Ferroptosis susceptibility in primary coenzyme Q10 deficiency: Cellular insights from patient fibroblasts and clinical course of six individuals.

BACKGROUND

Primary coenzyme Q10 (CoQ10) deficiency is a group of mitochondrial disorders caused by pathogenic variants of genes involved in CoQ10 biosynthesis. Although some patients respond to oral CoQ10 supplementation, the pathophysiology remains poorly understood. Ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation, is suppressed by reduced CoQ10via ferroptosis suppressor protein 1 (FSP1). However, its involvement in primary CoQ10 deficiency has not yet been studied using patient-derived cells.

CASES AND

RESULTS

We reported six patients from three families and investigated ferroptosis susceptibility in fibroblasts from three representative patients: one with COQ2 variants and two with COQ4 variants. Fibroblasts with COQ2 variants showed increased vulnerability to ferroptosis inducers, plasma membrane lipid peroxidation. In contrast, fibroblasts with COQ4 variants exhibited only mild changes. Notably, susceptibility to ferroptosis remained unchanged after increasing intracellular CoQ10 levels. Despite this persistent ferroptosis sensitivity in vitro, the COQ2 patient exhibited significant clinical improvement following CoQ10 supplementation. These findings suggest that ferroptosis may contribute to cellular vulnerability in primary CoQ10 deficiency but may not be the primary driver of renal and neurological symptoms.

CONCLUSIONS

Our results highlight a complex interplay between CoQ10 biosynthesis, ferroptosis defense, and therapeutic response, warranting further investigation of subcellular CoQ10 distribution and ferroptosis-related mechanisms.