Propionic Acid Remodels Mitochondrial Metabolism in SH-SY5Y Cells

Mitochondrial mechanisms are increasingly implicated in complex neurological conditions, including Autism Spectrum Disorder (ASD). Propionic acid (PPA) is widely used to study mitochondrial dysfunction in preclinical models of ASD. However, the molecular mechanisms that drive PPA-induced neurotoxicity are unresolved. Here, we examined mitochondrial remodeling under PPA-induced stress in neuroblastoma SH-SY5Y cells. PPA systemically altered the transcriptional regulation of mitochondrial dynamics and disrupted canonical proteins involved in mitochondrial fusion (L-OPA1, MFN2), fission (DRP1) and quality control (LC3-II). Confocal microscopy revealed an upregulation of both fission and fusion events and impairments to mitochondrial integrity, connectivity and turnover. Live-cell respirometry demonstrated consequent deficits in both oxidative and glycolytic energy production, while respiratory chain electron flow assays illustrated a shift in TCA cycle flux driven by a remodeling of mitochondrial substrate utilization. This work describes a molecular signature of metabolic stress in the SH-SY5Y system, providing novel insights into the mechanisms and manifestations of PPA-induced neurotoxicity.