Mito-TEMPO improves survival rates in <i>npc1</i>-knockout zebrafish by reducing oxidative stress and enhancing mitophagy via Sod2.

Abstract

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder primarily caused by mutations in the <i>NPC1</i> gene. Most patients present with early-life symptoms including hepatosplenomegaly and digestive system impairment, followed by progressive neurodegeneration. However, effective therapeutic approaches to improve survival in NPC disease remain limited. In this study, using an <i>npc1</i>-knockout (NPC1-KO) zebrafish model established in our laboratory, our team suggests that <i>npc1</i> deficiency appears to correlate with marked down-regulation of superoxide dismutase 2 (Sod2) expression, concurrent with excessive oxidative stress (OS), mitochondrial dysfunction, and defective mitophagy. Treatment with Mito-TEMPO, a mitochondria-targeted antioxidant acting on SOD, increased survival rates and ameliorated cholesterol accumulation and liver function impairment in early-stage NPC1-KO zebrafish. The underlying mechanism may involve attenuation of OS and promotion of PINK1/Parkin-dependent mitophagic flux through SOD2 enhancement. Our findings support Mito-TEMPO as a potential therapeutic agent and SOD2 as a possible target for NPC disease.