Hydroxyhydroquinone as a novel modulator of mitochondrial metabolism with potential to restore CoQ10 homeostasis.

Mitochondrial dysfunction is a hallmark of diverse metabolic and neurodegenerative disorders, often linked to impaired coenzyme Q10 (CoQ10) homeostasis. Here, we have evaluated the activity of hydroxyhydroquinone (HHQ) as a novel modulator of mitochondrial metabolism. Molecular simulations revealed that HHQ can act as an alternative aromatic substrate for human COQ2 in the CoQ10 biosynthetic pathway. In cultured cells, HHQ exposure (5.10- 5 mol.L- 1) enhanced complex I activity while maintaining stable ATP levels. HHQ reduced nitric oxide accumulation without altering superoxide dismutase activity, suggesting selective redox modulation. By bypassing the 4-hydroxybenzoic acid (PHBA) pathway, HHQ restores mitochondrial homeostasis and supports aerobic metabolism. These findings highlight HHQ as a small aromatic compound with strong redox potential that may favor metabolic functions driven by CoQ10 deficiency and mitochondrial dysfunction.