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Molecular Mechanisms, Pathophysiology and Phenotypes of Mitochondrial Disorders

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

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 17833

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Special Issue Editor

Prof. Dr. Michelangelo Mancuso

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Guest Editor

Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, 56126 Pisa, Italy
Interests: mitochondrial diseases; neurogenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondrial diseases are the most common inheritable metabolic diseases resulting from defects in oxidative phosphorylation. They are caused by mutations of nuclear or mitochondrial DNA in genes involved in mitochondrial function. While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy), many involve multiple organ systems and often present with prominent neurologic features. Understanding the phenotypic diversity and elucidating the molecular mechanisms at the basis of these diseases has, however, proved challenging.

With this Special Issue, we intent to explore the molecular basis, the clinical spectrum, the diagnostic approach and the treatment advances of these devastating disorders.

Prof. Dr. Michelangelo Mancuso
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
clinical phenotypes
diagnostic approaches
genetics

Published Papers (5 papers)

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Research

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23 pages, 7050 KiB

Open AccessArticle

Aberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A

by Filippos Stavropoulos, Irene Sargiannidou, Louiza Potamiti, Alexia Kagiava, Mihalis I. Panayiotidis, Ji Hyun Bae, Su Cheong Yeom, Jae Young Lee and Kleopas A. Kleopa

Int. J. Mol. Sci. 2021, 22(21), 11569; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111569 - 26 Oct 2021

Cited by 8 | Viewed by 2998

Abstract

Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common hereditary axonal neuropathy caused by mutations in MFN2 encoding Mitofusin-2, a multifunctional protein located in the outer mitochondrial membrane. In order to study the effects of a novel MFN2^K357T mutation associated with early onset, autosomal dominant severe CMT2A, we generated a knock-in mouse model. While Mfn2^K357T/K357T mouse pups were postnatally lethal, Mfn2^+/K357T heterozygous mice were asymptomatic and had no histopathological changes in their sciatic nerves up to 10 months of age. However, immunofluorescence analysis of Mfn2^+/K357T mice revealed aberrant mitochondrial clustering in the sciatic nerves from 6 months of age, in optic nerves from 8 months, and in lumbar spinal cord white matter at 10 months, along with microglia activation. Ultrastructural analyses confirmed dysmorphic mitochondrial aggregates in sciatic and optic nerves. After exposure of 6-month-old mice to lipopolysaccharide, Mfn2^+/K357T mice displayed a higher immune response, a more severe motor impairment, and increased CNS inflammation, microglia activation, and macrophage infiltrates. Overall, ubiquitous Mfn2^K357T expression renders the CNS and peripheral nerves of Mfn2^+/K357T mice more susceptible to mitochondrial clustering, and augments their response to inflammation, modeling some cellular mechanisms that may be relevant for the development of neuropathy in patients with CMT2A. Full article

(This article belongs to the Special Issue Molecular Mechanisms, Pathophysiology and Phenotypes of Mitochondrial Disorders)

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19 pages, 2863 KiB

Open AccessArticle

Do Autophagy Enhancers/ROS Scavengers Alleviate Consequences of Mild Mitochondrial Dysfunction Induced in Neuronal-Derived Cells?

by Odeya Damri, Sarya Natur and Galila Agam

Int. J. Mol. Sci. 2021, 22(11), 5753; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115753 - 27 May 2021

Cited by 5 | Viewed by 2665

Abstract

Mitochondrial function is at the nexus of pathways regulating synaptic-plasticity and cellular resilience. The involvement of brain mitochondrial dysfunction along with increased reactive oxygen species (ROS) levels, accumulating mtDNA mutations, and attenuated autophagy is implicated in psychiatric and neurodegenerative diseases. We have previously modeled mild mitochondrial dysfunction assumed to occur in bipolar disorder (BPD) using exposure of human neuronal cells (SH-SY5Y) to rotenone (an inhibitor of mitochondrial-respiration complex-I) for 72 and 96 h, which exhibited up- and down-regulation of mitochondrial respiration, respectively. In this study, we aimed to find out whether autophagy enhancers (lithium, trehalose, rapamycin, and resveratrol) and/or ROS scavengers [resveratrol, N-acetylcysteine (NAC), and Mn-Tbap) can ameliorate neuronal mild mitochondrial dysfunction. Only lithium (added for the last 24/48 h of the exposure to rotenone for 72/96 h, respectively) counteracted the effect of rotenone on most of the mitochondrial respiration parameters (measured as oxygen consumption rate (OCR)). Rapamycin, resveratrol, NAC, and Mn-Tbap counteracted most of rotenone’s effects on OCR parameters after 72 h, possibly via different mechanisms, which are not necessarily related to their ROS scavenging and/or autophagy enhancement effects. The effect of lithium reversing rotenone’s effect on OCR parameters is compatible with lithium’s known positive effects on mitochondrial function and is possibly mediated via its effect on autophagy. By-and-large it may be summarized that some autophagy enhancers/ROS scavengers alleviate some rotenone-induced mild mitochondrial changes in SH-SY5Y cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms, Pathophysiology and Phenotypes of Mitochondrial Disorders)

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19 pages, 18542 KiB

Open AccessArticle

Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study

by Sara Laine-Menéndez, Cristina Domínguez-González, Alberto Blázquez, Aitor Delmiro, Inés García-Consuegra, Miguel Fernández-de la Torre, Aurelio Hernández-Laín, Javier Sayas, Miguel Ángel Martín and María Morán

Int. J. Mol. Sci. 2021, 22(11), 5598; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115598 - 25 May 2021

Cited by 5 | Viewed by 2010

Abstract

Our goal was to analyze postmortem tissues of an adult patient with late-onset thymidine kinase 2 (TK2) deficiency who died of respiratory failure. Compared with control tissues, we found a low mtDNA content in the patient’s skeletal muscle, liver, kidney, small intestine, and particularly in the diaphragm, whereas heart and brain tissue showed normal mtDNA levels. mtDNA deletions were present in skeletal muscle and diaphragm. All tissues showed a low content of OXPHOS subunits, and this was especially evident in diaphragm, which also exhibited an abnormal protein profile, expression of non-muscular β-actin and loss of GAPDH and α-actin. MALDI-TOF/TOF mass spectrometry analysis demonstrated the loss of the enzyme fructose-bisphosphate aldolase, and enrichment for serum albumin in the patient’s diaphragm tissue. The TK2-deficient patient’s diaphragm showed a more profound loss of OXPHOS proteins, with lower levels of catalase, peroxiredoxin 6, cytosolic superoxide dismutase, p62 and the catalytic subunits of proteasome than diaphragms of ventilated controls. Strong overexpression of TK1 was observed in all tissues of the patient with diaphragm showing the highest levels. TK2 deficiency induces a more profound dysfunction of the diaphragm than of other tissues, which manifests as loss of OXPHOS and glycolytic proteins, sarcomeric components, antioxidants and overactivation of the TK1 salvage pathway that is not attributed to mechanical ventilation. Full article

(This article belongs to the Special Issue Molecular Mechanisms, Pathophysiology and Phenotypes of Mitochondrial Disorders)

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Review

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18 pages, 1213 KiB

Open AccessReview

Pathophysiology and Management of Fatigue in Neuromuscular Diseases

by Francesca Torri, Piervito Lopriore, Vincenzo Montano, Gabriele Siciliano, Michelangelo Mancuso and Giulia Ricci

Int. J. Mol. Sci. 2023, 24(5), 5005; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24055005 - 05 Mar 2023

Cited by 3 | Viewed by 5030

Abstract

Fatigue is a major determinant of quality of life and motor function in patients affected by several neuromuscular diseases, each of them characterized by a peculiar physiopathology and the involvement of numerous interplaying factors. This narrative review aims to provide an overview on the pathophysiology of fatigue at a biochemical and molecular level with regard to muscular dystrophies, metabolic myopathies, and primary mitochondrial disorders with a focus on mitochondrial myopathies and spinal muscular atrophy, which, although fulfilling the definition of rare diseases, as a group represent a representative ensemble of neuromuscular disorders that the neurologist may encounter in clinical practice. The current use of clinical and instrumental tools for fatigue assessment, and their significance, is discussed. A summary of therapeutic approaches to address fatigue, encompassing pharmacological treatment and physical exercise, is also overviewed. Full article

(This article belongs to the Special Issue Molecular Mechanisms, Pathophysiology and Phenotypes of Mitochondrial Disorders)

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15 pages, 1158 KiB

Open AccessReview

Mitochondrial Epilepsy, a Challenge for Neurologists

by Piervito Lopriore, Fábio Gomes, Vincenzo Montano, Gabriele Siciliano and Michelangelo Mancuso

Int. J. Mol. Sci. 2022, 23(21), 13216; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113216 - 30 Oct 2022

Cited by 20 | Viewed by 4375

Abstract

Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect tissues with high energy requirements, including the brain. Epilepsy affects >1% of the worldwide population, making it one of the most common neurological illnesses; it may be the presenting feature of a mitochondrial disease, but is often part of a multisystem clinical presentation. The major genetic causes of mitochondrial epilepsy are mutations in mitochondrial DNA and in the nuclear-encoded gene POLG. Treatment of mitochondrial epilepsy may be challenging, often representing a poor prognostic feature. This narrative review will cover the most recent advances in the field of mitochondrial epilepsy, from pathophysiology and genetic etiologies to phenotype and treatment options. Full article

(This article belongs to the Special Issue Molecular Mechanisms, Pathophysiology and Phenotypes of Mitochondrial Disorders)

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