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Mitochondrial Dysfunctions and Metabolisms
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Mitochondrial Dysfunctions and Metabolisms

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

Deadline for manuscript submissions: 31 August 2024 | Viewed by 4796

Special Issue Editor

Dr. Paola Costantini

E-Mail Website
Guest Editor
Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy
Interests: mitochondrial diseases caused by FeS-clusters deficiency; neurodegenerative disease; Friedreich ataxia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the last 30 years, significant advances have been achieved towards the elucidation of the mechanistic aspects of mitochondrial diseases, a heterogeneous group of inherited metabolic disorders characterized by defective ATP production through oxidative phosphorylation. While each of them is rare, taken together, their prevalence has been estimated to be 5–15 individuals per 100,000 at birth and 3–10 per 100,000 adults. They are caused by mutations in both mitochondrial- and nuclear-gene-encoding proteins with a wide variety of functions, ranging from structural subunits and/or assembly factors of respiratory complexes to biosynthesis of prosthetic groups, clearance of toxic compounds, protein quality control and degradation, mitochondrial fusion and fission, and several others. It is therefore not surprising that mitochondrial diseases have an impact, either directly or indirectly, on the overall metabolism, especially in high-energy-demanding cells, such as neurons and cardiomyocytes. Many issues are still open, and the treatment of patients remains a challenge.

This Special Issue is calling for both original articles and reviews providing insights into the molecular mechanisms leading to metabolic dysfunctions afflicting patients with mitochondrial disorders, and into pharmacological strategies to fight them.

Dr. Paola Costantini
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mitochondrial diseases
  • OXPHOS deficiency
  • electron transfer chain defects
  • biosynthesis of redox cofactors
  • oxidative stress
  • mitochondrial biogenesis
  • mitochondrial shape and dynamics
  • mitochondrial iron metabolism
  • translation into the clinic
  • drug strategies

Published Papers (5 papers)

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Research

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18 pages, 3681 KiB  
Article
Searching for Frataxin Function: Exploring the Analogy with Nqo15, the Frataxin-like Protein of Respiratory Complex I from Thermus thermophilus
by Davide Doni, Eva Cavallari, Martin Ezequiel Noguera, Hernan Gustavo Gentili, Federica Cavion, Gustavo Parisi, Maria Silvina Fornasari, Geppo Sartori, Javier Santos, Massimo Bellanda, Donatella Carbonera, Paola Costantini and Marco Bortolus
Int. J. Mol. Sci. 2024, 25(3), 1912; https://doi.org/10.3390/ijms25031912 - 5 Feb 2024
Viewed by 812
Abstract
Nqo15 is a subunit of respiratory complex I of the bacterium Thermus thermophilus, with strong structural similarity to human frataxin (FXN), a protein involved in the mitochondrial disease Friedreich’s ataxia (FRDA). Recently, we showed that the expression of recombinant Nqo15 can ameliorate [...] Read more.
Nqo15 is a subunit of respiratory complex I of the bacterium Thermus thermophilus, with strong structural similarity to human frataxin (FXN), a protein involved in the mitochondrial disease Friedreich’s ataxia (FRDA). Recently, we showed that the expression of recombinant Nqo15 can ameliorate the respiratory phenotype of FRDA patients’ cells, and this prompted us to further characterize both the Nqo15 solution’s behavior and its potential functional overlap with FXN, using a combination of in silico and in vitro techniques. We studied the analogy of Nqo15 and FXN by performing extensive database searches based on sequence and structure. Nqo15’s folding and flexibility were investigated by combining nuclear magnetic resonance (NMR), circular dichroism, and coarse-grained molecular dynamics simulations. Nqo15’s iron-binding properties were studied using NMR, fluorescence, and specific assays and its desulfurase activation by biochemical assays. We found that the recombinant Nqo15 isolated from complex I is monomeric, stable, folded in solution, and highly dynamic. Nqo15 does not share the iron-binding properties of FXN or its desulfurase activation function. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunctions and Metabolisms)
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17 pages, 2815 KiB  
Article
The Effect of SARS-CoV-2 Spike Protein RBD-Epitope on Immunometabolic State and Functional Performance of Cultured Primary Cardiomyocytes Subjected to Hypoxia and Reoxygenation
by Vytenis Keturakis, Deimantė Narauskaitė, Zbigniev Balion, Dovydas Gečys, Gabrielė Kulkovienė, Milda Kairytė, Ineta Žukauskaitė, Rimantas Benetis, Edgaras Stankevičius and Aistė Jekabsone
Int. J. Mol. Sci. 2023, 24(23), 16554; https://doi.org/10.3390/ijms242316554 - 21 Nov 2023
Viewed by 1109
Abstract
Cardio complications such as arrhythmias and myocardial damage are common in COVID-19 patients. SARS-CoV-2 interacts with the cardiovascular system primarily via the ACE2 receptor. Cardiomyocyte damage in SARS-CoV-2 infection may stem from inflammation, hypoxia–reoxygenation injury, and direct toxicity; however, the precise mechanisms are [...] Read more.
Cardio complications such as arrhythmias and myocardial damage are common in COVID-19 patients. SARS-CoV-2 interacts with the cardiovascular system primarily via the ACE2 receptor. Cardiomyocyte damage in SARS-CoV-2 infection may stem from inflammation, hypoxia–reoxygenation injury, and direct toxicity; however, the precise mechanisms are unclear. In this study, we simulated hypoxia–reoxygenation conditions commonly seen in SARS-CoV-2-infected patients and studied the impact of the SARS-CoV-2 spike protein RBD-epitope on primary rat cardiomyocytes to gain insight into the potential mechanisms underlying COVID-19-related cardiac complications. Cell metabolic activity was evaluated with PrestoBlueTM. Gene expression of proinflammatory markers was measured by qRT-PCR and their secretion was quantified by Luminex assay. Cardiomyocyte contractility was analysed using the Myocyter plugin of ImageJ. Mitochondrial respiration was determined through Seahorse Mito Stress Test. In hypoxia–reoxygenation conditions, treatment of the SARS-CoV-2 spike RBD-epitope reduced the metabolic activity of primary cardiomyocytes, upregulated Il1β and Cxcl1 expression, and elevated GM-CSF and CCL2 cytokines secretion. Contraction time increased, while amplitude and beating frequency decreased. Acute treatment with a virus RBD-epitope inhibited mitochondrial respiration and lowered ATP production. Under ischaemia-reperfusion, the SARS-CoV-2 RBD-epitope induces cardiomyocyte injury linked to impaired mitochondrial activity. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunctions and Metabolisms)
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Review

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17 pages, 2289 KiB  
Review
Exploring the Gut–Mitochondrial Axis: p66Shc Adapter Protein and Its Implications for Metabolic Disorders
by Ana Clara da C. Pinaffi-Langley, Elizabeth Melia and Franklin A. Hays
Int. J. Mol. Sci. 2024, 25(7), 3656; https://doi.org/10.3390/ijms25073656 - 25 Mar 2024
Viewed by 693
Abstract
This review investigates the multifaceted role of the p66Shc adaptor protein and the gut microbiota in regulating mitochondrial function and oxidative stress, and their collective impact on the pathogenesis of chronic diseases. The study delves into the molecular mechanisms by which p66Shc influences [...] Read more.
This review investigates the multifaceted role of the p66Shc adaptor protein and the gut microbiota in regulating mitochondrial function and oxidative stress, and their collective impact on the pathogenesis of chronic diseases. The study delves into the molecular mechanisms by which p66Shc influences cellular stress responses through Rac1 activation, Forkhead-type transcription factors inactivation, and mitochondria-mediated apoptosis, alongside modulatory effects of gut microbiota-derived metabolites and endotoxins. Employing an integrative approach, the review synthesizes findings from a broad array of studies, including molecular biology techniques and analyses of microbial metabolites’ impacts on host cellular pathways. The results underscore a complex interplay between microbial metabolites, p66Shc activation, and mitochondrial dysfunction, highlighting the significance of the gut microbiome in influencing disease outcomes through oxidative stress pathways. Conclusively, the review posits that targeting the gut microbiota-p66Shc–mitochondrial axis could offer novel therapeutic strategies for mitigating the development and progression of metabolic diseases. This underscores the potential of dietary interventions and microbiota modulation in managing oxidative stress and inflammation, pivotal factors in chronic disease etiology. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunctions and Metabolisms)
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12 pages, 796 KiB  
Review
Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms?
by Camila D. S. Barros, Aryane Coutinho and Celia H. Tengan
Int. J. Mol. Sci. 2024, 25(7), 3629; https://doi.org/10.3390/ijms25073629 - 24 Mar 2024
Viewed by 740
Abstract
MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists [...] Read more.
MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunctions and Metabolisms)
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23 pages, 2267 KiB  
Review
Mitochondrial Cation Signalling in the Control of Inflammatory Processes
by Pampa Pain, Francesca Spinelli and Gaia Gherardi
Int. J. Mol. Sci. 2023, 24(23), 16724; https://doi.org/10.3390/ijms242316724 - 24 Nov 2023
Cited by 1 | Viewed by 885
Abstract
Mitochondria are the bioenergetic organelles responsible for the maintenance of cellular homeostasis and have also been found to be associated with inflammation. They are necessary to induce and maintain innate and adaptive immune cell responses, acting as signalling platforms and mediators in effector [...] Read more.
Mitochondria are the bioenergetic organelles responsible for the maintenance of cellular homeostasis and have also been found to be associated with inflammation. They are necessary to induce and maintain innate and adaptive immune cell responses, acting as signalling platforms and mediators in effector responses. These organelles are also known to play a pivotal role in cation homeostasis as well, which regulates the inflammatory responses through the modulation of these cation channels. In particular, this review focuses on mitochondrial Ca2+ and K+ fluxes in the regulation of inflammatory response. Nevertheless, this review aims to understand the interplay of these inflammation inducers and pathophysiological conditions. In detail, we discuss some examples of chronic inflammation such as lung, bowel, and metabolic inflammatory diseases caused by a persistent activation of the innate immune response due to a dysregulation of mitochondrial cation homeostasis. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunctions and Metabolisms)
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