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Molecular Research on Mitochondrial Dysfunction

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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 41368

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Special Issue Editors

Dr. María Eugenia Soriano

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Guest Editor

Università degli Studi di Padova, Padua, Italy
Interests: mitochondria; complexomic analysis; crisate remodelling; nucleoid dynamics; mitochondrial disease

Prof. Dr. Carlo Viscomi

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Guest Editor

Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
Interests: mitochondrial disease; gene therapy; mitochondrial DNA

Special Issue Information

Dear Colleagues,

It is becoming increasingly clear and widely accepted that mitochondria play a central role in human pathology, not only in relation to primary OxPhos defects but also in a wide range of diseases, including neurodegenerative and immunological disorders. However, how central homeostatic and signalling pathways, such as mitophagy, fusion–fission, and mtDNA heteroplasmy levels, impact on the onset and progression of these diseases has only recently started to emerge. Thus, this is an exciting and thrilling new subject of investigation. Contributions to this Special Issue will provide a general overview and critical insight on our current understanding of these aspects. Our hope is to open a forum where the molecular mechanisms and pathophysiological consequences of mitochondrial dysfunction will be debated with the final aim of increassing our understanding of this emerging and exciting branch of mitochondrial biology and pathophysiology.

Dr. María Eugenia Soriano
Dr. Carlo Viscomi
Guest Editors

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

mitochondria
mitochondrial dysfunction
mtDNA
heteroplasmy
fusion-fission unbalance
mitophagy
oxidative phosphorilation

Published Papers (7 papers)

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Editorial

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3 pages, 473 KiB

Open AccessEditorial

Molecular Research on Mitochondrial Dysfunction

by Carlo Viscomi and Maria Eugenia Soriano

Int. J. Mol. Sci. 2022, 23(12), 6845; https://doi.org/10.3390/ijms23126845 - 20 Jun 2022

Cited by 2 | Viewed by 1597

Abstract

This Special Issue collects current knowledge on the molecular mechanisms underlying mitochondrial dysfunction and its related diseases, as well as therapies and perspectives pertaining to their treatment [...] Full article

(This article belongs to the Special Issue Molecular Research on Mitochondrial Dysfunction)

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Review

Jump to: Editorial

19 pages, 1861 KiB

Open AccessReview

RNA Granules in the Mitochondria and Their Organization under Mitochondrial Stresses

by Vanessa Joanne Xavier and Jean-Claude Martinou

Int. J. Mol. Sci. 2021, 22(17), 9502; https://doi.org/10.3390/ijms22179502 - 01 Sep 2021

Cited by 19 | Viewed by 7099

Abstract

The human mitochondrial genome (mtDNA) regulates its transcription products in specialised and distinct ways as compared to nuclear transcription. Thanks to its mtDNA mitochondria possess their own set of tRNAs, rRNAs and mRNAs that encode a subset of the protein subunits of the electron transport chain complexes. The RNA regulation within mitochondria is organised within specialised, membraneless, compartments of RNA-protein complexes, called the Mitochondrial RNA Granules (MRGs). MRGs were first identified to contain nascent mRNA, complexed with many proteins involved in RNA processing and maturation and ribosome assembly. Most recently, double-stranded RNA (dsRNA) species, a hybrid of the two complementary mRNA strands, were found to form granules in the matrix of mitochondria. These RNA granules are therefore components of the mitochondrial post-transcriptional pathway and as such play an essential role in mitochondrial gene expression. Mitochondrial dysfunctions in the form of, for example, RNA processing or RNA quality control defects, or inhibition of mitochondrial fission, can cause the loss or the aberrant accumulation of these RNA granules. These findings underline the important link between mitochondrial maintenance and the efficient expression of its genome. Full article

(This article belongs to the Special Issue Molecular Research on Mitochondrial Dysfunction)

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19 pages, 1963 KiB

Open AccessReview

Mitochondria-Induced Immune Response as a Trigger for Neurodegeneration: A Pathogen from Within

by Marta Luna-Sánchez, Patrizia Bianchi and Albert Quintana

Int. J. Mol. Sci. 2021, 22(16), 8523; https://doi.org/10.3390/ijms22168523 - 07 Aug 2021

Cited by 18 | Viewed by 5379

Abstract

Symbiosis between the mitochondrion and the ancestor of the eukaryotic cell allowed cellular complexity and supported life. Mitochondria have specialized in many key functions ensuring cell homeostasis and survival. Thus, proper communication between mitochondria and cell nucleus is paramount for cellular health. However, due to their archaebacterial origin, mitochondria possess a high immunogenic potential. Indeed, mitochondria have been identified as an intracellular source of molecules that can elicit cellular responses to pathogens. Compromised mitochondrial integrity leads to release of mitochondrial content into the cytosol, which triggers an unwanted cellular immune response. Mitochondrial nucleic acids (mtDNA and mtRNA) can interact with the same cytoplasmic sensors that are specialized in recognizing genetic material from pathogens. High-energy demanding cells, such as neurons, are highly affected by deficits in mitochondrial function. Notably, mitochondrial dysfunction, neurodegeneration, and chronic inflammation are concurrent events in many severe debilitating disorders. Interestingly in this context of pathology, increasing number of studies have detected immune-activating mtDNA and mtRNA that induce an aberrant production of pro-inflammatory cytokines and interferon effectors. Thus, this review provides new insights on mitochondria-driven inflammation as a potential therapeutic target for neurodegenerative and primary mitochondrial diseases. Full article

(This article belongs to the Special Issue Molecular Research on Mitochondrial Dysfunction)

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44 pages, 2166 KiB

Open AccessReview

Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

by Cameron L. McKnight, Yau Chung Low, David A. Elliott, David R. Thorburn and Ann E. Frazier

Int. J. Mol. Sci. 2021, 22(14), 7730; https://doi.org/10.3390/ijms22147730 - 20 Jul 2021

Cited by 14 | Viewed by 6861

Abstract

Mitochondrial diseases disrupt cellular energy production and are among the most complex group of inherited genetic disorders. Affecting approximately 1 in 5000 live births, they are both clinically and genetically heterogeneous, and can be highly tissue specific, but most often affect cell types with high energy demands in the brain, heart, and kidneys. There are currently no clinically validated treatment options available, despite several agents showing therapeutic promise. However, modelling these disorders is challenging as many non-human models of mitochondrial disease do not completely recapitulate human phenotypes for known disease genes. Additionally, access to disease-relevant cell or tissue types from patients is often limited. To overcome these difficulties, many groups have turned to human pluripotent stem cells (hPSCs) to model mitochondrial disease for both nuclear-DNA (nDNA) and mitochondrial-DNA (mtDNA) contexts. Leveraging the capacity of hPSCs to differentiate into clinically relevant cell types, these models permit both detailed investigation of cellular pathomechanisms and validation of promising treatment options. Here we catalogue hPSC models of mitochondrial disease that have been generated to date, summarise approaches and key outcomes of phenotypic profiling using these models, and discuss key criteria to guide future investigations using hPSC models of mitochondrial disease. Full article

(This article belongs to the Special Issue Molecular Research on Mitochondrial Dysfunction)

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25 pages, 3716 KiB

Open AccessReview

Mitochondrial Heteroplasmy Shifting as a Potential Biomarker of Cancer Progression

by Carlos Jhovani Pérez-Amado, Amellalli Bazan-Cordoba, Alfredo Hidalgo-Miranda and Silvia Jiménez-Morales

Int. J. Mol. Sci. 2021, 22(14), 7369; https://doi.org/10.3390/ijms22147369 - 09 Jul 2021

Cited by 23 | Viewed by 4088

Abstract

Cancer is a serious health problem with a high mortality rate worldwide. Given the relevance of mitochondria in numerous physiological and pathological mechanisms, such as adenosine triphosphate (ATP) synthesis, apoptosis, metabolism, cancer progression and drug resistance, mitochondrial genome (mtDNA) analysis has become of great interest in the study of human diseases, including cancer. To date, a high number of variants and mutations have been identified in different types of tumors, which coexist with normal alleles, a phenomenon named heteroplasmy. This mechanism is considered an intermediate state between the fixation or elimination of the acquired mutations. It is suggested that mutations, which confer adaptive advantages to tumor growth and invasion, are enriched in malignant cells. Notably, many recent studies have reported a heteroplasmy-shifting phenomenon as a potential shaper in tumor progression and treatment response, and we suggest that each cancer type also has a unique mitochondrial heteroplasmy-shifting profile. So far, a plethora of data evidencing correlations among heteroplasmy and cancer-related phenotypes are available, but still, not authentic demonstrations, and whether the heteroplasmy or the variation in mtDNA copy number (mtCNV) in cancer are cause or consequence remained unknown. Further studies are needed to support these findings and decipher their clinical implications and impact in the field of drug discovery aimed at treating human cancer. Full article

(This article belongs to the Special Issue Molecular Research on Mitochondrial Dysfunction)

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Graphical abstract

35 pages, 973 KiB

Open AccessReview

Therapy Prospects for Mitochondrial DNA Maintenance Disorders

by Javier Ramón, Ferran Vila-Julià, David Molina-Granada, Miguel Molina-Berenguer, Maria Jesús Melià, Elena García-Arumí, Javier Torres-Torronteras, Yolanda Cámara and Ramon Martí

Int. J. Mol. Sci. 2021, 22(12), 6447; https://doi.org/10.3390/ijms22126447 - 16 Jun 2021

Cited by 11 | Viewed by 4060

Abstract

Mitochondrial DNA depletion and multiple deletions syndromes (MDDS) constitute a group of mitochondrial diseases defined by dysfunctional mitochondrial DNA (mtDNA) replication and maintenance. As is the case for many other mitochondrial diseases, the options for the treatment of these disorders are rather limited today. Some aggressive treatments such as liver transplantation or allogeneic stem cell transplantation are among the few available options for patients with some forms of MDDS. However, in recent years, significant advances in our knowledge of the biochemical pathomechanisms accounting for dysfunctional mtDNA replication have been achieved, which has opened new prospects for the treatment of these often fatal diseases. Current strategies under investigation to treat MDDS range from small molecule substrate enhancement approaches to more complex treatments, such as lentiviral or adenoassociated vector-mediated gene therapy. Some of these experimental therapies have already reached the clinical phase with very promising results, however, they are hampered by the fact that these are all rare disorders and so the patient recruitment potential for clinical trials is very limited. Full article

(This article belongs to the Special Issue Molecular Research on Mitochondrial Dysfunction)

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24 pages, 2269 KiB

Open AccessReview

Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

by Russel J. Reiter, Ramaswamy Sharma and Sergio Rosales-Corral

Int. J. Mol. Sci. 2021, 22(2), 764; https://doi.org/10.3390/ijms22020764 - 14 Jan 2021

Cited by 35 | Viewed by 11264

Abstract

Glucose is an essential nutrient for every cell but its metabolic fate depends on cellular phenotype. Normally, the product of cytosolic glycolysis, pyruvate, is transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase. This altered metabolism is referred to as aerobic glycolysis (Warburg effect) and is common in solid tumors and in other pathological cells. Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and the activation of pentose phosphate pathway (PPP) which provides nucleotides required for elevated cellular metabolism. Molecules, called glycolytics, inhibit aerobic glycolysis and convert cells to a healthier phenotype. Glycolytics often function by inhibiting hypoxia-inducible factor-1α leading to PDC disinhibition allowing for intramitochondrial conversion of pyruvate into acetyl coenzyme A. Melatonin is a glycolytic which converts diseased cells to the healthier phenotype. Herein we propose that melatonin’s function as a glycolytic explains its actions in inhibiting a variety of diseases. Thus, the common denominator is melatonin’s action in switching the metabolic phenotype of cells. Full article

(This article belongs to the Special Issue Molecular Research on Mitochondrial Dysfunction)

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