitophagy, further contributing to mitochondrial dysfunction and synapse loss. Finally, we examine current strategies to ameliorate S-nitrosylation-mediated mitochondrial dysfunction in preclinical models of neurodegenerative diseases and explore future directions for developing neurotherapeutics aimed at restoring mitochondrial metabolism in the context of nitro-oxidative stress.