Peroxiredoxins in Mitochondrial Dysfunction and Endoplasmic Reticulum Stress: Implications for Neurodegenerative Diseases

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are increasingly recognized as coupled, rather than independent, contributors to neurodegeneration, converging at ER–mitochondria contact sites (MERCs) that coordinate Ca2+ transfer, redox signaling, and mitochondrial dynamics. Disruption of this crosstalk is implicated in Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Peroxiredoxins (PRDXs), a family of thiol-dependent peroxidases distributed across distinct subcellular compartments, are positioned to regulate this inter-organelle crosstalk in an isoform-specific manner. This review summarizes evidence that ER-resident PRDX4 supports oxidative protein folding and limits ER stress signaling, mitochondrial PRDX3 restricts peroxide accumulation and mitochondrial oxidative injury, and PRDX2 and PRDX5 regulate ER–mitochondria coupling through effects on mitochondrial trafficking and mitochondrial fission, respectively, although neither is a core structural component of MERCs. We also discuss how PRDX-dependent suppression of ER and oxidative stress may relate to mitochondrial quality control and mitophagy, and how these mechanisms may relate to MERC dysfunction across AD, PD, and ALS. Overall, the evidence suggests that PRDXs act as organelle-specific redox regulators whose loss may contribute to ER–mitochondria dysfunction, and that restoring or supporting PRDX activity represents a possible therapeutic direction.