CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome

Abstract

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. Therefore, SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism. In cerebrum of Coq9 R239X mice, the deficit in SQR induces an increase in thiosulfate sulfurtransferase and sulfite oxidase, as well as modifications in the levels of thiols. As a result, biosynthetic pathways of glutamate, serotonin, and catecholamines were altered in the cerebrum, and the blood pressure was reduced. Therefore, this study reveals the reduction in SQR activity as one of the pathomechanisms associated with CoQ deficiency syndrome.

Dietary restriction transforms the protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

“…As aging is a multifaceted and complex decline in numerous physiological and metabolic functions, the role H2S plays in combating these declines theoretically should not be limited to one molecular pathway, receptor, system, or mechanism. Most likely, it is through H2S performing several nonmutually exclusive functions related to antioxidant and redox homeostasis , mitochondrial electron transfer (Luna-Sanchez et al, 2017), and protein modification and signaling via persulfidation/sulfhydration (Filipovic et al, 2018;Gao et al, 2015;Mustafa et al, 2009). Here, we focused on the latter mechanism, as little has been revealed regarding the entirety and scope of sulfhydration in mammals across several organ systems while under an anti-aging intervention.…”

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

“…For Western blot analyses in brain mitochondria, the pellets containing the mitochondrial fraction were re‐suspended in RIPA buffer with protease inhibitor cocktail. Protein band intensity was normalized to VDAC1 (mitochondrial proteins), and the data were expressed in terms of percent relative to wild‐type mice or control cells (Luna‐Sanchez et al , , ). The following primary antibodies were used: anti‐SQRDL (Proteintech, 17256‐1‐AP, dilution 1:500), anti‐PDSS2 (Proteintech, 13544‐1‐AP, dilution 1:500), anti‐COQ2 (Origene, TA341982, dilution 1:2,500), anti‐COQ4 (Proteintech, 16654‐1‐AP, dilution 1:2,000), anti‐COQ5 (Proteintech, 17453‐1‐AP, dilution 1:1,000), anti‐COQ6 (Proteintech, 12481‐1‐AP, dilution 1:500), anti‐COQ7 (Proteintech, 15083‐1‐AP, dilution 1:1,000), anti‐COQ8A (Proteintech, 15528‐1‐AP, dilution 1:2,500), anti‐S6R (Cell Signaling, 2217, dilution 1:1,000), anti‐S6RP (Cell Signaling, 2211, dilution 1:1,000), anti‐FGF21 (Abcam, ab171941, dilution 1:1,000), anti‐VDAC1 (Abcam, ab14734, dilution 1:5,000), anti‐TOM20 (Proteintech, 11802‐1‐AP, dilution 1:5,000), and anti‐GAPDH (Santacruz, sc‐166574, dilution 1:200).…”

“…These mutations are homologues to the mutations identified in a patient ( COQ9 R244X ; Duncan et al , ). The resulting dysfunctional COQ9 protein causes a profound reduction in the levels of COQ7 protein and disruption of the multiprotein complex for CoQ biosynthesis (Complex Q), resulting in a severe CoQ deficiency with accumulation of demethoxyubiquinone (DMQ = 2‐polyprenyl‐6‐methoxy‐3‐methyl‐1,4‐benzoquinone), brain mitochondrial dysfunction, oxidative damage, disruption of sulfide metabolism, reactive astrogliosis, spongiform degeneration, hypotension, and premature death (Garcia‐Corzo et al , ; Luna‐Sanchez et al , ). These pathological features are similar to those described in patients with mutations in COQ7 and COQ9 , who presented a severe early‐onset multisystemic disease dominated by encephalopathy, the phenotype associated with CoQ deficiency with the most limited response to oral CoQ 10 supplementation (Lopez et al , ; Duncan et al , ; Emmanuele et al , ; Danhauser et al , ; Smith et al , ).…”

Antioxidant effect of exercise: Exploring the role of the mitochondrial complex I superassembly

“…Mitochondrial isolation was performed as previously described [17]. One aliquot of the crude mitochondrial fraction was used for protein determination.…”