Coenzyme Q (CoQ) is an essential lipid with many cellular functions, such as electron transport for cellular respiration, antioxidant protection, redox homeostasis, and ferroptosis suppression. ...Deficiencies in CoQ due to aging, genetic disease, or medication can be ameliorated by high-dose supplementation. As such, an understanding of the uptake and transport of CoQ may inform methods of clinical use and identify how to better treat deficiency. Here, we review what is known about the cellular uptake and intracellular distribution of CoQ from yeast, mammalian cell culture, and rodent models, as well as its absorption at the organism level. We discuss the use of these model organisms to probe the mechanisms of uptake and distribution. The literature indicates that CoQ uptake and distribution are multifaceted processes likely to have redundancies in its transport, utilizing the endomembrane system and newly identified proteins that function as lipid transporters. Impairment of the trafficking of either endogenous or exogenous CoQ exerts profound effects on metabolism and stress response. This review also highlights significant gaps in our knowledge of how CoQ is distributed within the cell and suggests future directions of research to better understand this process.
Coenzyme Q is a redox active lipid essential for aerobic respiration. The Coq4 polypeptide is required for Q biosynthesis and growth on non-fermentable carbon sources, however its exact function in ...this pathway is not known. Here we probe the functional roles of Coq4p in a yeast Q biosynthetic polypeptide complex. A yeast
coq4-1 mutant harboring an E226K substitution is unable to grow on nonfermentable carbon sources. The
coq4-1 yeast mutant retains significant Coq3p
O-methyltransferase activity, and mitochondria isolated from
coq4-1 and
coq4-2 (E
121K) yeast point mutants contain normal steady state levels of Coq polypeptides, unlike the decreased levels of Coq polypeptides generally found in strains harboring
coq gene deletions. Digitonin-solubilized mitochondrial extracts prepared from yeast
coq4 point mutants show that Coq3p and Coq4 polypeptides no longer co-migrate as high molecular mass complexes by one- and two-dimensional Blue Native-PAGE. Similarly, gel filtration chromatography confirms that
O-methyltransferase activity, Coq3p, Coq4p, and Coq7p migration are disorganized in the
coq4-1 mutant mitochondria. The data suggest that Coq4p plays an essential role in organizing a Coq enzyme complex required for Q biosynthesis.
Substitution of −CD2– at the reactive centers of linoleic and linolenic acids reduces the rate of abstraction of D by a tocopheryl radical by as much as 36-fold, compared to the abstraction of H from ...a corresponding −CH2– center. This H atom transfer reaction is the rate-determining step in the tocopherol-mediated peroxidation of lipids in human low-density lipoproteins, a process that has been linked to coronary artery disease. The unanticipated large kinetic isotope effects reported here for the tocopherol-mediated oxidation of linoleic and linolenic acids and esters suggests that tunneling makes this process favorable.
The structures of two new oxide chalcogenide phases, Sr
CuO
Cu
S
and Sr
CuO
Cu
Se
, are reported, both of which contain infinite CuO
planes containing Cu
and which have Cu
ions in the sulfide or ...selenide layers. Powder neutron diffraction measurements show that Sr
CuO
Cu
Se
exhibits long-range magnetic ordering with a magnetic structure based on antiferromagnetic interactions between nearest-neighbor Cu
ions, leading to a √2 a × √2 a × 2 c expansion of the nuclear cell. The ordered moment of 0.39(6) μ
on the Cu
ions at 1.7 K is consistent with the value predicted by density functional theory calculations. The compounds are structurally related to the cuprate superconductors and may also be considered as analogues of the parent phases of this class of superconductor such as Sr
CuO
Cl
or La
CuO
. In the present case, however, the top of the chalcogenide-based valence band is very close to the vacant Cu
3d states of the conduction band, leading to relatively high measured conductivity.
The structures of two new oxide chalcogenide phases, Sr2CuO2Cu2S2 and Sr2CuO2Cu2Se2, are reported, both of which contain infinite CuO2 planes containing Cu2+ and which have Cu+ ions in the sulfide or ...selenide layers. Powder neutron diffraction measurements show that Sr2CuO2Cu2Se2 exhibits long-range magnetic ordering with a magnetic structure based on antiferromagnetic interactions between nearest-neighbor Cu2+ ions, leading to a √2a × √2a × 2c expansion of the nuclear cell. The ordered moment of 0.39(6) μB on the Cu2+ ions at 1.7 K is consistent with the value predicted by density functional theory calculations. The compounds are structurally related to the cuprate superconductors and may also be considered as analogues of the parent phases of this class of superconductor such as Sr2CuO2Cl2 or La2CuO4. In the present case, however, the top of the chalcogenide-based valence band is very close to the vacant Cu2+ 3d states of the conduction band, leading to relatively high measured conductivity.
Mitochondrial energy production and function rely on optimal concentrations of the essential redox-active lipid, coenzyme Q (CoQ). CoQ deficiency results in mitochondrial dysfunction associated with ...increased mitochondrial oxidative stress and a range of pathologies. What drives CoQ deficiency in many of these pathologies is unknown, just as there currently is no effective therapeutic strategy to overcome CoQ deficiency in humans. To date, large-scale studies aimed at systematically interrogating endogenous systems that control CoQ biosynthesis and their potential utility to treat disease have not been carried out. Therefore, we developed a quantitative high-throughput method to determine CoQ concentrations in yeast cells. Applying this method to the Yeast Deletion Collection as a genome-wide screen, 30 genes not known previously to regulate cellular concentrations of CoQ were discovered. In combination with untargeted lipidomics and metabolomics, phosphatidylethanolamine N-methyltransferase (PEMT) deficiency was confirmed as a positive regulator of CoQ synthesis, the first identified to date. Mechanistically, PEMT deficiency alters mitochondrial concentrations of one-carbon metabolites, characterized by an increase in the S-adenosylmethionine to S-adenosylhomocysteine (SAM-to-SAH) ratio that reflects mitochondrial methylation capacity, drives CoQ synthesis, and is associated with a decrease in mitochondrial oxidative stress. The newly described regulatory pathway appears evolutionary conserved, as ablation of PEMT using antisense oligonucleotides increases mitochondrial CoQ in mouse-derived adipocytes that translates to improved glucose utilization by these cells, and protection of mice from high-fat diet-induced insulin resistance. Our studies reveal a previously unrecognized relationship between two spatially distinct lipid pathways with potential implications for the treatment of CoQ deficiencies, mitochondrial oxidative stress/dysfunction, and associated diseases.
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•Mitochondrial CoQ deficiency results in oxidative stress and a range of pathologies•The drivers of mitochondrial CoQ deficiency remain largely unknown•PEMT deficiency is the first identified positive regulator of mitochondrial CoQ•PEMT deficiency increases CoQ by increasing the mitochondrial SAM-to-SAH ratio•PEMT deficiency prevents insulin resistance by increasing mitochondrial CoQ
Coenzyme Q (CoQ) is a vital lipid that functions as an electron carrier in the mitochondrial electron transport chain and as a membrane-soluble antioxidant. Deficiencies in CoQ lead to metabolic ...diseases with a wide range of clinical manifestations. There are currently few treatments that can slow or stop disease progression. Primary CoQ
deficiency can arise from mutations in any of the
genes responsible for CoQ biosynthesis. While many mutations in these genes have been identified, the clinical significance of most of them remains unclear. Here we analyzed the structural and functional impact of 429 human missense single nucleotide variants (SNVs) that give rise to amino acid substitutions in the conserved and functional regions of human genes encoding a high molecular weight complex known as the CoQ synthome (or Complex Q), consisting of the
-
and
gene products. Using structures of COQ polypeptides, close homologs, and AlphaFold models, we identified 115 SNVs that are potentially pathogenic. Further biochemical characterizations in model organisms such as
are required to validate the pathogenicity of the identified SNVs. Collectively, our results will provide a resource for clinicians during patient diagnosis and guide therapeutic efforts toward combating primary CoQ
deficiency.
The synthesis, structure, and electrical properties of the oxysulfide CaZnOS are reported. The white compound has a band gap of 3.7(1) eV and crystallizes in hexagonal space group P63 mc (No. 186) ...with a = 3.75726(3) Å, c = 11.4013(1) Å, and Z = 2. The noncentrosymmetric structure, which has few analogues, is composed of isotypic puckered hexagonal ZnS and CaO layers arranged so that ZnS3O tetrahedra are all aligned parallel, resulting in a polar structure. The compound shows type 1 non-phase-matchable second harmonic generation, determined using 1064 nm radiation, with an efficiency approximately 100 times that of α-SiO2 and a piezoelectric coefficient of 38 pm V-1. Although polar, CaZnOS is not ferroelectric and the pyroelectric coefficient is very small, approximately 0.0 μC m-2 K-1 between room temperature and 100 °C.
Dietary fats are important for human health, yet it is not fully understood how different fats affect various health problems. Although polyunsaturated fatty acids (PUFAs) are generally considered as ...highly oxidizable, those of the n-3 series can ameliorate the risk of many age-related disorders. Coenzyme Q (CoQ) is both an essential component of the mitochondrial electron transport chain and the only lipid-soluble antioxidant that animal cells can synthesize. Previous work has documented the protective antioxidant properties of CoQ against the autoxidation products of PUFAs. Here, we have explored in vitro and in vivo models to better understand the regulation of CoQ biosynthesis by dietary fats. In mouse liver, PUFAs increased CoQ content, and PUFAs of the n-3 series increased preferentially CoQ10. This response was recapitulated in hepatic cells cultured in the presence of lipid emulsions, where we additionally demonstrated a role for n-3 PUFAs as regulators of CoQ biosynthesis via the upregulation of several COQ proteins and farnesyl pyrophosphate levels. In both models, n-3 PUFAs altered the mitochondrial network without changing the overall mitochondrial mass. Furthermore, in cellular systems, n-3 PUFAs favored the synthesis of CoQ10 over CoQ9, thus altering the ratio between CoQ isoforms through a mechanism that involved downregulation of farnesyl diphosphate synthase activity. This effect was recapitulated by both siRNA silencing and by pharmacological inhibition of farnesyl diphosphate synthase with zoledronic acid. We highlight here the ability of n-3 PUFAs to regulate CoQ biosynthesis, CoQ content, and the ratio between its isoforms, which might be relevant to better understand the health benefits associated with this type of fat. Additionally, we identify for the first time zoledronic acid as a drug that inhibits CoQ biosynthesis, which must be also considered with respect to its biological effects on patients.
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•Dietary fats exert differential actions on CoQ biosynthesis.•n-3 PUFAs increase CoQ biosynthesis and elevate hepatic CoQ content.•CoQ biosynthesis is influenced by COQ proteins expression and FPP content.•Farnesyldiphosphate synthase plays a key role in regulating the CoQ9/CoQ10 ratio.•Zoledronic acid is identified as a drug that inhibits CoQ biosynthesis.
Coenzyme Q (CoQ) is an essential player in the respiratory electron transport chain and is the only lipid-soluble antioxidant synthesized endogenously in mammalian and yeast cells. In humans, genetic ...mutations, pathologies, certain medical treatments, and aging, result in CoQ deficiencies, which are linked to mitochondrial, cardiovascular, and neurodegenerative diseases. The only strategy available for these patients is CoQ supplementation. CoQ supplements benefit a small subset of patients, but the poor solubility of CoQ greatly limits treatment efficacy. Consequently, the efficient delivery of CoQ to the mitochondria and restoration of respiratory function remains a major challenge. A better understanding of CoQ uptake and mitochondrial delivery is crucial to make this molecule a more efficient and effective therapeutic tool. In this study, we investigated the mechanism of CoQ uptake and distribution using the yeast Saccharomyces cerevisiae as a model organism. The addition of exogenous CoQ was tested for the ability to restore growth on non-fermentable medium in several strains that lack CoQ synthesis (coq mutants). Surprisingly, we discovered that the presence of CoQ biosynthetic intermediates impairs assimilation of CoQ into a functional respiratory chain in yeast cells. Moreover, a screen of 40 gene deletions considered to be candidates to prevent exogenous CoQ from rescuing growth of the CoQ-less coq2Δ mutant, identified six novel genes (CDC10, RTS1, RVS161, RVS167, VPS1, and NAT3) as necessary for efficient trafficking of CoQ to mitochondria. The proteins encoded by these genes represent essential steps in the pathways responsible for transport of exogenously supplied CoQ to its functional sites in the cell, and definitively associate CoQ distribution with endocytosis and intracellular vesicular trafficking pathways conserved from yeast to human cells.
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•CoQ biosynthetic intermediates impair assimilation of exogenously supplied CoQ.•CDC10, RTS1, RVS161, RVS167, NAT3, and VPS1 genes are necessary for CoQ trafficking.•These proteins mediate transport of exogenous CoQ to functional sites in the cell.•CoQ transport is associated with endocytosis and intracellular vesicular trafficking.
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