scholarly journals Ubiquinone. Biosynthesis of quinone ring and its isoprenoid side chain. Intracellular localization.

2000 ◽  
Vol 47 (2) ◽  
pp. 469-480 ◽  
Author(s):  
A Szkopińska
Keyword(s):  
Metabolic Pathways ◽  
Mitochondrial Membrane ◽  
Coenzyme Q ◽  
Intracellular Localization ◽  
Mitochondrial Respiratory Chain ◽  
Cellular Level ◽  
Reduced Form ◽  
Side Chain ◽  
Inner Mitochondrial Membrane ◽  
Genes Encoding

Ubiquinone, known as coenzyme Q, was shown to be the part of the metabolic pathways by Crane et al. in 1957. Its function as a component of the mitochondrial respiratory chain is well established. However, ubiquinone has recently attracted increasing attention with regard to its function, in the reduced form, as an antioxidant. In ubiquinone synthesis the para-hydroxybenzoate ring (which is the derivative of tyrosine or phenylalanine) is condensed with a hydrophobic polyisoprenoid side chain, whose length varies from 6 to 10 isoprene units depending on the organism. para-Hydroxybenzoate (PHB) polyprenyltransferase that catalyzes the condensation of PHB with polyprenyl diphosphate has a broad substrate specificity. Most of the genes encoding (all-E)-prenyltransferases which synthesize polyisoprenoid chains, have been cloned. Their structure is either homo- or heterodimeric. Genes that encode prenyltransferases catalysing the transfer of the isoprenoid chain to para-hydroxybenzoate were also cloned in bacteria and yeast. To form ubiquinone, prenylated PHB undergoes several modifications such as hydroxylations, O-methylations, methylations and decarboxylation. In eukaryotes ubiquinones were found in the inner mitochondrial membrane and in other membranes such as the endoplasmic reticulum, Golgi vesicles, lysosomes and peroxisomes. Still, the subcellular site of their biosynthesis remains unclear. Considering the diversity of functions of ubiquinones, and their multistep biosynthesis, identification of factors regulating their cellular level remains an elusive task.

scholarly journals Mitochondrial potassium channels: A novel calcitriol target

2022 ◽  
Vol 27 (1) ◽  
Author(s):  
Anna M. Olszewska ◽  
Adam K. Sieradzan ◽  
Piotr Bednarczyk ◽  
Adam Szewczyk ◽  
Michał A. Żmijewski
Keyword(s):  
Vitamin D ◽  
Potassium Channels ◽  
Potassium Channel ◽  
Mitochondrial Membrane ◽  
Human Keratinocytes ◽  
Inner Mitochondrial Membrane ◽  
Open Probability ◽  
Expression Of Genes ◽  
High Calcium ◽  
Genes Encoding

Abstract Background Calcitriol (an active metabolite of vitamin D) modulates the expression of hundreds of human genes by activation of the vitamin D nuclear receptor (VDR). However, VDR-mediated transcriptional modulation does not fully explain various phenotypic effects of calcitriol. Recently a fast non-genomic response to vitamin D has been described, and it seems that mitochondria are one of the targets of calcitriol. These non-classical calcitriol targets open up a new area of research with potential clinical applications. The goal of our study was to ascertain whether calcitriol can modulate mitochondrial function through regulation of the potassium channels present in the inner mitochondrial membrane. Methods The effects of calcitriol on the potassium ion current were measured using the patch-clamp method modified for the inner mitochondrial membrane. Molecular docking experiments were conducted in the Autodock4 program. Additionally, changes in gene expression were investigated by qPCR, and transcription factor binding sites were analyzed in the CiiiDER program. Results For the first time, our results indicate that calcitriol directly affects the activity of the mitochondrial large-conductance Ca2+-regulated potassium channel (mitoBKCa) from the human astrocytoma (U-87 MG) cell line but not the mitochondrial calcium-independent two-pore domain potassium channel (mitoTASK-3) from human keratinocytes (HaCaT). The open probability of the mitoBKCa channel in high calcium conditions decreased after calcitriol treatment and the opposite effect was observed in low calcium conditions. Moreover, using the AutoDock4 program we predicted the binding poses of calcitriol to the calcium-bound BKCa channel and identified amino acids interacting with the calcitriol molecule. Additionally, we found that calcitriol influences the expression of genes encoding potassium channels. Such a dual, genomic and non-genomic action explains the pleiotropic activity of calcitriol. Conclusions Calcitriol can regulate the mitochondrial large-conductance calcium-regulated potassium channel. Our data open a new chapter in the study of non-genomic responses to vitamin D with potential implications for mitochondrial bioenergetics and cytoprotective mechanisms.

scholarly journals Membrane-tethering of cytochrome c accelerates regulated cell death in yeast

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Alexandra Toth ◽  
Andreas Aufschnaiter ◽  
Olga Fedotovskaya ◽  
Hannah Dawitz ◽  
Pia Ädelroth ◽  
...  
Keyword(s):  
Cell Death ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Membrane ◽  
Mitochondrial Respiratory Chain ◽  
Intermembrane Space ◽  
Inner Mitochondrial Membrane ◽  
Fitness Advantage ◽  
Regulated Cell Death ◽  
Membrane Tethering ◽  
Membrane Anchoring

Abstract Intrinsic apoptosis as a modality of regulated cell death is intimately linked to permeabilization of the outer mitochondrial membrane and subsequent release of the protein cytochrome c into the cytosol, where it can participate in caspase activation via apoptosome formation. Interestingly, cytochrome c release is an ancient feature of regulated cell death even in unicellular eukaryotes that do not contain an apoptosome. Therefore, it was speculated that cytochrome c release might have an additional, more fundamental role for cell death signalling, because its absence from mitochondria disrupts oxidative phosphorylation. Here, we permanently anchored cytochrome c with a transmembrane segment to the inner mitochondrial membrane of the yeast Saccharomyces cerevisiae, thereby inhibiting its release from mitochondria during regulated cell death. This cytochrome c retains respiratory growth and correct assembly of mitochondrial respiratory chain supercomplexes. However, membrane anchoring leads to a sensitisation to acetic acid-induced cell death and increased oxidative stress, a compensatory elevation of cellular oxygen-consumption in aged cells and a decreased chronological lifespan. We therefore conclude that loss of cytochrome c from mitochondria during regulated cell death and the subsequent disruption of oxidative phosphorylation is not required for efficient execution of cell death in yeast, and that mobility of cytochrome c within the mitochondrial intermembrane space confers a fitness advantage that overcomes a potential role in regulated cell death signalling in the absence of an apoptosome.

EFFECT OF ADRENOCORTICOTROPHIN ON INTRACELLULAR CHOLESTEROL TRANSPORT

1980 ◽  
Vol 84 (2) ◽  
pp. 179-188 ◽  
Author(s):  
MASAHISA NAKAMURA ◽  
MASAAKI WATANUKI ◽  
B. E. TILLEY ◽  
P. F. HALL
Keyword(s):  
Mitochondrial Membrane ◽  
Cholesterol Content ◽  
Tumour Cells ◽  
Side Chain ◽  
Adrenal Tumour ◽  
Inner Mitochondrial Membrane ◽  
Side Chain Cleavage ◽  
Isolated Mitochondria ◽  
Chain Cleavage ◽  
Significant Difference

The rate of side-chain cleavage of cholesterol by mitochondria derived from mouse adrenal tumour cells was measured. Incubation of the cells in the presence of adrenocorticotrophin (ACTH) for periods of up to 1 h was without effect on the subsequent side-chain cleavage by mitochondria. However, if the cells were incubated in the presence of aminoglutethimide phosphate (0·76 mmol/l), addition of ACTH (final concentration 86 u./l) to the medium containing the cells increased the subsequent rate of side-chain cleavage by the isolated mitochondria. This response reached a maximum after incubation of cells with ACTH for 2 h and decayed when the isolated mitochondria were left at 0 °C, although a significant difference was still apparent after 120 min. Similar stimulation of mitochondrial side-chain cleavage by ACTH was observed when the reaction was inhibited by anaerobiosis instead of aminoglutethimide phosphate. Addition of dibutyryl cyclic AMP, at final concentrations greater than 10−5 mol/l, to cells during incubation with aminoglutethimide phosphate (0·76 mmol/l) also stimulated the conversion of cholesterol to pregnenolone by the mitochondria. Provided the adrenal tumour cells were incubated with aminoglutethimide, or anaerobically, the mean cholesterol content of the inner mitochondrial membrane was significantly higher (P < 0·01) when ACTH was included in the incubation medium than when it was not. It is concluded that ACTH increases the movement of cholesterol to the mitochondrial membrane which contains the side-chain cleavage enzyme system and that part of this cholesterol is used for the enhanced conversion of cholesterol to pregnenolone brought about by ACTH.

scholarly journals UbiB proteins regulate cellular CoQ distribution in Saccharomyces cerevisiae

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zachary A. Kemmerer ◽  
Kyle P. Robinson ◽  
Jonathan M. Schmitz ◽  
Mateusz Manicki ◽  
Brett R. Paulson ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mitochondrial Membrane ◽  
Coenzyme Q ◽  
Mitochondrial Proteins ◽  
Inner Mitochondrial Membrane ◽  
Lipid Profiling ◽  
Enhanced Resistance ◽  
Biochemical Fractionation ◽  
Process Loss ◽  
Sites Of Action

AbstractBeyond its role in mitochondrial bioenergetics, Coenzyme Q (CoQ, ubiquinone) serves as a key membrane-embedded antioxidant throughout the cell. However, how CoQ is mobilized from its site of synthesis on the inner mitochondrial membrane to other sites of action remains a longstanding mystery. Here, using a combination of Saccharomyces cerevisiae genetics, biochemical fractionation, and lipid profiling, we identify two highly conserved but poorly characterized mitochondrial proteins, Ypl109c (Cqd1) and Ylr253w (Cqd2), that reciprocally affect this process. Loss of Cqd1 skews cellular CoQ distribution away from mitochondria, resulting in markedly enhanced resistance to oxidative stress caused by exogenous polyunsaturated fatty acids, whereas loss of Cqd2 promotes the opposite effects. The activities of both proteins rely on their atypical kinase/ATPase domains, which they share with Coq8—an essential auxiliary protein for CoQ biosynthesis. Overall, our results reveal protein machinery central to CoQ trafficking in yeast and lend insights into the broader interplay between mitochondria and the rest of the cell.

scholarly journals Amyloid-Beta Interaction with Mitochondria

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Lucia Pagani ◽  
Anne Eckert
Keyword(s):  
Mitochondrial Dysfunction ◽  
Amyloid Beta ◽  
Mitochondrial Membrane ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Intracellular Localization ◽  
Protein A ◽  
Postmortem Brain ◽  
Intermembrane Space ◽  
Inner Mitochondrial Membrane

Mitochondrial dysfunction is a hallmark of amyloid-beta(Aβ)-induced neuronal toxicity in Alzheimer's disease (AD). The recent emphasis on the intracellular biology of Aβand its precursor protein (AβPP) has led researchers to consider the possibility that mitochondria-associated and/or intramitochondrial Aβmay directly cause neurotoxicity. In this paper, we will outline current knowledge of the intracellular localization of both Aβand AβPP addressing the question of how Aβcan access mitochondria. Moreover, we summarize evidence from AD postmortem brain as well as cellular and animal AD models showing that Aβtriggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species (ROS) production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. In particular, we focus on Aβinteraction with different mitochondrial targets including the outer mitochondrial membrane, intermembrane space, inner mitochondrial membrane, and the matrix. Thus, this paper establishes a modified model of the Alzheimer cascade mitochondrial hypothesis.

Effects of alkyl side chain modification of coenzyme Q 10 on mitochondrial respiratory chain function and cytoprotection

2013 ◽  
Vol 21 (8) ◽  
pp. 2346-2354 ◽  
Author(s):  
David M. Fash ◽  
Omar M. Khdour ◽  
Sunil J. Sahdeo ◽  
Ruth Goldschmidt ◽  
Jennifer Jaruvangsanti ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Coenzyme Q ◽  
Mitochondrial Respiratory Chain ◽  
Side Chain ◽  
Alkyl Side Chain ◽  
Mitochondrial Respiratory

scholarly journals Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Manuel J. Acosta Lopez ◽  
Eva Trevisson ◽  
Marcella Canton ◽  
Luis Vazquez-Fonseca ◽  
Valeria Morbidoni ◽  
...  
Keyword(s):  
Vanillic Acid ◽  
Coenzyme Q ◽  
Mitochondrial Respiratory Chain ◽  
Human Cell Line ◽  
Food Additive ◽  
Large Set ◽  
Promising Alternative ◽  
Atp Production ◽  
Redox Active ◽  
Genes Encoding

Coenzyme Q (CoQ), a redox-active lipid, is comprised of a quinone group and a polyisoprenoid tail. It is an electron carrier in the mitochondrial respiratory chain, a cofactor of other mitochondrial dehydrogenases, and an essential antioxidant. CoQ requires a large set of enzymes for its biosynthesis; mutations in genes encoding these proteins cause primary CoQ deficiency, a clinically and genetically heterogeneous group of diseases. Patients with CoQ deficiency often respond to oral CoQ10 supplementation. Treatment is however problematic because of the low bioavailability of CoQ10 and the poor tissue delivery. In recent years, bypass therapy using analogues of the precursor of the aromatic ring of CoQ has been proposed as a promising alternative. We have previously shown using a yeast model that vanillic acid (VA) can bypass mutations of COQ6, a monooxygenase required for the hydroxylation of the C5 carbon of the ring. In this work, we have generated a human cell line lacking functional COQ6 using CRISPR/Cas9 technology. We show that these cells cannot synthesize CoQ and display severe ATP deficiency. Treatment with VA can recover CoQ biosynthesis and ATP production. Moreover, these cells display increased ROS production, which is only partially corrected by exogenous CoQ, while VA restores ROS to normal levels. Furthermore, we show that these cells accumulate 3-decaprenyl-1,4-benzoquinone, suggesting that in mammals, the decarboxylation and C1 hydroxylation reactions occur before or independently of the C5 hydroxylation. Finally, we show that COQ6 isoform c (transcript NM_182480) does not encode an active enzyme. VA can be produced in the liver by the oxidation of vanillin, a nontoxic compound commonly used as a food additive, and crosses the blood-brain barrier. These characteristics make it a promising compound for the treatment of patients with CoQ deficiency due to COQ6 mutations.

Generating, Partitioning, Targeting and Functioning of Superoxide in Mitochondria

1997 ◽  
Vol 17 (3) ◽  
pp. 259-272 ◽  
Author(s):  
Shu-sen Liu
Keyword(s):  
Experimental Evidence ◽  
Respiratory Chain ◽  
Mitochondrial Membrane ◽  
Reactive Oxygen ◽  
Mitochondrial Respiratory Chain ◽  
Proton Leak ◽  
Inner Mitochondrial Membrane ◽  
Hypothetical Model ◽  
Q Cycle ◽  
Oxygen Cycle

Recently, we proposed a hypothetical model of coexistence of “Reactive oxygen cycle” with Q cycle and H+ cycle in mitochondrial respiratory chain to combine both processes of univalent electron leak for production of superoxide and of proton leak across inner mitochondrial membrane. This review presents a more detailed description of this model and summarizes the supporting experimental evidence obtained.

Iron Does Not “Jiggle Free” in Mitochondria: Is Mitoferrin the Only Answer?.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-27-sci-27
Author(s):  
Barry H. Paw
Keyword(s):  
Mitochondrial Membrane ◽  
Iron Homeostasis ◽  
Reduced Form ◽  
Loss Of Function ◽  
Inner Mitochondrial Membrane ◽  
The Matrix ◽  
Conventional Models ◽  
Definitive Erythropoiesis ◽  
Yeast Mutants

The developing erythron requires tremendous amounts of iron (Fe) for the synthesis of heme for hemoproteins, such as hemoglobin, and iron-sulfur (Fe/S) clusters of proteins, which are required to catalyze redox reactions and regulate Fe uptake and storage. The uptake of Fe from transferrin (Tf) involves the binding of Tf to its cognate receptor (TfR), followed by the endocytosis of the Tf-TfR complex.1,2 In the late endosome, the release of Fe3+ from TfR is achieved by acidification of the vesicle by the v-ATPase H+-pump. Steap3 reduces the liberated Fe3+ prior to its transport out of the endosome by the DMT1 transporter. In contrast to previous conventional models for a cytosolic intermediate state, new data have emerged showing the direct interorganellar transfer of Fe from the endosome to the mitochondria.3 Although it is assumed that the exported Fe is targeted to the mitochondria for eventual incorporation into heme and Fe/S clusters, our understanding of the precise mechanism of how Fe traverses the outer and inner mitochondrial membranes remains poorly understood. Work in yeast mutants have implicated the role of solute carriers, Mrs3/4p, in mitochondrial iron homeostasis and revealed that it is the reduced form of iron, Fe2+, that is imported into the mitochondria. Subsequent studies of the zebrafish mutant, frascati, led to the discovery of mitoferrin 1 (Mfrn1, slc25a37), the vertebrate ortholog of Mrs3/4, as the major iron importer across the inner mitochondrial membrane in developing erythroblasts.4 A structurally related paralog, mitoferrin 2 (Mfrn2, slc25a28), plays the analogous role of Fe importer in non-erythroid cells. Loss-of-function studies of Mfrn1 in the mouse have confirmed its requirement in mammalian primitive and definitive erythropoiesis and its essential role in heme and Fe/S biosynthesis. Several questions remain unanswered in mitochondrial Fe metabolism: Do the two Mfrn importers account for all Fe imported into the mitochondria? How does Fe get across the outer mitochondrial membrane to reach the Mfrn importers? How does the translocated Fe in the matrix ultimately reach ferrochelatase to form heme? How is Fe translocated across the inner mitochondrial membrane?

Rhabdomyolysis secondary to lovastatin therapy

1990 ◽  
Vol 36 (12) ◽  
pp. 2145-2147 ◽  
Author(s):  
A A Manoukian ◽  
N V Bhagavan ◽  
T Hayashi ◽  
T A Nestor ◽  
C Rios ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Adverse Reactions ◽  
Clinical Course ◽  
Coenzyme Q ◽  
Serum Creatine Kinase ◽  
Clinical Settings ◽  
Inner Mitochondrial Membrane ◽  
Electron Microscopic ◽  
Microscopic Studies ◽  
Life Threatening

Abstract We report a case of lovastatin-induced rhabdomyolysis and resulting life-threatening renal failure. Lovastatin, a hypocholesterolemic agent, decreases endogenous cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.88). This agent has been implicated in causing rare serious side effects in various clinical settings; however, the mechanism of these adverse reactions is not understood. The clinical course of our patient was characterized by profound muscle weakness with marked increases in serum creatine kinase and myoglobin. Light- and electron-microscopic studies of skeletal muscle of our patient demonstrated a noninflammatory myopathy suggestive of ongoing rhabdomyolysis with vacuolization and focal degeneration of myocytes. The patient's symptoms and the laboratory values referable to rhabdomyolysis resolved after discontinuation of the drug. We speculate that the rhabdomyolysis was due to mitochondrial damage secondary to inadequate synthesis of coenzyme Q and heme A, members of the electron-transport system of the inner mitochondrial membrane.

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