Impact of Chemical Analogs of 4-Hydroxybenzoic Acid on Coenzyme Q Biosynthesis: From Inhibition to Bypass of Coenzyme Q Deficiency

Abstract

Coenzyme Q is a lipid that participates to important physiological functions. Coenzyme Q is synthesized in multiple steps from the precursor 4-hydroxybenzoic acid. Mutations in enzymes that participate to coenzyme Q biosynthesis result in primary coenzyme Q deficiency, a type of mitochondrial disease. Coenzyme Q10 supplementation of patients is the classical treatment but it shows limited efficacy in some cases. The molecular understanding of the coenzyme Q biosynthetic pathway allowed the design of experiments to bypass deficient biosynthetic steps with analogs of 4-hydroxybenzoic acid. These molecules provide the defective chemical group and can reactivate endogenous coenzyme Q biosynthesis as demonstrated recently in yeast, mammalian cell cultures, and mouse models of primary coenzyme Q deficiency. This mini review presents how the chemical properties of various analogs of 4-hydroxybenzoic acid dictate the effect of the molecules on CoQ biosynthesis and how the reactivation of endogenous coenzyme Q biosynthesis may achieve better results than exogenous CoQ10 supplementation.

β‐ RA reduces DMQ /CoQ ratio and rescues the encephalopathic phenotype in Coq9 R239X mice

“…In either case, our data on the Coq9 R239X mouse model together with those obtained in the Coq7 conditional KO model indicate that it is possible to influence the CoQ biosynthesis in vivo with the use of the appropriated 4-HB analog(s). These results partially corroborate previous data in vitro using mutant yeasts and human skin fibroblasts derived from patients with primary CoQ deficiency (Ozeir et al, 2011;Xie et al, 2012;Doimo et al, 2014;Freyer et al, 2015;Luna-Sanchez et al, 2015;Herebian et al, 2017b,c;Pierrel, 2017;Wang et al, 2017).…”

“…The initial hypothesis for this study was that β‐RA could be used in the CoQ biosynthetic pathway and bypasses the defect in COQ9‐COQ7, increasing the endogenous levels of CoQ (Luna‐Sanchez et al , ; Pierrel, ). However, our results show that the bypass effect would be limited because only the kidneys, the tissue with higher levels of β‐RA, showed a moderate increase in the levels of CoQ in the mutant mice after the treatment.…”

“…Nevertheless, the levels of DMQ 9 were significantly decreased not only in the kidneys but also in the skeletal muscle, liver, and heart. Those results hint that the CoQ biosynthetic pathway might use β‐RA as a substrate whose Km is probably higher than the natural substrate, 4‐HB, and for that reason the reduction of the DMQ 9 levels is not accompanied by an increase of CoQ 9 in tissues where the β‐RA does not reach a threshold (Pierrel, ). Also, the stabilization of the Complex Q may contribute to this effect, since the levels of COQ4, COQ5, COQ6, and COQ8A were slightly increased in the kidneys and heart after β‐RA treatment.…”

“…Therefore, β‐RA should be preferentially considered for the treatment of human CoQ 10 deficiency with accumulation of DMQ 10 , as it has been reported in patients with mutations in COQ9 , COQ7, or COQ4 (Duncan et al , ; Freyer et al , ; Danhauser et al , ; Herebian et al , 2017b; Wang et al , ; Smith et al , ) but also in cells under siRNA knockdown of COQ3 , COQ5 and COQ6 (Herebian et al , 2017b). Similar principles could be applied for 3,4‐hydroxybenzoic acid, vanillic acid, 2‐methyl‐4‐hydroxybenzoic acid, or 2,3‐dimethoxy‐4‐hydroxybenzoic acid in the cases of mutations in COQ6, COQ5, or COQ3 (Heeringa et al , ; Yoo et al , ; Ribas et al , ; Gigante et al , ; Herebian et al , ; Pierrel, ), respectively. Furthermore, 4‐HB analogs may provide therapeutic effects in other conditions, e.g., mitochondrial disorders, since secondary CoQ deficiency due to decreased levels of CoQ biosynthetic proteins have been recently reported in various mouse models of mitochondrial diseases (Kuhl et al , ); or metabolic diseases due to insulin resistance since secondary CoQ deficiency due to decreased levels of CoQ biosynthetic proteins have been recently described in in vitro insulin resistance models and adipose tissue from insulin‐resistant humans (Fazakerley et al , ).…”

“…This strategy was partially successful in vitro in COQ7 null yeasts, as well as in mouse and human fibroblasts with mutations in COQ7 or COQ9 (Xie et al, 2012;Freyer et al, 2015;Luna-Sanchez et al, 2015). Additionally, b-RA is a structural analogue of salicylic acid (2-hydroxybenzoic acid), an anti-inflammatory molecule that may be potentially valuable to reduce the neuroinflammation (Lan et al, 2011;Gomez-Guzman et al, 2014), a factor that has been recently postulated as an essential pathomechanism and a therapeutic target in mitochondrial encephalopathies (Ignatenko et al, 2018), leukoencephalopathy, and neurodegenerative diseases (Eto et al, 2002;Liddelow & Barres, 2015, 2017. Also salicylic derivate, known as salicylates, may act as mTOR inhibitors (Cameron et al, 2016), and this action may be therapeutic in mitochondrial diseases (Johnson et al, 2013).…”