Coenzyme Q4is a functional substitute for coenzyme Q10and can be targeted to the mitochondria

Abstract

ABSTRACTCoenzyme 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 oral CoQ10is often ineffective, likely due to the extreme hydrophobicity and high molecular weight of CoQ10. Here, we show that less hydrophobic CoQ species with shorter isoprenoid tails can serve as viable substitutes for CoQ10in human cells. We demonstrate that CoQ4can perform multiple functions of CoQ10in CoQ-deficient cells at markedly lower treatment concentrations, motivating further investigation of CoQ4as a supplement for CoQ10deficiencies. In addition, we describe the synthesis and evaluation of an initial set of compounds designed to target CoQ4selectively to mitochondria using triphenylphosphonium (TPP). 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.