scholarly journals Learning from Yeast about Mitochondrial Carriers

2021 ◽  
Vol 9 (10) ◽  
pp. 2044
Author(s):  
Marek Mentel ◽  
Petra Chovančíková ◽  
Igor Zeman ◽  
Peter Polčic
Keyword(s):  
Mitochondrial Membrane ◽  
Cell Metabolism ◽  
Model Organism ◽  
Human Diseases ◽  
Eukaryotic Cells ◽  
Mitochondrial Matrix ◽  
Inner Mitochondrial Membrane ◽  
Yeast Saccharomyces Cerevisiae ◽  
Mitochondrial Carriers ◽  
Genes Encoding

Mitochondria are organelles that play an important role in both energetic and synthetic metabolism of eukaryotic cells. The flow of metabolites between the cytosol and mitochondrial matrix is controlled by a set of highly selective carrier proteins localised in the inner mitochondrial membrane. As defects in the transport of these molecules may affect cell metabolism, mutations in genes encoding for mitochondrial carriers are involved in numerous human diseases. Yeast Saccharomyces cerevisiae is a traditional model organism with unprecedented impact on our understanding of many fundamental processes in eukaryotic cells. As such, the yeast is also exceptionally well suited for investigation of mitochondrial carriers. This article reviews the advantages of using yeast to study mitochondrial carriers with the focus on addressing the involvement of these carriers in human diseases.

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 Role of cytochrome c heme lyase in mitochondrial import and accumulation of cytochrome c in Saccharomyces cerevisiae.

1991 ◽  
Vol 11 (11) ◽  
pp. 5487-5496 ◽  
Author(s):  
M E Dumont ◽  
T S Cardillo ◽  
M K Hayes ◽  
F Sherman
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cytochrome C ◽  
Mitochondrial Membrane ◽  
Intermembrane Space ◽  
Inner Mitochondrial Membrane ◽  
Yeast Saccharomyces Cerevisiae ◽  
Apocytochrome C ◽  
Cytochrome C Heme Lyase

Heme is covalently attached to cytochrome c by the enzyme cytochrome c heme lyase. To test whether heme attachment is required for import of cytochrome c into mitochondria in vivo, antibodies to cytochrome c have been used to assay the distributions of apo- and holocytochromes c in the cytoplasm and mitochondria from various strains of the yeast Saccharomyces cerevisiae. Strains lacking heme lyase accumulate apocytochrome c in the cytoplasm. Similar cytoplasmic accumulation is observed for an altered apocytochrome c in which serine residues were substituted for the two cysteine residues that normally serve as sites of heme attachment, even in the presence of normal levels of heme lyase. However, detectable amounts of this altered apocytochrome c are also found inside mitochondria. The level of internalized altered apocytochrome c is decreased in a strain that completely lacks heme lyase and is greatly increased in a strain that overexpresses heme lyase. Antibodies recognizing heme lyase were used to demonstrate that the enzyme is found on the outer surface of the inner mitochondrial membrane and is not enriched at sites of contact between the inner and outer mitochondrial membranes. These results suggest that apocytochrome c is transported across the outer mitochondrial membrane by a freely reversible process, binds to heme lyase in the intermembrane space, and is then trapped inside mitochondria by an irreversible conversion to holocytochrome c accompanied by folding to the native conformation. Altered apocytochrome c lacking the ability to have heme covalently attached accumulates in mitochondria only to the extent that it remains bound to heme lyase.

scholarly journals Mitochondrial metabolite carrier family, topology, structure and functional properties: an overview.

1996 ◽  
Vol 43 (2) ◽  
pp. 349-360 ◽  
Author(s):  
F E Sluse
Keyword(s):  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Kinetic Mechanism ◽  
Transport Processes ◽  
Site Directed Mutagenesis ◽  
Mitochondrial Matrix ◽  
Chemiosmotic Theory ◽  
Inner Mitochondrial Membrane ◽  
The Third ◽  
Function Relationship

A set of metabolite carriers operates the traffic of numerous molecules consumed or produced in mitochondrial matrix and/or cytosolic compartments. As their existence has been predicted by the chemiosmotic theory, the first challenge, in the late sixties, was to prove their presence in the inner mitochondrial membrane and to describe the various transports carried out. The second challenge was to understand their mechanisms by the kinetic approach in intact mitochondria (seventies). The third challenge (late seventies-eighties) was to isolate and to reconstitute the carriers in liposomes in order to characterize the proteins and to establish the concept of a structural and a functional family as well as some structure-function relationship with the help of primary sequences. Genetics, molecular biology and genomic sequencing bring the fourth challenge (nineties): a raising number of putative carriers becomes known only by their primary sequences but their functions have to be discovered. The actual challenge of the future is the elucidation of the ternary structure of carrier proteins that together with site-directed mutagenesis and kinetic mechanism will permit to advance in the understanding of molecular mechanisms of transport processes.

scholarly journals SLC54 Mitochondrial pyruvate carriers (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

2020 ◽  
Vol 2020 (5) ◽  
Author(s):  
Calum Wilson
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Mitochondrial Membrane ◽  
Family Members ◽  
Embryonic Lethality ◽  
Mitochondrial Matrix ◽  
Inner Mitochondrial Membrane ◽  
Acetyl Coa ◽  
Insulin Sensitizers ◽  
Mitochondrial Pyruvate Carrier

Pyruvate is oxidized to acetyl‐CoA by pyruvate dehydrogenase which is localized in the mitochondrial matrix. The mitochondrial pyruvate carrier (MPC) is a hetero-oligomer composed of SLC54 family members (MPC1 and MPC2). The MPC is expressed in the inner mitochondrial membrane and involved in the import of pyruvate into mitochondria [1, 5]. Ubiquitous disruption of either MPC1 or MPC2 expression results in embryonic lethality [7, 8]. Clinically relevant concentrations of the insulin sensitizers, thiazolidinediones, specifically inhibit the MPC [3].

scholarly journals Single-cell phenomics in budding yeast

2015 ◽  
Vol 26 (22) ◽  
pp. 3920-3925 ◽  
Author(s):  
Yoshikazu Ohya ◽  
Yoshitaka Kimori ◽  
Hiroki Okada ◽  
Shinsuke Ohnuki
Keyword(s):  
Cell Imaging ◽  
Budding Yeast ◽  
Model Organism ◽  
Eukaryotic Cells ◽  
High Dimensional ◽  
Biological Knowledge ◽  
Yeast Saccharomyces Cerevisiae ◽  
Cellular Processes ◽  
Designed Experiment ◽  
High Throughput Phenotyping

The demand for phenomics, a high-dimensional and high-throughput phenotyping method, has been increasing in many fields of biology. The budding yeast Saccharomyces cerevisiae, a unicellular model organism, provides an invaluable system for dissecting complex cellular processes using high-resolution phenotyping. Moreover, the addition of spatial and temporal attributes to subcellular structures based on microscopic images has rendered this cell phenotyping system more reliable and amenable to analysis. A well-designed experiment followed by appropriate multivariate analysis can yield a wealth of biological knowledge. Here we review recent advances in cell imaging and illustrate their broad applicability to eukaryotic cells by showing how these techniques have advanced our understanding of budding yeast.

scholarly journals Hypoxia-inducible gene domain 1 proteins in yeast mitochondria protect against proton leak through complex IV

2019 ◽  
Vol 294 (46) ◽  
pp. 17669-17677 ◽  
Author(s):  
Ngoc H. Hoang ◽  
Vera Strogolova ◽  
Jaramys J. Mosley ◽  
Rosemary A. Stuart ◽  
Jonathan Hosler
Keyword(s):  
Mitochondrial Membrane ◽  
Model Organism ◽  
Proton Pumping ◽  
Integral Membrane Proteins ◽  
Complex Iii ◽  
Proton Leak ◽  
Yeast Mitochondria ◽  
Inner Mitochondrial Membrane ◽  
Complex Iv ◽  
Inducible Gene

Hypoxia-inducible gene domain 1 (HIGD1) proteins are small integral membrane proteins, conserved from bacteria to humans, that associate with oxidative phosphorylation supercomplexes. Using yeast as a model organism, we have shown previously that its two HIGD1 proteins, Rcf1 and Rcf2, are required for the generation and maintenance of a normal membrane potential (ΔΨ) across the inner mitochondrial membrane (IMM). We postulated that the lower ΔΨ observed in the absence of the HIGD1 proteins may be due to decreased proton pumping by complex IV (CIV) or enhanced leak of protons across the IMM. Here we measured the ΔΨ generated by complex III (CIII) to discriminate between these possibilities. First, we found that the decreased ΔΨ observed in the absence of the HIGD1 proteins cannot be due to decreased proton pumping by CIV because CIII, operating alone, also exhibited a decreased ΔΨ when HIGD1 proteins were absent. Because CIII can neither lower its pumping stoichiometry nor transfer protons completely across the IMM, this result indicates that HIGD1 protein ablation enhances proton leak across the IMM. Second, we demonstrate that this proton leak occurs through CIV because ΔΨ generation by CIII is restored when CIV is removed from the cell. Third, the proton leak appeared to take place through an inactive population of CIV that accumulates when HIGD1 proteins are absent. We conclude that HIGD1 proteins in yeast prevent CIV inactivation, likely by preventing the loss of lipids bound within the Cox3 protein of CIV.

scholarly journals Drosophila as a Model Organism to Understand the Effects during Development of TFIIH-Related Human Diseases

2020 ◽  
Vol 21 (2) ◽  
pp. 630 ◽  
Author(s):  
Mario Zurita ◽  
Juan Manuel Murillo-Maldonado
Keyword(s):  
Cell Death ◽  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Xeroderma Pigmentosum ◽  
Excision Repair ◽  
Model Organism ◽  
Human Diseases ◽  
Eukaryotic Cells ◽  
Developmental Processes ◽  
Nucleotide Excision

Human mutations in the transcription and nucleotide excision repair (NER) factor TFIIH are linked with three human syndromes: xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS). In particular, different mutations in the XPB, XPD and p8 subunits of TFIIH may cause one or a combination of these syndromes, and some of these mutations are also related to cancer. The participation of TFIIH in NER and transcription makes it difficult to interpret the different manifestations observed in patients, particularly since some of these phenotypes may be related to problems during development. TFIIH is present in all eukaryotic cells, and its functions in transcription and DNA repair are conserved. Therefore, Drosophila has been a useful model organism for the interpretation of different phenotypes during development as well as the understanding of the dynamics of this complex. Interestingly, phenotypes similar to those observed in humans caused by mutations in the TFIIH subunits are present in mutant flies, allowing the study of TFIIH in different developmental processes. Furthermore, studies performed in Drosophila of mutations in different subunits of TFIIH that have not been linked to any human diseases, probably because they are more deleterious, have revealed its roles in differentiation and cell death. In this review, different achievements made through studies in the fly to understand the functions of TFIIH during development and its relationship with human diseases are analysed and discussed.

scholarly journals Mitochondrial Cristae Architecture and Functions: Lessons from Minimal Model Systems

Membranes ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 465
Author(s):  
Frédéric Joubert ◽  
Nicolas Puff
Keyword(s):  
Minimal Model ◽  
Mitochondrial Membrane ◽  
Energy Production ◽  
Lipid Membrane ◽  
Model Systems ◽  
Eukaryotic Cells ◽  
Membrane Composition ◽  
Inner Mitochondrial Membrane ◽  
Dynamic Membrane

Mitochondria are known as the powerhouse of eukaryotic cells. Energy production occurs in specific dynamic membrane invaginations in the inner mitochondrial membrane called cristae. Although the integrity of these structures is recognized as a key point for proper mitochondrial function, less is known about the mechanisms at the origin of their plasticity and organization, and how they can influence mitochondria function. Here, we review the studies which question the role of lipid membrane composition based mainly on minimal model systems.

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.

Structure and function of Pet100p, a molecular chaperone required for the assembly of cytochrome c oxidase in Saccharomyces cerevisiae

2001 ◽  
Vol 29 (4) ◽  
pp. 436-441 ◽  
Author(s):  
D. Forsha ◽  
C. Church ◽  
P. Wazny ◽  
R. O. Poyton
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Molecular Chaperone ◽  
Mitochondrial Membrane ◽  
Protein Complexes ◽  
Structure And Function ◽  
Eukaryotic Cells ◽  
Mitochondrial Membranes ◽  
Inner Mitochondrial Membrane ◽  
And Function

The assembly of cytochrome c oxidase in the inner mitochondrial membranes of eukaryotic cells requires the protein products of a large number of nuclear genes. In yeast, some of these act globally and affect the assembly of several respiratory-chain protein complexes, whereas others act in a cytochrome c oxidase-specific fashion. Many of these yeast proteins have human counterparts, which when mutated lead to energy-related diseases. One of these proteins, Pet100p, is a novel molecular chaperone that functions to incorporate a subcomplex containing cytochrome c oxidase subunits VII, VIIa and VIII into holo-(cytochrome c oxidase). Here we report the topological disposition of Pet100p in the inner mitochondrial membrane and show that its C-terminal domain is essential for its function as a cytochrome c oxidase-specific ‘assembly facilitator’.

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