Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria

Abstract

Coenzyme Q10 (CoQ₁₀) is an important cofactor and antioxidant for numerous cellular processes, and its deficiency has been linked to human disorders including mitochondrial disease, heart failure, Parkinson's disease, and hypertension. Unfortunately, treatment with exogenous CoQ₁₀ is often ineffective, likely due to its extreme hydrophobicity and high molecular weight. Here, we show that less hydrophobic CoQ species with shorter isoprenoid tails can serve as viable substitutes for CoQ₁₀ in human cells. We demonstrate that CoQ₄ can perform multiple functions of CoQ₁₀ in CoQ-deficient cells at markedly lower treatment concentrations, motivating further investigation of CoQ₄ as a supplement for CoQ₁₀ deficiencies. In addition, we describe the synthesis and evaluation of an initial set of compounds designed to target CoQ₄ selectively to mitochondria using triphenylphosphonium. Our results indicate that select versions of these compounds can successfully be delivered to mitochondria in a cell model and be cleaved to produce CoQ₄, laying the groundwork for further development.

Keywords: antioxidant; bioenergetics; coenzyme Q10 (CoQ10); ferroptosis; membrane lipid; mitochondrial respiratory chain complex; mitochondrial therapeutics; pyrimidine biosynthesis; ubiquinone.