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Mitochondrial Research: Yeast and Human Cells as Models 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (25 November 2023) | Viewed by 12423

Special Issue Editors


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Guest Editor
Institute of Biomembrane, Bioenergetics and Molecular Biotechnologies, National Research Council of Italy, Via Amendola 122/O, 70126 Bari, Italy
Interests: yeast; mitochondria; cell death; cancer; drug discovery
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Guest Editor
Faculty of Medicine, Scientific Research Center, University of Montenegro, Kruševac bb, 81000 Podgorica, Montenegro
Interests: cancer metabolism; mitochondria; cell signalling

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Guest Editor
CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), 70126 Bari, Italy
Interests: mitochondrial proteome in aging; muscle unloading; cancer; mitochondrial biogenesis; mitochondrial antioxidant proteins; mitochondrial DNA-binding proteins; mitochondrial dynamics; metabolomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue "Mitochondrial Research: Yeast and Human Cells as Models".

It has been over twenty years since cytochrome c release from mitochondria was revealed as a key step in the initiation of apoptotic cell death, and since then, mitochondrial research has experienced a tremendous boost. Researchers have amassed a growing wealth of knowledge that recognizes the central role of these organelles in the maintenance of eukaryotic cell homeostasis. This role is not restricted to the generation of intermediary metabolites and ATP production through the tricarboxylic acid cycle and oxidative phosphorylation. Not only can mitochondria synthesize fundamental molecules, such as heme and iron–sulfur clusters, but they are also major sites of amino acid, nucleotide, and fatty acid metabolism, and can receive, integrate, and relay intracellular signals.

Mitochondrial biogenesis and functions are under tight nuclear control through the so-called anterograde regulation of gene expression. This involves signaling pathways that coordinate gene transcription to tune finely metabolic requirements with nutritional and environmental cues. On the other hand, environmental changes trigger intracellular stress responses, which may disturb mitochondrial structure and/or function. To maintain cell homeostasis, damaged mitochondria relay signals through retrograde, instead of to anterograde, communication pathways that drive specific nuclear gene-transcription patterns in response to stress. Recent advances, made primarily in budding yeast, have provided novel insights into the existence of distinct microdomains between intracellular organelles, known as membrane contact sites, that coordinate diverse activities, including mitochondrial dynamics and cell-stress signaling pathways. Finally, it is becoming increasingly clear that mitochondrial and cytosolic proteostasis are intimately related.

In view of this, and following the discovery of pathogenic mitochondrial DNA defects in the 1980s, mitochondrial dysfunction is now recognized as a common factor underlying many pathological conditions. Many of these advancements would not have been possible without the model organism Saccharomyces cerevisiae and human cell lines. This Special Issue will present and discuss achievements and perspectives in the research on the multiple pathways of crosstalk between mitochondria and other cell organelles and components in the form of research or review articles. At the cutting edge of cell biology research, the results of these studies will lay the foundations for the elucidation of mitochondrial physiology at a systems biology level.

Prof. Dr. Sergio Giannattasio
Dr. Maša Ždralević
Dr. Clara Musicco
Guest Editors

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Keywords

  • mitochondria
  • OXPHOS
  • mtDNA
  • energy metabolism
  • ROS
  • interorganelle communication
  • proteostasis
  • mitochondrial dynamics
  • contact sites
  • yeast
  • human cell lines

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Published Papers (7 papers)

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Editorial

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3 pages, 162 KiB  
Editorial
Editorial: Mitochondrial Research: Yeast and Human Cells as Models 2.0
by Maša Ždralević, Clara Musicco and Sergio Giannattasio
Int. J. Mol. Sci. 2024, 25(12), 6344; https://doi.org/10.3390/ijms25126344 - 8 Jun 2024
Viewed by 610
Abstract
Mitochondrial research stands at the forefront of modern biology, unraveling the intricate mechanisms governing cellular metabolism, energy production, and disease pathogenesis [...] Full article
(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models 2.0)

Research

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12 pages, 1239 KiB  
Article
Mitochondrial Protein SLIRP Affects Biosynthesis of Cytochrome c Oxidase Subunits in HEK293T Cells
by Mariia V. Baleva, Uliana Piunova, Ivan Chicherin, Ruslan Vasilev, Sergey Levitskii and Piotr Kamenski
Int. J. Mol. Sci. 2024, 25(1), 93; https://doi.org/10.3390/ijms25010093 - 20 Dec 2023
Viewed by 1337
Abstract
Mitochondria carry out various vital roles in eukaryotic cells, including ATP energy synthesis, the regulation of apoptosis, Fe-S cluster formation, and the metabolism of fatty acids, amino acids, and nucleotides. Throughout evolution, mitochondria lost most of their ancestor’s genome but kept the replication, [...] Read more.
Mitochondria carry out various vital roles in eukaryotic cells, including ATP energy synthesis, the regulation of apoptosis, Fe-S cluster formation, and the metabolism of fatty acids, amino acids, and nucleotides. Throughout evolution, mitochondria lost most of their ancestor’s genome but kept the replication, transcription, and translation machinery. Protein biosynthesis in mitochondria is specialized in the production of highly hydrophobic proteins encoded by mitochondria. These proteins are components of oxidative phosphorylation chain complexes. The coordination of protein synthesis must be precise to ensure the correct assembly of nuclear-encoded subunits for these complexes. However, the regulatory mechanisms of mitochondrial translation in human cells are not yet fully understood. In this study, we examined the contribution of the SLIRP protein in regulating protein biosynthesis in mitochondria. Using a click-chemistry approach, we discovered that deletion of the SLIRP gene disturbs mitochondrial translation, leading to the dysfunction of complexes I and IV, but it has no significant effect on complexes III and V. We have shown that this protein interacts only with the small subunit of the mitochondrial ribosome, which may indicate its involvement in the regulation of the mitochondrial translation initiation stage. Full article
(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models 2.0)
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15 pages, 10536 KiB  
Article
Carnation Italian Ringspot Virus p36 Expression Induces Mitochondrial Fission and Respiratory Chain Complex Impairment in Yeast
by Giuseppe Petrosillo, Angelo De Stradis, Domenico Marzulli, Luisa Rubino and Sergio Giannattasio
Int. J. Mol. Sci. 2023, 24(22), 16166; https://doi.org/10.3390/ijms242216166 - 10 Nov 2023
Viewed by 1022
Abstract
Positive-strand RNA virus replication invariably occurs in association with host cell membranes, which are induced to proliferate and rearrange to form vesicular structures where the virus replication complex is assembled. In particular, carnation Italian ringspot virus (CIRV) replication takes place on the mitochondrial [...] Read more.
Positive-strand RNA virus replication invariably occurs in association with host cell membranes, which are induced to proliferate and rearrange to form vesicular structures where the virus replication complex is assembled. In particular, carnation Italian ringspot virus (CIRV) replication takes place on the mitochondrial outer membrane in plant and yeast cells. In this work, the model host Saccharomyces cerevisiae was used to investigate the effects of CIRV p36 expression on the mitochondrial structure and function through the determination of mitochondrial morphology, mitochondrial respiratory parameters, and respiratory chain complex activities in p36-expressing cells. CIRV p36 ectopic expression was shown to induce alterations in the mitochondrial network associated with a decrease in mitochondrial respiration and the activities of NADH–cyt c, succinate–cyt c (C II-III), and cytochrome c oxidase (C IV) complexes. Our results suggest that the decrease in respiratory complex activity could be due, at least in part, to alterations in mitochondrial dynamics. This yeast-based model will be a valuable tool for identifying molecular targets to develop new anti-viral strategies. Full article
(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models 2.0)
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10 pages, 3270 KiB  
Article
Yeast Bax Inhibitor (Bxi1p/Ybh3p) Is Not Required for the Action of Bcl-2 Family Proteins on Cell Viability
by Marek Mentel, Miroslava Illová, Veronika Krajčovičová, Gabriela Kroupová, Zuzana Mannová, Petra Chovančíková and Peter Polčic
Int. J. Mol. Sci. 2023, 24(15), 12011; https://doi.org/10.3390/ijms241512011 - 27 Jul 2023
Cited by 2 | Viewed by 1410
Abstract
Permeabilization of mitochondrial membrane by proteins of the BCL-2 family is a key decisive event in the induction of apoptosis in mammalian cells. Although yeast does not have homologs of the BCL-2 family, when these are expressed in yeast, they modulate the survival [...] Read more.
Permeabilization of mitochondrial membrane by proteins of the BCL-2 family is a key decisive event in the induction of apoptosis in mammalian cells. Although yeast does not have homologs of the BCL-2 family, when these are expressed in yeast, they modulate the survival of cells in a way that corresponds to their activity in mammalian cells. The yeast gene, alternatively referred to as BXI1 or YBH3, encodes for membrane protein in the endoplasmic reticulum that was, contradictorily, shown to either inhibit Bax or to be required for Bax activity. We have tested the effect of the deletion of this gene on the pro-apoptotic activity of Bax and Bak and the anti-apoptotic activity of Bcl-XL and Bcl-2, as well on survival after treatment with inducers of regulated cell death in yeast, hydrogen peroxide and acetic acid. While deletion resulted in increased sensitivity to acetic acid, it did not affect the sensitivity to hydrogen peroxide nor to BCL-2 family members. Thus, our results do not support any model in which the activity of BCL-2 family members is directly affected by BXI1 but rather indicate that it may participate in modulating survival in response to some specific forms of stress. Full article
(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models 2.0)
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22 pages, 5655 KiB  
Article
Cell-Based Measurement of Mitochondrial Function in Human Airway Smooth Muscle Cells
by Sanjana Mahadev Bhat, Jane Q. Yap, Oscar A. Ramirez-Ramirez, Philippe Delmotte and Gary C. Sieck
Int. J. Mol. Sci. 2023, 24(14), 11506; https://doi.org/10.3390/ijms241411506 - 15 Jul 2023
Cited by 1 | Viewed by 3819
Abstract
Cellular mitochondrial function can be assessed using high-resolution respirometry that measures the O2 consumption rate (OCR) across a number of cells. However, a direct measurement of cellular mitochondrial function provides valuable information and physiological insight. In the present study, we used a [...] Read more.
Cellular mitochondrial function can be assessed using high-resolution respirometry that measures the O2 consumption rate (OCR) across a number of cells. However, a direct measurement of cellular mitochondrial function provides valuable information and physiological insight. In the present study, we used a quantitative histochemical technique to measure the activity of succinate dehydrogenase (SDH), a key enzyme located in the inner mitochondrial membrane, which participates in both the tricarboxylic acid (TCA) cycle and electron transport chain (ETC) as Complex II. In this study, we determine the maximum velocity of the SDH reaction (SDHmax) in individual human airway smooth muscle (hASM) cells. To measure SDHmax, hASM cells were exposed to a solution containing 80 mM succinate and 1.5 mM nitroblue tetrazolium (NBT, reaction indicator). As the reaction proceeded, the change in optical density (OD) due to the reduction of NBT to its diformazan (peak absorbance wavelength of 570 nm) was measured using a confocal microscope with the pathlength for light absorbance tightly controlled. SDHmax was determined during the linear period of the SDH reaction and expressed as mmol fumarate/liter of cell/min. We determine that this technique is rigorous and reproducible, and reliable for the measurement of mitochondrial function in individual cells. Full article
(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models 2.0)
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16 pages, 3144 KiB  
Article
The APC/C Activator Cdh1p Plays a Role in Mitochondrial Metabolic Remodelling in Yeast
by Ana Cláudia Leite, Maria Barbedo, Vítor Costa and Clara Pereira
Int. J. Mol. Sci. 2023, 24(4), 4111; https://doi.org/10.3390/ijms24044111 - 18 Feb 2023
Viewed by 1992
Abstract
Cdh1p is one of the two substrate adaptor proteins of the anaphase promoting complex/cyclosome (APC/C), a ubiquitin ligase that regulates proteolysis during cell cycle. In this work, using a proteomic approach, we found 135 mitochondrial proteins whose abundance was significantly altered in the [...] Read more.
Cdh1p is one of the two substrate adaptor proteins of the anaphase promoting complex/cyclosome (APC/C), a ubiquitin ligase that regulates proteolysis during cell cycle. In this work, using a proteomic approach, we found 135 mitochondrial proteins whose abundance was significantly altered in the cdh1Δ mutant, with 43 up-regulated proteins and 92 down-regulated proteins. The group of significantly up-regulated proteins included subunits of the mitochondrial respiratory chain, enzymes from the tricarboxylic acid cycle and regulators of mitochondrial organization, suggesting a metabolic remodelling towards an increase in mitochondrial respiration. In accordance, mitochondrial oxygen consumption and Cytochrome c oxidase activity increased in Cdh1p-deficient cells. These effects seem to be mediated by the transcriptional activator Yap1p, a major regulator of the yeast oxidative stress response. YAP1 deletion suppressed the increased Cyc1p levels and mitochondrial respiration in cdh1Δ cells. In agreement, Yap1p is transcriptionally more active in cdh1Δ cells and responsible for the higher oxidative stress tolerance of cdh1Δ mutant cells. Overall, our results unveil a new role for APC/C-Cdh1p in the regulation of the mitochondrial metabolic remodelling through Yap1p activity. Full article
(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models 2.0)
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Review

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20 pages, 1267 KiB  
Review
Human mtDNA-Encoded Long ncRNAs: Knotty Molecules and Complex Functions
by Francesco Bruni
Int. J. Mol. Sci. 2024, 25(3), 1502; https://doi.org/10.3390/ijms25031502 - 25 Jan 2024
Cited by 1 | Viewed by 1481
Abstract
Until a few decades ago, most of our knowledge of RNA transcription products was focused on protein-coding sequences, which were later determined to make up the smallest portion of the mammalian genome. Since 2002, we have learnt a great deal about the intriguing [...] Read more.
Until a few decades ago, most of our knowledge of RNA transcription products was focused on protein-coding sequences, which were later determined to make up the smallest portion of the mammalian genome. Since 2002, we have learnt a great deal about the intriguing world of non-coding RNAs (ncRNAs), mainly due to the rapid development of bioinformatic tools and next-generation sequencing (NGS) platforms. Moreover, interest in non-human ncRNAs and their functions has increased as a result of these technologies and the accessibility of complete genome sequences of species ranging from Archaea to primates. Despite not producing proteins, ncRNAs constitute a vast family of RNA molecules that serve a number of regulatory roles and are essential for cellular physiology and pathology. This review focuses on a subgroup of human ncRNAs, namely mtDNA-encoded long non-coding RNAs (mt-lncRNAs), which are transcribed from the mitochondrial genome and whose disparate localisations and functions are linked as much to mitochondrial metabolism as to cellular physiology and pathology. Full article
(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models 2.0)
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