TY - JOUR
T1 - Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria
AU - Steenberge, Laura H.
AU - Rogers, Sean
AU - Sung, Andrew Y.
AU - Fan, Jing
AU - Pagliarini, David J.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/5
Y1 - 2024/5
N2 - 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.
AB - 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.
KW - antioxidant
KW - bioenergetics
KW - coenzyme Q10 (CoQ10)
KW - ferroptosis
KW - membrane lipid
KW - mitochondrial respiratory chain complex
KW - mitochondrial therapeutics
KW - pyrimidine biosynthesis
KW - ubiquinone
UR - http://www.scopus.com/inward/record.url?scp=85192008020&partnerID=8YFLogxK
U2 - 10.1016/j.jbc.2024.107269
DO - 10.1016/j.jbc.2024.107269
M3 - Article
C2 - 38588811
AN - SCOPUS:85192008020
SN - 0021-9258
VL - 300
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 5
M1 - 107269
ER -