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Recent Advances on Mitochondrial Diseases
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Recent Advances on Mitochondrial Diseases

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 (20 April 2023) | Viewed by 15198

Special Issue Editor

Dr. Rick Kamps

E-Mail Website
Guest Editor
Department of Toxicogenomics (TGX), School for Mental Health and Neuroscience (MHeNs), Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
Interests: next-generation sequencing; third-generation sequencing; variant classification models; inherited disease; single-cell sequencing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria are considered the powerhouses of the cell, as organelles that convert sugars, fats and proteins inside the mitochondrial double membrane into adenosine triphosphate (ATP), the cellular source of energy. Mitochondria vary in number by cell type, tissue, and organs, depending on their energy requirements. Originally, mitochondria were free-living prokaryotes, but more than a billion years ago an endosymbiotic event made the free-living bacterium part of what would become a eukaryotic cell. Therefore, mitochondria have a dual genetic origin, with a small part of the genetic information being present in the mitochondrial DNA (mtDNA), and the vast majority in the nuclear DNA (nDNA). The majority of the structural proteins of the oxidative phosphorylation (OXPHOS) complexes and the proteins involved in mtDNA replication, transcription, translation, assembly of the OXPHOS protein complexes, maintenance, and in mitochondrial quality control are encoded by around 1500 nDNA genes. Although energy production is the main function of mitochondria, other cellular processes, such as heme synthesis, cellular apoptosis, and calcium homeostasis, are also carried out by mitochondria. Mitochondrial diseases (MD) are the most common genetic metabolic diseases, affecting approximately 1 in 5,000 individuals. MD form a clinically and genetically heterogeneous group of disorders, which generally manifest in tissues or organs with a high energy requirement. The adagium is that MD can display any symptom, at any age and any time. In general, the course of MD is progressive, causing substantial morbidity and mortality. Currently, no effective treatment exists for the vast majority of MD.

Therefore, this Special Issue aims to provide a current overview of mitochondrial diseases to highlight the recent advances in our understanding of the mechanisms, diagnosis and treatment of mitochondrial diseases. Reviews and research papers are encouraged, on topics including, but not limited to, the following:

  • Molecular mechanisms of mitochondrial diseases;
  • Genetic diagnosis in genes encoding mitochondrial proteins;
  • Role of mitochondria in diseases;
  • Mitochondrial translation defects in diseases;
  • Mitochondrial bioenergetics defects in diseases;
  • Mitochondrial damage and mitophagy in diseases;
  • Transmission of mitochondrial DNA mutations in diseases;
  • Treatment and prevention of mitochondrial diseases; or mitochondria-targeted therapy.

Dr. Kamps Rick
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
  • molecular mechanism
  • mitochondrial damage
  • mitophagy
  • mitochondrial DNA mutations
  • targeted therapy

Published Papers (5 papers)

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Research

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17 pages, 2362 KiB  
Article
Methylene Blue Induces Antioxidant Defense and Reparation of Mitochondrial DNA in a Nrf2-Dependent Manner during Cisplatin-Induced Renal Toxicity
by Natalia A. Samoylova, Artem P. Gureev and Vasily N. Popov
Int. J. Mol. Sci. 2023, 24(7), 6118; https://doi.org/10.3390/ijms24076118 - 24 Mar 2023
Cited by 2 | Viewed by 3195
Abstract
Cisplatin is a platinum-based cytostatic drug that is widely used for cancer treatment. Mitochondria and mtDNA are important targets for platinum-based cytostatics, which mediates its nephrotoxicity. It is important to develop therapeutic approaches to protect the kidneys from cisplatin during chemotherapy. We showed [...] Read more.
Cisplatin is a platinum-based cytostatic drug that is widely used for cancer treatment. Mitochondria and mtDNA are important targets for platinum-based cytostatics, which mediates its nephrotoxicity. It is important to develop therapeutic approaches to protect the kidneys from cisplatin during chemotherapy. We showed that the exposure of mitochondria to cisplatin increased the level of lipid peroxidation products in the in vitro experiment. Cisplatin caused strong damage to renal mtDNA, both in the in vivo and in vitro experiments. Cisplatin injections induced oxidative stress by depleting renal antioxidants at the transcriptome level but did not increase the rate of H2O2 production in isolated mitochondria. Methylene blue, on the contrary, induced mitochondrial H2O2 production. We supposed that methylene blue-induced H2O2 production led to activation of the Nrf2/ARE signaling pathway. The consequences of activation of this signaling pathway were manifested in an increase in the expression of some antioxidant genes, which likely caused a decrease in the amount of mtDNA damage. Methylene blue treatment induced an increase in the expression of genes that were involved in the base excision repair (BER) pathway: the main pathway for mtDNA reparation. It is known that the expression of these genes can also be regulated by the Nrf2/ARE signaling pathway. We can assume that the protective effect of methylene blue is related to the activation of Nrf2/ARE signaling pathways, which can activate the expression of genes related to antioxidant defense and mtDNA reparation. Thus, the protection of kidney mitochondria from cisplatin-induced damage using methylene blue can significantly expand its application in medicine. Full article
(This article belongs to the Special Issue Recent Advances on Mitochondrial Diseases)
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11 pages, 3049 KiB  
Article
Fusion of Wild-Type Mesoangioblasts with Myotubes of mtDNA Mutation Carriers Leads to a Proportional Reduction in mtDNA Mutation Load
by Ruby Zelissen, Somaieh Ahmadian, Joaquin Montilla-Rojo, Erika Timmer, Monique Ummelen, Anton Hopman, Hubert Smeets and Florence van Tienen
Int. J. Mol. Sci. 2023, 24(3), 2679; https://doi.org/10.3390/ijms24032679 - 31 Jan 2023
Cited by 2 | Viewed by 1631
Abstract
In 25% of patients with mitochondrial myopathies, pathogenic mitochondrial DNA (mtDNA) mutation are the cause. For heteroplasmic mtDNA mutations, symptoms manifest when the mutation load exceeds a tissue-specific threshold. Therefore, lowering the mutation load is expected to ameliorate disease manifestations. This can be [...] Read more.
In 25% of patients with mitochondrial myopathies, pathogenic mitochondrial DNA (mtDNA) mutation are the cause. For heteroplasmic mtDNA mutations, symptoms manifest when the mutation load exceeds a tissue-specific threshold. Therefore, lowering the mutation load is expected to ameliorate disease manifestations. This can be achieved by fusing wild-type mesoangioblasts with mtDNA mutant myotubes. We have tested this in vitro for female carriers of the m.3271T>C or m.3291T>C mutation (mutation load >90%) using wild-type male mesoangioblasts. Individual fused myotubes were collected by a newly-developed laser capture microdissection (LCM) protocol, visualized by immunostaining using an anti-myosin antibody. Fusion rates were determined based on male-female nuclei ratios by fluorescently labelling the Y-chromosome. Using combined ‘wet’ and ‘air dried’ LCM imaging improved fluorescence imaging quality and cell yield. Wild-type mesoangioblasts fused in different ratios with myotubes containing either the m.3271T>C or the m.3291T>C mutation. This resulted in the reduction of the mtDNA mutation load proportional to the number of fused wild-type mesoangioblasts for both mtDNA mutations. The proportional reduction in mtDNA mutation load in vitro after fusion is promising in the context of muscle stem cell therapy for mtDNA mutation carriers in vivo, in which we propose the same strategy using autologous wild-type mesoangioblasts. Full article
(This article belongs to the Special Issue Recent Advances on Mitochondrial Diseases)
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19 pages, 3804 KiB  
Article
Stimulating Mitochondrial Biogenesis with Deoxyribonucleosides Increases Functional Capacity in ECHS1-Deficient Cells
by Harrison James Burgin, Jordan James Crameri, Diana Stojanovski, M. Isabel G. Lopez Sanchez, Mark Ziemann and Matthew McKenzie
Int. J. Mol. Sci. 2022, 23(20), 12610; https://doi.org/10.3390/ijms232012610 - 20 Oct 2022
Cited by 1 | Viewed by 1880
Abstract
The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that stimulate mitochondrial biogenesis to boost ATP production. Here, we examined the effects of deoxyribonucleosides (dNs) on mitochondrial biogenesis and function in Short chain enoyl-CoA hydratase [...] Read more.
The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that stimulate mitochondrial biogenesis to boost ATP production. Here, we examined the effects of deoxyribonucleosides (dNs) on mitochondrial biogenesis and function in Short chain enoyl-CoA hydratase 1 (ECHS1) ‘knockout’ (KO) cells, which exhibit combined defects in both oxidative phosphorylation (OXPHOS) and mitochondrial fatty acid β-oxidation (FAO). DNs treatment increased mitochondrial DNA (mtDNA) copy number and the expression of mtDNA-encoded transcripts in both CONTROL (CON) and ECHS1 KO cells. DNs treatment also altered global nuclear gene expression, with key gene sets including ‘respiratory electron transport’ and ‘formation of ATP by chemiosmotic coupling’ increased in both CON and ECHS1 KO cells. Genes involved in OXPHOS complex I biogenesis were also upregulated in both CON and ECHS1 KO cells following dNs treatment, with a corresponding increase in the steady-state levels of holocomplex I in ECHS1 KO cells. Steady-state levels of OXPHOS complex V, and the CIII2/CIV and CI/CIII2/CIV supercomplexes, were also increased by dNs treatment in ECHS1 KO cells. Importantly, treatment with dNs increased both basal and maximal mitochondrial oxygen consumption in ECHS1 KO cells when metabolizing either glucose or the fatty acid palmitoyl-L-carnitine. These findings highlight the ability of dNs to improve overall mitochondrial respiratory function, via the stimulation mitochondrial biogenesis, in the face of combined defects in OXPHOS and FAO due to ECHS1 deficiency. Full article
(This article belongs to the Special Issue Recent Advances on Mitochondrial Diseases)
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Review

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12 pages, 1047 KiB  
Review
Mitochondrial Dysfunction, Altered Mitochondrial Oxygen, and Energy Metabolism Associated with the Pathogenesis of Schizophrenia
by Iveta Fizíková, Jozef Dragašek and Peter Račay
Int. J. Mol. Sci. 2023, 24(9), 7991; https://doi.org/10.3390/ijms24097991 - 28 Apr 2023
Cited by 5 | Viewed by 3810
Abstract
The significant complexity of the brain can lead to the development of serious neuropsychiatric disorders, including schizophrenia. A number of mechanisms are involved in the etiopathogenesis of schizophrenia, pointing to its complexity and opening a new perspective on studying this disorder. In this [...] Read more.
The significant complexity of the brain can lead to the development of serious neuropsychiatric disorders, including schizophrenia. A number of mechanisms are involved in the etiopathogenesis of schizophrenia, pointing to its complexity and opening a new perspective on studying this disorder. In this review of currently published studies, we focused on the contribution of mitochondria to the process, with an emphasis on oxidative damage, ROS, and energy metabolism. In addition, we point out the influence of redox imbalance, which can lead to the occurrence of oxidative stress with increased lipid peroxidation, linked to the formation of toxic aldehydes such as 4-hydroxynonenal (4-HNE) and HNE protein adducts. We also analysed the role of lactate in the process of energy metabolism and cognitive functions in schizophrenia. Full article
(This article belongs to the Special Issue Recent Advances on Mitochondrial Diseases)
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19 pages, 1094 KiB  
Review
Mitochondrial Protein Homeostasis and Cardiomyopathy
by Emily Wachoski-Dark, Tian Zhao, Aneal Khan, Timothy E. Shutt and Steven C. Greenway
Int. J. Mol. Sci. 2022, 23(6), 3353; https://doi.org/10.3390/ijms23063353 - 20 Mar 2022
Cited by 11 | Viewed by 3850
Abstract
Human mitochondrial disorders impact tissues with high energetic demands and can be associated with cardiac muscle disease (cardiomyopathy) and early mortality. However, the mechanistic link between mitochondrial disease and the development of cardiomyopathy is frequently unclear. In addition, there is often marked phenotypic [...] Read more.
Human mitochondrial disorders impact tissues with high energetic demands and can be associated with cardiac muscle disease (cardiomyopathy) and early mortality. However, the mechanistic link between mitochondrial disease and the development of cardiomyopathy is frequently unclear. In addition, there is often marked phenotypic heterogeneity between patients, even between those with the same genetic variant, which is also not well understood. Several of the mitochondrial cardiomyopathies are related to defects in the maintenance of mitochondrial protein homeostasis, or proteostasis. This essential process involves the importing, sorting, folding and degradation of preproteins into fully functional mature structures inside mitochondria. Disrupted mitochondrial proteostasis interferes with mitochondrial energetics and ATP production, which can directly impact cardiac function. An inability to maintain proteostasis can result in mitochondrial dysfunction and subsequent mitophagy or even apoptosis. We review the known mitochondrial diseases that have been associated with cardiomyopathy and which arise from mutations in genes that are important for mitochondrial proteostasis. Genes discussed include DnaJ heat shock protein family member C19 (DNAJC19), mitochondrial import inner membrane translocase subunit TIM16 (MAGMAS), translocase of the inner mitochondrial membrane 50 (TIMM50), mitochondrial intermediate peptidase (MIPEP), X-prolyl-aminopeptidase 3 (XPNPEP3), HtraA serine peptidase 2 (HTRA2), caseinolytic mitochondrial peptidase chaperone subunit B (CLPB) and heat shock 60-kD protein 1 (HSPD1). The identification and description of disorders with a shared mechanism of disease may provide further insights into the disease process and assist with the identification of potential therapeutics. Full article
(This article belongs to the Special Issue Recent Advances on Mitochondrial Diseases)
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