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Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 April 2023) | Viewed by 39337

Special Issue Editors

Dr. Stefano Doccini

E-Mail Website
Guest Editor
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy
Interests: bioenrgetics; mitochondrial disorders; omics; bioinformatics; neurosciences; in vitro disease models; biomarker discovery; biochemical pathways; diagnostic and therapeutic targets
Special Issues, Collections and Topics in MDPI journals
Dr. Federica Morani

E-Mail Website
Guest Editor
Department of Biology, University of Pisa, 56126 Pisa, Italy
Interests: molecular mechanisms of neurodegeneration and cancer; autophagy; disease biomarkers; gene editing; omics; mitochondrial dysfunction in neurological diseases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Wieslawa Jarmuszkiewicz

E-Mail Website
Guest Editor
Department of Bioenergetics, Adam Mickiewicz University, 61-614 Poznan, Poland
Interests: mitochondrial ROS production; Coenzyme Q; Coenzyme Q deficiency; Coenzyme Q supplementation; mitochondrial Coenzyme Q in disorders; Coenzyme Q and mitochondrial function/dysfunction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Mitochondrial diseases are a large group of genetically determined multisystem disorders, characterized by extreme phenotypic heterogeneity, attributable in part to the dual genomic control of the mitochondrial proteome. The correct use of biochemical and histology testing, in combination with imaging studies, has proved helpful in genotype-phenotype correlations.

However, new therapeutic research approaches are improving our knowledge in the functions of mitochondrial genes, their expression pattern, features of gene defects or risk of transmission.

This Special Issue focuses on mitochondrial dysfunction in neurodegenerative and cardiovascular diseases, aging, cancer and signaling pathways leading to mitochondrial biogenesis and mitophagy. We will welcome original research articles, comprehensive reviews and novel communications dealing with the molecular pathways underlying the role of mitochondria in disease mechanisms or expanding genotype-phenotype correlations.

Dr. Stefano Doccini
Dr. Federica Morani
Prof. Dr. Wieslawa Jarmuszkiewicz
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

  • bioenergetics
  • mitochondrial disorders
  • biomarkers
  • OxPhos complexes
  • mitochondrial DNA
  • aging
  • neurodegenerative diseases
  • cardiovascular diseases
  • metabolic diseases
  • therapies to counteract mitochondrial dysfunction

Published Papers (15 papers)

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Research

Jump to: Review

18 pages, 3635 KiB  
Article
Converging Role for REEP1/SPG31 in Oxidative Stress
by Valentina Naef, Maria C. Meschini, Alessandra Tessa, Federica Morani, Debora Corsinovi, Asahi Ogi, Maria Marchese, Michela Ori, Filippo M. Santorelli and Stefano Doccini
Int. J. Mol. Sci. 2023, 24(4), 3527; https://doi.org/10.3390/ijms24043527 - 09 Feb 2023
Viewed by 1802
Abstract
Mutations in the receptor expression-enhancing protein 1 gene (REEP1) are associated with hereditary spastic paraplegia type 31 (SPG31), a neurological disorder characterized by length-dependent degeneration of upper motor neuron axons. Mitochondrial dysfunctions have been observed in patients harboring pathogenic variants in REEP1, [...] Read more.
Mutations in the receptor expression-enhancing protein 1 gene (REEP1) are associated with hereditary spastic paraplegia type 31 (SPG31), a neurological disorder characterized by length-dependent degeneration of upper motor neuron axons. Mitochondrial dysfunctions have been observed in patients harboring pathogenic variants in REEP1, suggesting a key role of bioenergetics in disease-related manifestations. Nevertheless, the regulation of mitochondrial function in SPG31 remains unclear. To elucidate the pathophysiology underlying REEP1 deficiency, we analyzed in vitro the impact of two different mutations on mitochondrial metabolism. Together with mitochondrial morphology abnormalities, loss-of-REEP1 expression highlighted a reduced ATP production with increased susceptibility to oxidative stress. Furthermore, to translate these findings from in vitro to preclinical models, we knocked down REEP1 in zebrafish. Zebrafish larvae showed a significant defect in motor axon outgrowth leading to motor impairment, mitochondrial dysfunction, and reactive oxygen species accumulation. Protective antioxidant agents such as resveratrol rescued free radical overproduction and ameliorated the SPG31 phenotype both in vitro and in vivo. Together, our findings offer new opportunities to counteract neurodegeneration in SPG31. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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15 pages, 5673 KiB  
Article
Contraction Band Necrosis with Dephosphorylated Connexin 43 in Rat Myocardium after Daily Cocaine Administration
by Shuheng Wen, Kana Unuma, Takeshi Funakoshi, Toshihiko Aki and Koichi Uemura
Int. J. Mol. Sci. 2022, 23(19), 11978; https://doi.org/10.3390/ijms231911978 - 09 Oct 2022
Cited by 1 | Viewed by 1780
Abstract
Contraction band necrosis (CBN) is a common abnormality found in the myocardium of cocaine abusers, but is rarely reported in experimental models of cocaine abuse. Connexin 43 (Cx43) is essential for cardiac intercellular communication and the propagation of CBN. Under stress or injury, [...] Read more.
Contraction band necrosis (CBN) is a common abnormality found in the myocardium of cocaine abusers, but is rarely reported in experimental models of cocaine abuse. Connexin 43 (Cx43) is essential for cardiac intercellular communication and the propagation of CBN. Under stress or injury, cardiac Cx43 is dephosphorylated, which is related to cardiomyocyte dysfunction and pathogenesis, whereas adiponectin exerts beneficial effects in the myocardium. In this study, we explore the effects of cocaine on cardiac Cx43 in vivo. Rats were administered cocaine via the tail vein at 20 mg/kg/day for 14 days, and showed widespread CBN, microfocal myocarditis and myocardial fibrosis, corresponding to a dysfunction of cardiac mitochondria under increased oxidative stress. The increase in dephosphorylated cardiac Cx43 and its negative correlation with the myocardial distribution of CBN after cocaine administration were determined. In addition, apoptosis and necroptosis, as well as increased adiponectin levels, were observed in the myocardium after cocaine exposure. Accordingly, we found altered profiles of cardiac Cx43, CBN and its negative correlation with dephosphorylated cardiac Cx43, and the possible involvement of adiponectin in the myocardium after 14 days of cocaine administration. The latter might play a protective role in the cardiotoxicity of cocaine. The current findings would be beneficial for establishing novel therapeutic strategies in cocaine-induced cardiac consequences. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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15 pages, 1768 KiB  
Article
SP1 and NFY Regulate the Expression of PNPT1, a Gene Encoding a Mitochondrial Protein Involved in Cancer
by Ignacio Ventura, Fernando Revert, Francisco Revert-Ros, Lucía Gómez-Tatay, Jesús A. Prieto-Ruiz and José Miguel Hernández-Andreu
Int. J. Mol. Sci. 2022, 23(19), 11399; https://doi.org/10.3390/ijms231911399 - 27 Sep 2022
Cited by 1 | Viewed by 1849
Abstract
The Polyribonucleotide nucleotidyltransferase 1 gene (PNPT1) encodes polynucleotide phosphorylase (PNPase), a 3′-5′ exoribonuclease involved in mitochondrial RNA degradation and surveillance and RNA import into the mitochondrion. Here, we have characterized the PNPT1 promoter by in silico analysis, luciferase reporter assays, electrophoretic [...] Read more.
The Polyribonucleotide nucleotidyltransferase 1 gene (PNPT1) encodes polynucleotide phosphorylase (PNPase), a 3′-5′ exoribonuclease involved in mitochondrial RNA degradation and surveillance and RNA import into the mitochondrion. Here, we have characterized the PNPT1 promoter by in silico analysis, luciferase reporter assays, electrophoretic mobility shift assays (EMSA), chromatin immunoprecipitation (ChIP), siRNA-based mRNA silencing and RT-qPCR. We show that the Specificity protein 1 (SP1) transcription factor and Nuclear transcription factor Y (NFY) bind the PNPT1 promoter, and have a relevant role regulating the promoter activity, PNPT1 expression, and mitochondrial activity. We also found in Kaplan–Meier survival curves that a high expression of either PNPase, SP1 or NFY subunit A (NFYA) is associated with a poor prognosis in liver cancer. In summary, our results show the relevance of SP1 and NFY in PNPT1 expression, and point to SP1/NFY and PNPase as possible targets in anti-cancer therapy. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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14 pages, 529 KiB  
Article
Direct Analysis of Mitochondrial Damage Caused by Misfolded/Destabilized Proteins
by Jannatul Aklima, Sawaros Onchaiya, Tomonori Saotome, Punitha Velmurugan, Taihei Motoichi, Jannatul Naima, Yutaka Kuroda and Yoshihiro Ohta
Int. J. Mol. Sci. 2022, 23(17), 9881; https://doi.org/10.3390/ijms23179881 - 31 Aug 2022
Viewed by 1800
Abstract
Protein quality control is essential for cellular homeostasis. In this study, we examined the effect of improperly folded proteins that do not form amyloid fibrils on mitochondria, which play important roles in ATP production and cell death. First, we prepared domain 3 of [...] Read more.
Protein quality control is essential for cellular homeostasis. In this study, we examined the effect of improperly folded proteins that do not form amyloid fibrils on mitochondria, which play important roles in ATP production and cell death. First, we prepared domain 3 of the dengue envelope protein in wild type and four mutants with widely different biophysical properties in misfolded/aggregated or destabilized states. The effects of the different proteins were detected using fluorescence microscopy and Western blotting, which revealed that three of the five proteins disrupted both inner and outer membrane integrity, while the other two proteins, including the wild type, did not. Next, we examined the common characteristics of the proteins that displayed toxicity against mitochondria by measuring oligomer size, molten globule-like properties, and thermal stability. The common feature of all three toxic proteins was thermal instability. Therefore, our data strongly suggest that thermally unstable proteins generated in the cytosol can cause cellular damage by coming into direct contact with mitochondria. More importantly, we revealed that this damage is not amyloid-specific. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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14 pages, 2383 KiB  
Article
Influence of Microbial Metabolites and Itaconic Acid Involved in Bacterial Inflammation on the Activity of Mitochondrial Enzymes and the Protective Role of Alkalization
by Nadezhda Fedotcheva and Natalia Beloborodova
Int. J. Mol. Sci. 2022, 23(16), 9069; https://doi.org/10.3390/ijms23169069 - 14 Aug 2022
Cited by 6 | Viewed by 1936
Abstract
Human microbiota produces metabolites that may enter the bloodstream and exert systemic influence on various functions including mitochondrial. Mitochondria are not only a target for microbial metabolites, but also themselves, due to the inhibition of several enzymes, produce metabolites involved in infectious processes [...] Read more.
Human microbiota produces metabolites that may enter the bloodstream and exert systemic influence on various functions including mitochondrial. Mitochondria are not only a target for microbial metabolites, but also themselves, due to the inhibition of several enzymes, produce metabolites involved in infectious processes and immune response. The influence of indolic acids, microbial derivatives of tryptophan, as well as itaconic acid, formed in the tricarboxylic acid cycle under the action of bacterial lipopolysaccharides, on the activity of mitochondrial enzymes was studied by methyl thiazolyl tetrazolium (MTT), dichlorophenolindophenol (DCPIP) and pyridine nucleotide fluorescence assays. Thus, it was found that indolic acids suppressed succinate and glutamate oxidation, shifting the redox potential of pyridine nucleotides to a more oxidized state. Itaconic acid, in addition to the well-known inhibition of succinate oxidation, also decreased NAD reduction in reactions with glutamate as a substrate. Unlike itaconic acid, indolic acids are not direct inhibitors of succinate dehydrogenase and glutamate dehydrogenase as their effects could be partially eliminated by the thiol antioxidant dithiothreitol (DTT) and the scavenger of lipid radicals butyl-hydroxytoluene (BHT). Alkalization turned out to be the most effective means to decrease the action of these metabolites, including itaconic acid, which is due to the protective influence on redox-dependent processes. Thus, among mitochondrial oxidative enzymes, the most accessible targets of these microbial-related metabolites are succinate dehydrogenase and glutamate dehydrogenase. These are important in the context of the shifting of metabolic pathways involved in bacterial inflammation and sepsis as well as the detection of new markers of these pathologies. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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Review

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27 pages, 1685 KiB  
Review
Mitochondrial Dysfunction in Intensive Care Unit-Acquired Weakness and Critical Illness Myopathy: A Narrative Review
by Felix Klawitter, Johannes Ehler, Rika Bajorat and Robert Patejdl
Int. J. Mol. Sci. 2023, 24(6), 5516; https://doi.org/10.3390/ijms24065516 - 14 Mar 2023
Cited by 7 | Viewed by 2681
Abstract
Mitochondria are key structures providing most of the energy needed to maintain homeostasis. They are the main source of adenosine triphosphate (ATP), participate in glucose, lipid and amino acid metabolism, store calcium and are integral components in various intracellular signaling cascades. However, due [...] Read more.
Mitochondria are key structures providing most of the energy needed to maintain homeostasis. They are the main source of adenosine triphosphate (ATP), participate in glucose, lipid and amino acid metabolism, store calcium and are integral components in various intracellular signaling cascades. However, due to their crucial role in cellular integrity, mitochondrial damage and dysregulation in the context of critical illness can severely impair organ function, leading to energetic crisis and organ failure. Skeletal muscle tissue is rich in mitochondria and, therefore, particularly vulnerable to mitochondrial dysfunction. Intensive care unit-acquired weakness (ICUAW) and critical illness myopathy (CIM) are phenomena of generalized weakness and atrophying skeletal muscle wasting, including preferential myosin breakdown in critical illness, which has also been linked to mitochondrial failure. Hence, imbalanced mitochondrial dynamics, dysregulation of the respiratory chain complexes, alterations in gene expression, disturbed signal transduction as well as impaired nutrient utilization have been proposed as underlying mechanisms. This narrative review aims to highlight the current known molecular mechanisms immanent in mitochondrial dysfunction of patients suffering from ICUAW and CIM, as well as to discuss possible implications for muscle phenotype, function and therapeutic approaches. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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33 pages, 2267 KiB  
Review
Proteomics as a Tool for the Study of Mitochondrial Proteome, Its Dysfunctionality and Pathological Consequences in Cardiovascular Diseases
by Miroslava Stastna
Int. J. Mol. Sci. 2023, 24(5), 4692; https://doi.org/10.3390/ijms24054692 - 28 Feb 2023
Cited by 2 | Viewed by 2249
Abstract
The focus of this review is on the proteomic approaches applied to the study of the qualitative/quantitative changes in mitochondrial proteins that are related to impaired mitochondrial function and consequently different types of pathologies. Proteomic techniques developed in recent years have created a [...] Read more.
The focus of this review is on the proteomic approaches applied to the study of the qualitative/quantitative changes in mitochondrial proteins that are related to impaired mitochondrial function and consequently different types of pathologies. Proteomic techniques developed in recent years have created a powerful tool for the characterization of both static and dynamic proteomes. They can detect protein–protein interactions and a broad repertoire of post-translation modifications that play pivotal roles in mitochondrial regulation, maintenance and proper function. Based on accumulated proteomic data, conclusions can be derived on how to proceed in disease prevention and treatment. In addition, this article will present an overview of the recently published proteomic papers that deal with the regulatory roles of post-translational modifications of mitochondrial proteins and specifically with cardiovascular diseases connected to mitochondrial dysfunction. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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25 pages, 1589 KiB  
Review
Comprehensive Analysis of Mitochondrial Dynamics Alterations in Heart Diseases
by Giampaolo Morciano, Caterina Boncompagni, Daniela Ramaccini, Gaia Pedriali, Esmaa Bouhamida, Elena Tremoli, Carlotta Giorgi and Paolo Pinton
Int. J. Mol. Sci. 2023, 24(4), 3414; https://doi.org/10.3390/ijms24043414 - 08 Feb 2023
Cited by 6 | Viewed by 2657
Abstract
The most common alterations affecting mitochondria, and associated with cardiac pathological conditions, implicate a long list of defects. They include impairments of the mitochondrial electron transport chain activity, which is a crucial element for energy formation, and that determines the depletion of ATP [...] Read more.
The most common alterations affecting mitochondria, and associated with cardiac pathological conditions, implicate a long list of defects. They include impairments of the mitochondrial electron transport chain activity, which is a crucial element for energy formation, and that determines the depletion of ATP generation and supply to metabolic switches, enhanced ROS generation, inflammation, as well as the dysregulation of the intracellular calcium homeostasis. All these signatures significantly concur in the impairment of cardiac electrical characteristics, loss of myocyte contractility and cardiomyocyte damage found in cardiac diseases. Mitochondrial dynamics, one of the quality control mechanisms at the basis of mitochondrial fitness, also result in being dysregulated, but the use of this knowledge for translational and therapeutic purposes is still in its infancy. In this review we tried to understand why this is, by summarizing methods, current opinions and molecular details underlying mitochondrial dynamics in cardiac diseases. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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16 pages, 1033 KiB  
Review
The Non-Invasive Assessment of Circulating D-Loop and mt-ccf Levels Opens an Intriguing Spyhole into Novel Approaches for the Tricky Diagnosis of NASH
by Erika Paolini, Miriam Longo, Alberto Corsini and Paola Dongiovanni
Int. J. Mol. Sci. 2023, 24(3), 2331; https://doi.org/10.3390/ijms24032331 - 24 Jan 2023
Cited by 2 | Viewed by 2197
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest liver disease worldwide affecting both adults and children. Nowadays, no therapeutic strategies have been approved for NAFLD management, and hepatic biopsy remains the gold standard procedure for its diagnosis. NAFLD is a multifactorial disease whose [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is the commonest liver disease worldwide affecting both adults and children. Nowadays, no therapeutic strategies have been approved for NAFLD management, and hepatic biopsy remains the gold standard procedure for its diagnosis. NAFLD is a multifactorial disease whose pathogenesis is affected by environmental and genetic factors, and it covers a spectrum of conditions ranging from simple steatosis up to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Several studies underlined the urgent need to develop an NAFLD risk prediction model based on genetics, biochemical indicators, and metabolic disorders. The loss of mitochondrial dynamics represents a typical feature of progressive NAFLD. The imbalance of mitochondrial lifecycle together with the impairment of mitochondrial biomass and function trigger oxidative stress, which in turn damages mitochondrial DNA (mtDNA). We recently demonstrated that the main genetic predictors of NAFLD led to mitochondrial dysfunction. Moreover, emerging evidence shows that variations in the displacement loop (D-loop) region impair mtDNA replication, and they have been associated with advanced NAFLD. Finally, lower levels of mitophagy foster the overload of damaged mitochondria, resulting in the release of cell-free circulating mitochondrial DNA (mt-ccf) that exacerbates liver injury. Thus, in this review we summarized what is known about D-loop region alterations and mt-ccf content during NAFLD to propose them as novel non-invasive biomarkers. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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12 pages, 610 KiB  
Review
Mitochondrial Dysfunction: The Hidden Player in the Pathogenesis of Atherosclerosis?
by Giovanni Ciccarelli, Stefano Conte, Giovanni Cimmino, Patrizia Maiorano, Andrea Morrione and Antonio Giordano
Int. J. Mol. Sci. 2023, 24(2), 1086; https://doi.org/10.3390/ijms24021086 - 06 Jan 2023
Cited by 19 | Viewed by 4463
Abstract
Atherosclerosis is a multifactorial inflammatory pathology that involves metabolic processes. Improvements in therapy have drastically reduced the prognosis of cardiovascular disease. Nevertheless, a significant residual risk is still relevant, and is related to unmet therapeutic targets. Endothelial dysfunction and lipid infiltration are the [...] Read more.
Atherosclerosis is a multifactorial inflammatory pathology that involves metabolic processes. Improvements in therapy have drastically reduced the prognosis of cardiovascular disease. Nevertheless, a significant residual risk is still relevant, and is related to unmet therapeutic targets. Endothelial dysfunction and lipid infiltration are the primary causes of atherosclerotic plaque progression. In this contest, mitochondrial dysfunction can affect arterial wall cells, in particular macrophages, smooth muscle cells, lymphocytes, and endothelial cells, causing an increase in reactive oxygen species (ROS), leading to oxidative stress, chronic inflammation, and intracellular lipid deposition. The detection and characterization of mitochondrial DNA (mtDNA) is crucial for assessing mitochondrial defects and should be considered the goal for new future therapeutic interventions. In this review, we will focus on a new idea, based on the analysis of data from many research groups, namely the link between mitochondrial impairment and endothelial dysfunction and, in particular, its effect on atherosclerosis and aging. Therefore, we discuss known and novel mitochondria-targeting therapies in the contest of atherosclerosis. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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19 pages, 2289 KiB  
Review
Iron- and Neuromelanin-Weighted Neuroimaging to Study Mitochondrial Dysfunction in Patients with Parkinson’s Disease
by Benjamin Matis Pizarro-Galleguillos, Liesa Kunert, Norbert Brüggemann and Jannik Prasuhn
Int. J. Mol. Sci. 2022, 23(22), 13678; https://doi.org/10.3390/ijms232213678 - 08 Nov 2022
Cited by 6 | Viewed by 2337
Abstract
The underlying causes of Parkinson’s disease are complex, and besides recent advances in elucidating relevant disease mechanisms, no disease-modifying treatments are currently available. One proposed pathophysiological hallmark is mitochondrial dysfunction, and a plethora of evidence points toward the interconnected nature of mitochondria in [...] Read more.
The underlying causes of Parkinson’s disease are complex, and besides recent advances in elucidating relevant disease mechanisms, no disease-modifying treatments are currently available. One proposed pathophysiological hallmark is mitochondrial dysfunction, and a plethora of evidence points toward the interconnected nature of mitochondria in neuronal homeostasis. This also extends to iron and neuromelanin metabolism, two biochemical processes highly relevant to individual disease manifestation and progression. Modern neuroimaging methods help to gain in vivo insights into these intertwined pathways and may pave the road to individualized medicine in this debilitating disorder. In this narrative review, we will highlight the biological rationale for studying these pathways, how distinct neuroimaging methods can be applied in patients, their respective limitations, and which challenges need to be overcome for successful implementation in clinical studies. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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30 pages, 9836 KiB  
Review
Mitochondrial Dysfunction in Spinal Muscular Atrophy
by Eleonora Zilio, Valentina Piano and Brunhilde Wirth
Int. J. Mol. Sci. 2022, 23(18), 10878; https://doi.org/10.3390/ijms231810878 - 17 Sep 2022
Cited by 11 | Viewed by 4537
Abstract
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by recessive mutations in the SMN1 gene, globally affecting ~8–14 newborns per 100,000. The severity of the disease depends on the residual levels of functional survival of motor neuron protein, SMN. SMN is [...] Read more.
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by recessive mutations in the SMN1 gene, globally affecting ~8–14 newborns per 100,000. The severity of the disease depends on the residual levels of functional survival of motor neuron protein, SMN. SMN is a ubiquitously expressed RNA binding protein involved in a plethora of cellular processes. In this review, we discuss the effects of SMN loss on mitochondrial functions in the neuronal and muscular systems that are the most affected in patients with spinal muscular atrophy. Our aim is to highlight how mitochondrial defects may contribute to disease progression and how restoring mitochondrial functionality may be a promising approach to develop new therapies. We also collected from previous studies a list of transcripts encoding mitochondrial proteins affected in various SMA models. Moreover, we speculate that in adulthood, when motor neurons require only very low SMN levels, the natural deterioration of mitochondria associated with aging may be a crucial triggering factor for adult spinal muscular atrophy, and this requires particular attention for therapeutic strategies. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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17 pages, 751 KiB  
Review
Nutritional Interventions for Patients with Mitochondrial POLG-Related Diseases: A Systematic Review on Efficacy and Safety
by Zandra Overgaard Pedersen, Sonja Holm-Yildiz and Tina Dysgaard
Int. J. Mol. Sci. 2022, 23(18), 10658; https://doi.org/10.3390/ijms231810658 - 13 Sep 2022
Cited by 1 | Viewed by 2127
Abstract
Ketogenic diet is recommended as a treatment to reduce seizure frequency in patients with intractable epilepsy. The evidence and safety results are sparse for diet interventions in patients with pathogenic polymerase gamma (POLG) variants and intractable epilepsy. The aim of this systematic review [...] Read more.
Ketogenic diet is recommended as a treatment to reduce seizure frequency in patients with intractable epilepsy. The evidence and safety results are sparse for diet interventions in patients with pathogenic polymerase gamma (POLG) variants and intractable epilepsy. The aim of this systematic review is to summarize the efficacy of diet treatment on seizure frequency, clinical symptoms, and potential deleterious effect of liver involvement in patients with mitochondrial diseases caused by pathogenic POLG variants. Literature was searched in PubMed, Embase; and Cochrane in April 2022; no filter restrictions were imposed. The reference lists of retrieved studies were checked for additional literature. Eligibility criteria included verified pathogenic POLG variant and diet treatment. Overall, 880 studies were identified, providing eight case-reports representing nine patients eligible for inclusion. In eight of nine cases, clinical symptoms were improved; six out of nine cases reported improvements in seizure frequency. However, increasing levels of liver enzymes after initiating ketogenic diet were found in four of the nine cases, with one case revealing decreased levels of liver enzymes after initiating long-chain triglyceride restriction. Viewed together, the studies imply that ketogenic diet can have a positive impact on seizure frequency, but may induce progression of liver impairment in patients with pathogenic POLG variants. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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21 pages, 2739 KiB  
Review
Neuroimaging Methods to Map In Vivo Changes of OXPHOS and Oxidative Stress in Neurodegenerative Disorders
by Jannik Prasuhn, Liesa Kunert and Norbert Brüggemann
Int. J. Mol. Sci. 2022, 23(13), 7263; https://doi.org/10.3390/ijms23137263 - 30 Jun 2022
Cited by 11 | Viewed by 2463
Abstract
Mitochondrial dysfunction is a pathophysiological hallmark of most neurodegenerative diseases. Several clinical trials targeting mitochondrial dysfunction have been performed with conflicting results. Reliable biomarkers of mitochondrial dysfunction in vivo are thus needed to optimize future clinical trial designs. This narrative review highlights various [...] Read more.
Mitochondrial dysfunction is a pathophysiological hallmark of most neurodegenerative diseases. Several clinical trials targeting mitochondrial dysfunction have been performed with conflicting results. Reliable biomarkers of mitochondrial dysfunction in vivo are thus needed to optimize future clinical trial designs. This narrative review highlights various neuroimaging methods to probe mitochondrial dysfunction. We provide a general overview of the current biological understanding of mitochondrial dysfunction in degenerative brain disorders and how distinct neuroimaging methods can be employed to map disease-related changes. The reviewed methodological spectrum includes positron emission tomography, magnetic resonance, magnetic resonance spectroscopy, and near-infrared spectroscopy imaging, and how these methods can be applied to study alterations in oxidative phosphorylation and oxidative stress. We highlight the advantages and shortcomings of the different neuroimaging methods and discuss the necessary steps to use these for future research. This review stresses the importance of neuroimaging methods to gain deepened insights into mitochondrial dysfunction in vivo, its role as a critical disease mechanism in neurodegenerative diseases, the applicability for patient stratification in interventional trials, and the quantification of individual treatment responses. The in vivo assessment of mitochondrial dysfunction is a crucial prerequisite for providing individualized treatments for neurodegenerative disorders. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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16 pages, 954 KiB  
Review
Interplay between Zn2+ Homeostasis and Mitochondrial Functions in Cardiovascular Diseases and Heart Ageing
by Siarhei A. Dabravolski, Nikolay K. Sadykhov, Andrey G. Kartuesov, Evgeny E. Borisov, Vasily N. Sukhorukov and Alexander N. Orekhov
Int. J. Mol. Sci. 2022, 23(13), 6890; https://doi.org/10.3390/ijms23136890 - 21 Jun 2022
Cited by 16 | Viewed by 2825
Abstract
Zinc plays an important role in cardiomyocytes, where it exists in bound and histochemically reactive labile Zn2+ forms. Although Zn2+ concentration is under tight control through several Zn2+-transporters, its concentration and intracellular distribution may vary during normal cardiac function [...] Read more.
Zinc plays an important role in cardiomyocytes, where it exists in bound and histochemically reactive labile Zn2+ forms. Although Zn2+ concentration is under tight control through several Zn2+-transporters, its concentration and intracellular distribution may vary during normal cardiac function and pathological conditions, when the protein levels and efficacy of Zn2+ transporters can lead to zinc re-distribution among organelles in cardiomyocytes. Such dysregulation of cellular Zn2+ homeostasis leads to mitochondrial and ER stresses, and interrupts normal ER/mitochondria cross-talk and mitophagy, which subsequently, result in increased ROS production and dysregulated metabolic function. Besides cardiac structural and functional defects, insufficient Zn2+ supply was associated with heart development abnormalities, induction and progression of cardiovascular diseases, resulting in accelerated cardiac ageing. In the present review, we summarize the recently identified connections between cellular and mitochondrial Zn2+ homeostasis, ER stress and mitophagy in heart development, excitation–contraction coupling, heart failure and ischemia/reperfusion injury. Additionally, we discuss the role of Zn2+ in accelerated heart ageing and ageing-associated rise of mitochondrial ROS and cardiomyocyte dysfunction. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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