International Journal of Molecular Sciences

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Open AccessEditorial

Mitochondrial Research: Yeast and Human Cells as Models

by Maša Ždralević and Sergio Giannattasio

Int. J. Mol. Sci. 2022, 23(12), 6654; https://doi.org/10.3390/ijms23126654 - 15 Jun 2022

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Abstract

The evolution of complex eukaryotes would have been impossible without mitochondria, key cell organelles responsible for the oxidative metabolism of sugars and the bulk of ATP production [...] Full article

(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models)

Research

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16 pages, 4506 KiB

Open AccessArticle

Mitochondrial Retrograde Signaling Contributes to Metabolic Differentiation in Yeast Colonies

by Vítězslav Plocek, Kristýna Fadrhonc, Jana Maršíková, Libuše Váchová, Alexandra Pokorná, Otakar Hlaváček, Derek Wilkinson and Zdena Palková

Int. J. Mol. Sci. 2021, 22(11), 5597; https://doi.org/10.3390/ijms22115597 - 25 May 2021

Cited by 6 | Viewed by 2895

Abstract

During development of yeast colonies, various cell subpopulations form, which differ in their properties and specifically localize within the structure. Three branches of mitochondrial retrograde (RTG) signaling play a role in colony development and differentiation, each of them activating the production of specific [...] Read more.

During development of yeast colonies, various cell subpopulations form, which differ in their properties and specifically localize within the structure. Three branches of mitochondrial retrograde (RTG) signaling play a role in colony development and differentiation, each of them activating the production of specific markers in different cell types. Here, aiming to identify proteins and processes controlled by the RTG pathway, we analyzed proteomes of individual cell subpopulations from colonies of strains, mutated in genes of the RTG pathway. Resulting data, along with microscopic analyses revealed that the RTG pathway predominantly regulates processes in U cells, long-lived cells with unique properties, which are localized in upper colony regions. Rtg proteins therein activate processes leading to amino acid biosynthesis, including transport of metabolic intermediates between compartments, but also repress expression of mitochondrial ribosome components, thus possibly contributing to reduced mitochondrial translation in U cells. The results reveal the RTG pathway’s role in activating metabolic processes, important in U cell adaptation to altered nutritional conditions. They also point to the important role of Rtg regulators in repressing mitochondrial activity in U cells. Full article

(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models)

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11 pages, 2865 KiB

Open AccessArticle

A Crucial Role of Mitochondrial Dynamics in Dehydration Resistance in Saccharomyces cerevisiae

by Chang-Lin Chen, Ying-Chieh Chen, Wei-Ling Huang, Steven Lin, Rimantas Daugelavičius, Alexander Rapoport and Chuang-Rung Chang

Int. J. Mol. Sci. 2021, 22(9), 4607; https://doi.org/10.3390/ijms22094607 - 27 Apr 2021

Cited by 6 | Viewed by 3189

Abstract

Mitochondria are dynamic organelles as they continuously undergo fission and fusion. These dynamic processes conduct not only mitochondrial network morphology but also activity regulation and quality control. Saccharomyces cerevisiae has a remarkable capacity to resist stress from dehydration/rehydration. Although mitochondria are noted for [...] Read more.

Mitochondria are dynamic organelles as they continuously undergo fission and fusion. These dynamic processes conduct not only mitochondrial network morphology but also activity regulation and quality control. Saccharomyces cerevisiae has a remarkable capacity to resist stress from dehydration/rehydration. Although mitochondria are noted for their role in desiccation tolerance, the mechanisms underlying these processes remains obscure. Here, we report that yeast cells that went through stationary growth phase have a better survival rate after dehydration/rehydration. Dynamic defective yeast cells with reduced mitochondrial genome cannot maintain the mitochondrial activity and survival rate of wild type cells. Our results demonstrate that yeast cells balance mitochondrial fusion and fission according to growth conditions, and the ability to adjust dynamic behavior aids the dehydration resistance by preserving mitochondria. Full article

(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models)

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17 pages, 1798 KiB

Open AccessArticle

A Yeast-Based Screening Unravels Potential Therapeutic Molecules for Mitochondrial Diseases Associated with Dominant ANT1 Mutations

by Giulia di Punzio, Maria Antonietta Di Noia, Agnès Delahodde, Carole Sellem, Claudia Donnini, Luigi Palmieri, Tiziana Lodi and Cristina Dallabona

Int. J. Mol. Sci. 2021, 22(9), 4461; https://doi.org/10.3390/ijms22094461 - 24 Apr 2021

Cited by 10 | Viewed by 2911

Abstract

Mitochondrial diseases result from inherited or spontaneous mutations in mitochondrial or nuclear DNA, leading to an impairment of the oxidative phosphorylation responsible for the synthesis of ATP. To date, there are no effective pharmacological therapies for these pathologies. We performed a yeast-based screening [...] Read more.

Mitochondrial diseases result from inherited or spontaneous mutations in mitochondrial or nuclear DNA, leading to an impairment of the oxidative phosphorylation responsible for the synthesis of ATP. To date, there are no effective pharmacological therapies for these pathologies. We performed a yeast-based screening to search for therapeutic drugs to be used for treating mitochondrial diseases associated with dominant mutations in the nuclear ANT1 gene, which encodes for the mitochondrial ADP/ATP carrier. Dominant ANT1 mutations are involved in several degenerative mitochondrial pathologies characterized by the presence of multiple deletions or depletion of mitochondrial DNA in tissues of affected patients. Thanks to the presence in yeast of the AAC2 gene, orthologue of human ANT1, a yeast mutant strain carrying the M114P substitution equivalent to adPEO-associated L98P mutation was created. Five molecules were identified for their ability to suppress the defective respiratory growth phenotype of the haploid aac2^M114P. Furthermore, these molecules rescued the mtDNA mutability in the heteroallelic AAC2/aac2^M114P strain, which mimics the human heterozygous condition of adPEO patients. The drugs were effective in reducing mtDNA instability also in the heteroallelic strain carrying the R96H mutation equivalent to the more severe de novo dominant missense mutation R80H, suggesting a general therapeutic effect on diseases associated with dominant ANT1 mutations. Full article

(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models)

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10 pages, 5250 KiB

Open AccessArticle

Bisindolylpyrrole Induces a Cpr3- and Porin1/2-Dependent Transition in Yeast Mitochondrial Permeability in a Low Conductance State via the AACs-Associated Pore

by Masami Koushi and Rei Asakai

Int. J. Mol. Sci. 2021, 22(3), 1212; https://doi.org/10.3390/ijms22031212 - 26 Jan 2021

Cited by 1 | Viewed by 2226

Abstract

Although the mitochondrial permeability transition pore (PTP) is presumably formed by either ATP synthase or the ATP/ADP carrier (AAC), little is known about their differential roles in PTP activation. We explored the role of AAC and ATP synthase in PTP formation in Saccharomyces [...] Read more.

Although the mitochondrial permeability transition pore (PTP) is presumably formed by either ATP synthase or the ATP/ADP carrier (AAC), little is known about their differential roles in PTP activation. We explored the role of AAC and ATP synthase in PTP formation in Saccharomyces cerevisiae using bisindolylpyrrole (BP), an activator of the mammalian PTP. The yeast mitochondrial membrane potential, as indicated by tetramethylrhodamine methyl ester signals, dissipated over 2–4 h after treatment of cells with 5 μM BP, which was sensitive to cyclosporin A (CsA) and Cpr3 deficiency and blocked by porin1/2 deficiency. The BP-induced depolarization was inhibited by a specific AAC inhibitor, bongkrekate, and consistently blocked in a yeast strain lacking all three AACs, while it was not affected in the strain with defective ATP synthase dimerization, suggesting the involvement of an AAC-associated pore. Upon BP treatment, isolated yeast mitochondria underwent CsA- and bongkrekate-sensitive depolarization without affecting the mitochondrial calcein signals, indicating the induction of a low conductance channel. These data suggest that, upon BP treatment, yeast can form a porin1/2- and Cpr3-regulated PTP, which is mediated by AACs but not by ATP synthase dimers. This implies that yeast may be an excellent tool for the screening of PTP modulators. Full article

(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models)

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Review

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18 pages, 349 KiB

Open AccessReview

Mitochondrial Aminoacyl-tRNA Synthetase and Disease: The Yeast Contribution for Functional Analysis of Novel Variants

by Sonia Figuccia, Andrea Degiorgi, Camilla Ceccatelli Berti, Enrico Baruffini, Cristina Dallabona and Paola Goffrini

Int. J. Mol. Sci. 2021, 22(9), 4524; https://doi.org/10.3390/ijms22094524 - 26 Apr 2021

Cited by 14 | Viewed by 3791

Abstract

In most eukaryotes, mitochondrial protein synthesis is essential for oxidative phosphorylation (OXPHOS) as some subunits of the respiratory chain complexes are encoded by the mitochondrial DNA (mtDNA). Mutations affecting the mitochondrial translation apparatus have been identified as a major cause of mitochondrial diseases. [...] Read more.

In most eukaryotes, mitochondrial protein synthesis is essential for oxidative phosphorylation (OXPHOS) as some subunits of the respiratory chain complexes are encoded by the mitochondrial DNA (mtDNA). Mutations affecting the mitochondrial translation apparatus have been identified as a major cause of mitochondrial diseases. These mutations include either heteroplasmic mtDNA mutations in genes encoding for the mitochondrial rRNA (mtrRNA) and tRNAs (mttRNAs) or mutations in nuclear genes encoding ribosomal proteins, initiation, elongation and termination factors, tRNA-modifying enzymes, and aminoacyl-tRNA synthetases (mtARSs). Aminoacyl-tRNA synthetases (ARSs) catalyze the attachment of specific amino acids to their cognate tRNAs. Differently from most mttRNAs, which are encoded by mitochondrial genome, mtARSs are encoded by nuclear genes and then imported into the mitochondria after translation in the cytosol. Due to the extensive use of next-generation sequencing (NGS), an increasing number of mtARSs variants associated with large clinical heterogeneity have been identified in recent years. Being most of these variants private or sporadic, it is crucial to assess their causative role in the disease by functional analysis in model systems. This review will focus on the contributions of the yeast Saccharomyces cerevisiae in the functional validation of mutations found in mtARSs genes associated with human disorders. Full article

(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models)

22 pages, 3531 KiB

Open AccessReview

Common Principles and Specific Mechanisms of Mitophagy from Yeast to Humans

by Rajesh Kumar and Andreas S. Reichert

Int. J. Mol. Sci. 2021, 22(9), 4363; https://doi.org/10.3390/ijms22094363 - 22 Apr 2021

Cited by 23 | Viewed by 6912

Abstract

Mitochondria are double membrane-bound organelles in eukaryotic cells essential to a variety of cellular functions including energy conversion and ATP production, iron-sulfur biogenesis, lipid and amino acid metabolism, and regulating apoptosis and stress responses. Mitochondrial dysfunction is mechanistically linked to several neurodegenerative diseases, [...] Read more.

Mitochondria are double membrane-bound organelles in eukaryotic cells essential to a variety of cellular functions including energy conversion and ATP production, iron-sulfur biogenesis, lipid and amino acid metabolism, and regulating apoptosis and stress responses. Mitochondrial dysfunction is mechanistically linked to several neurodegenerative diseases, cancer, and ageing. Excessive and dysfunctional/damaged mitochondria are degraded by selective autophagic pathways known as mitophagy. Both budding yeast and mammals use the well-conserved machinery of core autophagy-related genes (ATGs) to execute and regulate mitophagy. In mammalian cells, the PINK1-PARKIN mitophagy pathway is a well-studied pathway that senses dysfunctional mitochondria and marks them for degradation in the lysosome. PINK1-PARKIN mediated mitophagy relies on ubiquitin-binding mitophagy adaptors that are non-ATG proteins. Loss-of-function mutations in PINK1 and PARKIN are linked to Parkinson´s disease (PD) in humans, and defective mitophagy is proposed to be a main pathomechanism. Despite the common view that yeast cells lack PINK1- and PARKIN-homologs and that mitophagy in yeast is solely regulated by receptor-mediated mitophagy, some studies suggest that a ubiquitination-dependent mitophagy pathway also exists. Here, we will discuss shared mechanisms between mammals and yeast, how mitophagy in the latter is regulated in a ubiquitin-dependent and -independent manner, and why these pathways are essential for yeast cell survival and fitness under various physiological stress conditions. Full article

(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models)

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17 pages, 1626 KiB

Open AccessReview

Contribution of Yeast Studies to the Understanding of BCL-2 Family Intracellular Trafficking

by Akandé Rouchidane Eyitayo, Mathilde Gonin, Hubert Arokium and Stéphen Manon

Int. J. Mol. Sci. 2021, 22(8), 4086; https://doi.org/10.3390/ijms22084086 - 15 Apr 2021

Cited by 5 | Viewed by 2318

Abstract

BCL-2 family members are major regulators of apoptotic cell death in mammals. They form an intricate regulatory network that ultimately regulates the release of apoptogenic factors from mitochondria to the cytosol. The ectopic expression of mammalian BCL-2 family members in the yeast Saccharomyces [...] Read more.

BCL-2 family members are major regulators of apoptotic cell death in mammals. They form an intricate regulatory network that ultimately regulates the release of apoptogenic factors from mitochondria to the cytosol. The ectopic expression of mammalian BCL-2 family members in the yeast Saccharomyces cerevisiae, which lacks BCL-2 homologs, has been long established as a useful addition to the available models to study their function and regulation. In yeast, individual proteins can be studied independently from the whole interaction network, thus providing insight into the molecular mechanisms underlying their function in a living context. Furthermore, one can take advantage of the powerful tools available in yeast to probe intracellular trafficking processes such as mitochondrial sorting and interactions/exchanges between mitochondria and other compartments, such as the endoplasmic reticulum that are largely conserved between yeast and mammals. Yeast molecular genetics thus allows the investigation of the role of these processes on the dynamic equilibrium of BCL-2 family members between mitochondria and extramitochondrial compartments. Here we propose a model of dynamic regulation of BCL-2 family member localization, based on available evidence from ectopic expression in yeast. Full article

(This article belongs to the Special Issue Mitochondrial Research: Yeast and Human Cells as Models)

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