Abstract:Coenzyme Q (Qn) is a vital lipid component of the electron transport chain that functions in cellular energy metabolism and as a membrane antioxidant. In the yeast Saccharomyces cerevisiae, coq1–coq9 deletion mutants are respiratory-incompetent, sensitive to lipid peroxidation stress, and unable to synthesize Q6. The yeast coq10 deletion mutant is also respiratory-deficient and sensitive to lipid peroxidation, yet it continues to produce Q6 at an impaired rate. Thus, Coq10 is required for the function of Q6 in… Show more
“…The final steps of CoQ biosynthesis in the inner mitochondrial membrane begin with the assembly of the polyisoprenoid side-chain and its attachment to the benzoquinone ring, which then undergoes a series of modifications (decarboxylation, hydroxylations and methylations) to obtain the final product [ [7] , [8] , [9] , [10] , [11] , [12] , [13] ]. In addition to the actual enzymes, several other proteins are necessary for CoQ biosynthesis [ [14] , [15] , [16] , [17] , [18] ]. Fig.…”
Coenzyme Q
10
(CoQ
10
; also known as ubiquinone) is a vital, redox-active membrane component that functions as obligate electron transporter in the mitochondrial respiratory chain, as cofactor in other enzymatic processes and as antioxidant. CoQ
10
supplementation has been widely investigated for treating a variety of acute and chronic conditions in which mitochondrial function or oxidative stress play a role. In addition, it is used as replacement therapy in patients with CoQ deficiency including inborn primary CoQ
10
deficiency due to mutations in CoQ
10
-biosynthetic genes as well as secondary CoQ
10
deficiency, which is frequently observed in patients with mitochondrial disease syndrome and in other conditions. However, despite many tests and some promising results, whether CoQ
10
treatment is beneficial in any indication has remained inconclusive. Because CoQ
10
is highly insoluble, it is only available in oral formulations, despite its very poor oral bioavailability. Using a novel model of CoQ-deficient cells, we screened a library of FDA-approved drugs for an activity that could increase the uptake of exogenous CoQ
10
by the cell. We identified the fungicide caspofungin as capable of increasing the aqueous solubility of CoQ
10
by several orders of magnitude. Caspofungin is a mild surfactant that solubilizes CoQ
10
by forming nano-micelles with unique properties favoring stability and cellular uptake. Intravenous administration of the formulation in mice achieves unprecedented increases in CoQ
10
plasma levels and in tissue uptake, with no observable toxicity. As it contains only two safe components (caspofungin and CoQ
10
), this injectable formulation presents a high potential for clinical safety and efficacy.
“…The final steps of CoQ biosynthesis in the inner mitochondrial membrane begin with the assembly of the polyisoprenoid side-chain and its attachment to the benzoquinone ring, which then undergoes a series of modifications (decarboxylation, hydroxylations and methylations) to obtain the final product [ [7] , [8] , [9] , [10] , [11] , [12] , [13] ]. In addition to the actual enzymes, several other proteins are necessary for CoQ biosynthesis [ [14] , [15] , [16] , [17] , [18] ]. Fig.…”
Coenzyme Q
10
(CoQ
10
; also known as ubiquinone) is a vital, redox-active membrane component that functions as obligate electron transporter in the mitochondrial respiratory chain, as cofactor in other enzymatic processes and as antioxidant. CoQ
10
supplementation has been widely investigated for treating a variety of acute and chronic conditions in which mitochondrial function or oxidative stress play a role. In addition, it is used as replacement therapy in patients with CoQ deficiency including inborn primary CoQ
10
deficiency due to mutations in CoQ
10
-biosynthetic genes as well as secondary CoQ
10
deficiency, which is frequently observed in patients with mitochondrial disease syndrome and in other conditions. However, despite many tests and some promising results, whether CoQ
10
treatment is beneficial in any indication has remained inconclusive. Because CoQ
10
is highly insoluble, it is only available in oral formulations, despite its very poor oral bioavailability. Using a novel model of CoQ-deficient cells, we screened a library of FDA-approved drugs for an activity that could increase the uptake of exogenous CoQ
10
by the cell. We identified the fungicide caspofungin as capable of increasing the aqueous solubility of CoQ
10
by several orders of magnitude. Caspofungin is a mild surfactant that solubilizes CoQ
10
by forming nano-micelles with unique properties favoring stability and cellular uptake. Intravenous administration of the formulation in mice achieves unprecedented increases in CoQ
10
plasma levels and in tissue uptake, with no observable toxicity. As it contains only two safe components (caspofungin and CoQ
10
), this injectable formulation presents a high potential for clinical safety and efficacy.
“…The Seahorse XF96 Extracellular Flux Analyzer (Seahorse Bioscience, Agilent Technologies) was used to detect respirations of WT and mutant yeast cells. The methods were similar as previous description ( Bradley et al, 2020 ). 25 μL 50 μg/mL Poly-D-Lysine were added to each well of the Seahorse plate and incubated for 30 min at room temperature.…”
Meiosis is essential for genetic stability and diversity during sexual reproduction in most eukaryotes. Chromatin structure and gene expression are drastically changed during meiosis, and various histone modifications have been reported to participate in this unique process. However, the dynamic of histone modifications during meiosis is still not well investigated. Here, by using multiple reaction monitoring (MRM) based LC-MS/MS, we detected dynamic changes of histone H3 lysine post-translational modifications (PTMs). We firstly quantified the precise percentage of H3 modifications on different lysine sites during mouse and yeast meiosis, and found H3 acetylation and methylation were dramatically changed. To further study the potential functions of H3 acetylation and methylation in meiosis, we performed histone H3 lysine mutant screening in yeast, and found that yeast strains lacking H3K18 acetylation (H3K18ac) failed to initiate meiosis due to insufficient IME1 expression. Further studies showed that the absence of H3K18ac impaired respiration, leading to the reduction of Rim101p, which further upregulated a negative regulator of IME1 transcription, Smp1p. Together, our studies reveal a novel meiosis initiation pathway mediated by histone H3 modifications.
“…Although Coq10 is required for respiration, its synthesis is only partially affected in log but not in stationary phase yeast cells, suggesting that its function is related to the delivery of coenzyme Q from the synthome located at the endoplasmic-mitochondrial contact sites to the regions of the inner membrane containing the respiratory chain complexes [ 226 , 244 ]. The respiratory deficiency of coq10 mutants is partially rescued in a coq11 mutant, which codes for a component of the synthome that has been proposed to down- regulate the synthesis of coenzyme Q [ 244 ]. Coq11 (human NDUFA9), a separate protein in yeast, is a component of the CoQ synthome [ 245 ] and appears to regulate its formation and stability [ 244 ].…”
Section: Pathological Mutations In Respiratory Chain and Atp Synthmentioning
confidence: 99%
“…The respiratory deficiency of coq10 mutants is partially rescued in a coq11 mutant, which codes for a component of the synthome that has been proposed to down- regulate the synthesis of coenzyme Q [ 244 ]. Coq11 (human NDUFA9), a separate protein in yeast, is a component of the CoQ synthome [ 245 ] and appears to regulate its formation and stability [ 244 ]. CoQ yeast and human genes are listed in Table 8 .…”
Section: Pathological Mutations In Respiratory Chain and Atp Synthmentioning
The ease with which the unicellular yeast Saccharomyces cerevisiae can be manipulated genetically and biochemically has established this organism as a good model for the study of human mitochondrial diseases. The combined use of biochemical and molecular genetic tools has been instrumental in elucidating the functions of numerous yeast nuclear gene products with human homologs that affect a large number of metabolic and biological processes, including those housed in mitochondria. These include structural and catalytic subunits of enzymes and protein factors that impinge on the biogenesis of the respiratory chain. This article will review what is currently known about the genetics and clinical phenotypes of mitochondrial diseases of the respiratory chain and ATP synthase, with special emphasis on the contribution of information gained from pet mutants with mutations in nuclear genes that impair mitochondrial respiration. Our intent is to provide the yeast mitochondrial specialist with basic knowledge of human mitochondrial pathologies and the human specialist with information on how genes that directly and indirectly affect respiration were identified and characterized in yeast.
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