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New Advances in Molecular Research on Impaired Mitochondrial Metabolism in Disease

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: 7 July 2024 | Viewed by 17011

Special Issue Editor

Special Issue Information

Dear Colleagues, 

Mitochondrial metabolism is central to the generation of the chemical energy required to power  biochemical functions within the cell, in addition to providing the building blocks necessary for the synthesis of macromolecules. Furthermore, mitochondria are also central mediators of cellular signalling, apoptosis and the maintenance of calcium homeostasis. Mitochondria are generally highly dynamic organelles undergoing fusion or fission, which is required to maintain functional mitochondria when cells experience metabolic or environmental stress. Given the many important roles of the mitochondria for normal cellular function, it is not surprising that mitochondrial dysfunction has been associated with a wide variety of diseases, which can arise from either genetic defects in nuclear or mitochondrial DNA (nDNA and  mtDNA, respectively) affecting core mitochondrial components, known as primary mitochondrial disorders, or as the result of malfunctioning pathways or the secondary consequences of disease pathophysiology, known as secondary mitochondrial disorders.

At present, the diagnosis of impaired mitochondrial metabolism is impeded by the paucity of reliable surrogate markers. The assessment of oxidative stress is also an important consideration in the context of mitochondrial dysfunction in view of the association between mitochondrial respiratory chain dysfunction and increased cellular reactive oxygen species generation. Although not a specific diagnostic parameter, it can provide important information about disease pathophysiology, as well as the therapeutic efficacy of antioxidant strategies utilised for treating these disorders. Overall, due to the lack of reliable validated biomarkers or surrogates available to evaluate evidence of impaired mitochondrial metabolism in disease, more invasive strategies, such as tissue biopsies, for the assessment of enzyme  activities are still required. Less invasive strategies using blood or buccal swabs for assessing nDNA and mtDNA defects, using techniques that reduce labour, time, and costs and increase accuracy, offer potential improvements in patient diagnoses.

The purpose of this Special Issue is to provide up-to-date information on new developments and methods available to elucidate evidence of impaired mitochondrial metabolism in disease. Since IJMS is a journal of molecular science, pure clinical studies are not suitable for submission. However, clinical or pure model studies with biomolecular experiments are welcome.

Dr. Iain P. Hargreaves
Guest Editor

Manuscript Submission Information

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Keywords

  • mitochondrial metabolism
  • mitochondrial dysfunction
  • mitochondrial disorder
  • oxidative stress

Published Papers (6 papers)

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Research

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15 pages, 1810 KiB  
Article
Microarrays, Enzymatic Assays, and MALDI-MS for Determining Specific Alterations to Mitochondrial Electron Transport Chain Activity, ROS Formation, and Lipid Composition in a Monkey Model of Parkinson’s Disease
by María Dolores García-Fernández, Ane Larrea, Roberto Fernández, Rafael Rodríguez-Puertas, Egoitz Astigarraga, Iván Manuel and Gabriel Barreda-Gómez
Int. J. Mol. Sci. 2023, 24(6), 5470; https://doi.org/10.3390/ijms24065470 - 13 Mar 2023
Viewed by 1659
Abstract
Multiple evidences suggest that mitochondrial dysfunction is implicated in the pathogenesis of Parkinson’s disease via the selective cell death of dopaminergic neurons, such as that which occurs after prolonged exposure to the mitochondrial electron transport chain (ETC) complex I inhibitor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP). However, [...] Read more.
Multiple evidences suggest that mitochondrial dysfunction is implicated in the pathogenesis of Parkinson’s disease via the selective cell death of dopaminergic neurons, such as that which occurs after prolonged exposure to the mitochondrial electron transport chain (ETC) complex I inhibitor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP). However, the effects of chronic MPTP on the ETC complexes and on enzymes of lipid metabolism have not yet been thoroughly determined. To face these questions, the enzymatic activities of ETC complexes and the lipidomic profile of MPTP-treated non-human primate samples were determined using cell membrane microarrays from different brain areas and tissues. MPTP treatment induced an increase in complex II activity in the olfactory bulb, putamen, caudate, and substantia nigra, where a decrease in complex IV activity was observed. The lipidomic profile was also altered in these areas, with a reduction in the phosphatidylserine (38:1) content being especially relevant. Thus, MPTP treatment not only modulates ETC enzymes, but also seems to alter other mitochondrial enzymes that regulate the lipid metabolism. Moreover, these results show that a combination of cell membrane microarrays, enzymatic assays, and MALDI-MS provides a powerful tool for identifying and validating new therapeutic targets that might accelerate the drug discovery process. Full article
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15 pages, 1571 KiB  
Article
Mitochondrial Transfer into Human Oocytes Improved Embryo Quality and Clinical Outcomes in Recurrent Pregnancy Failure Cases
by Yoshiharu Morimoto, Udayanga Sanath Kankanam Gamage, Takayuki Yamochi, Noriatsu Saeki, Naoharu Morimoto, Masaya Yamanaka, Akiko Koike, Yuki Miyamoto, Kumiko Tanaka, Aisaku Fukuda, Shu Hashimoto and Ryuzo Yanagimachi
Int. J. Mol. Sci. 2023, 24(3), 2738; https://doi.org/10.3390/ijms24032738 - 1 Feb 2023
Cited by 10 | Viewed by 3155
Abstract
One of the most critical issues to be solved in reproductive medicine is the treatment of patients with multiple failures of assisted reproductive treatment caused by low-quality embryos. This study investigated whether mitochondrial transfer to human oocytes improves embryo quality and provides subsequent [...] Read more.
One of the most critical issues to be solved in reproductive medicine is the treatment of patients with multiple failures of assisted reproductive treatment caused by low-quality embryos. This study investigated whether mitochondrial transfer to human oocytes improves embryo quality and provides subsequent acceptable clinical results and normality to children born due to the use of this technology. We transferred autologous mitochondria extracted from oogonia stem cells to mature oocytes with sperm at the time of intracytoplasmic sperm injection in 52 patients with recurrent failures (average 5.3 times). We assessed embryo quality using the following three methods: good-quality embryo rates, transferable embryo rates, and a novel embryo-scoring system (embryo quality score; EQS) in 33 patients who meet the preset inclusion criteria for analysis. We also evaluated the clinical outcomes of the in vitro fertilization and development of children born using this technology and compared the mtDNA sequences of the children and their mothers. The good-quality embryo rates, transferable embryo rates, and EQS significantly increased after mitochondrial transfer and resulted in 13 babies born in normal conditions. The mtDNA sequences were almost identical to the respective maternal sequences at the 83 major sites examined. Mitochondrial transfer into human oocytes is an effective clinical option to enhance embryo quality in recurrent in vitro fertilization-failure cases. Full article
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21 pages, 4332 KiB  
Article
A Mutation in Mouse MT-ATP6 Gene Induces Respiration Defects and Opposed Effects on the Cell Tumorigenic Phenotype
by Raquel Moreno-Loshuertos, Nieves Movilla, Joaquín Marco-Brualla, Ruth Soler-Agesta, Patricia Ferreira, José Antonio Enríquez and Patricio Fernández-Silva
Int. J. Mol. Sci. 2023, 24(2), 1300; https://doi.org/10.3390/ijms24021300 - 9 Jan 2023
Cited by 3 | Viewed by 2619
Abstract
As the last step of the OXPHOS system, mitochondrial ATP synthase (or complex V) is responsible for ATP production by using the generated proton gradient, but also has an impact on other important functions linked to this system. Mutations either in complex V [...] Read more.
As the last step of the OXPHOS system, mitochondrial ATP synthase (or complex V) is responsible for ATP production by using the generated proton gradient, but also has an impact on other important functions linked to this system. Mutations either in complex V structural subunits, especially in mtDNA-encoded ATP6 gene, or in its assembly factors, are the molecular cause of a wide variety of human diseases, most of them classified as neurodegenerative disorders. The role of ATP synthase alterations in cancer development or metastasis has also been postulated. In this work, we reported the generation and characterization of the first mt-Atp6 pathological mutation in mouse cells, an m.8414A>G transition that promotes an amino acid change from Asn to Ser at a highly conserved residue of the protein (p.N163S), located near the path followed by protons from the intermembrane space to the mitochondrial matrix. The phenotypic consequences of the p.N163S change reproduce the effects of MT-ATP6 mutations in human diseases, such as dependence on glycolysis, defective OXPHOS activity, ATP synthesis impairment, increased ROS generation or mitochondrial membrane potential alteration. These observations demonstrate that this mutant cell line could be of great interest for the generation of mouse models with the aim of studying human diseases caused by alterations in ATP synthase. On the other hand, mutant cells showed lower migration capacity, higher expression of MHC-I and slightly lower levels of HIF-1α, indicating a possible reduction of their tumorigenic potential. These results could suggest a protective role of ATP synthase inhibition against tumor transformation that could open the door to new therapeutic strategies in those cancer types relying on OXPHOS metabolism. Full article
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Review

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28 pages, 1482 KiB  
Review
Mitochondrial Bioenergy in Neurodegenerative Disease: Huntington and Parkinson
by Annalisa Tassone, Maria Meringolo, Giulia Ponterio, Paola Bonsi, Tommaso Schirinzi and Giuseppina Martella
Int. J. Mol. Sci. 2023, 24(8), 7221; https://doi.org/10.3390/ijms24087221 - 13 Apr 2023
Cited by 6 | Viewed by 2825
Abstract
Strong evidence suggests a correlation between degeneration and mitochondrial deficiency. Typical cases of degeneration can be observed in physiological phenomena (i.e., ageing) as well as in neurological neurodegenerative diseases and cancer. All these pathologies have the dyshomeostasis of mitochondrial bioenergy as a common [...] Read more.
Strong evidence suggests a correlation between degeneration and mitochondrial deficiency. Typical cases of degeneration can be observed in physiological phenomena (i.e., ageing) as well as in neurological neurodegenerative diseases and cancer. All these pathologies have the dyshomeostasis of mitochondrial bioenergy as a common denominator. Neurodegenerative diseases show bioenergetic imbalances in their pathogenesis or progression. Huntington’s chorea and Parkinson’s disease are both neurodegenerative diseases, but while Huntington’s disease is genetic and progressive with early manifestation and severe penetrance, Parkinson’s disease is a pathology with multifactorial aspects. Indeed, there are different types of Parkinson/Parkinsonism. Many forms are early-onset diseases linked to gene mutations, while others could be idiopathic, appear in young adults, or be post-injury senescence conditions. Although Huntington’s is defined as a hyperkinetic disorder, Parkinson’s is a hypokinetic disorder. However, they both share a lot of similarities, such as neuronal excitability, the loss of striatal function, psychiatric comorbidity, etc. In this review, we will describe the start and development of both diseases in relation to mitochondrial dysfunction. These dysfunctions act on energy metabolism and reduce the vitality of neurons in many different brain areas. Full article
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25 pages, 1556 KiB  
Review
Mitochondrial Base Editing: Recent Advances towards Therapeutic Opportunities
by Bibekananda Kar, Santiago R. Castillo, Ankit Sabharwal, Karl J. Clark and Stephen C. Ekker
Int. J. Mol. Sci. 2023, 24(6), 5798; https://doi.org/10.3390/ijms24065798 - 18 Mar 2023
Cited by 6 | Viewed by 3579
Abstract
Mitochondria are critical organelles that form networks within our cells, generate energy dynamically, contribute to diverse cell and organ function, and produce a variety of critical signaling molecules, such as cortisol. This intracellular microbiome can differ between cells, tissues, and organs. Mitochondria can [...] Read more.
Mitochondria are critical organelles that form networks within our cells, generate energy dynamically, contribute to diverse cell and organ function, and produce a variety of critical signaling molecules, such as cortisol. This intracellular microbiome can differ between cells, tissues, and organs. Mitochondria can change with disease, age, and in response to the environment. Single nucleotide variants in the circular genomes of human mitochondrial DNA are associated with many different life-threatening diseases. Mitochondrial DNA base editing tools have established novel disease models and represent a new possibility toward personalized gene therapies for the treatment of mtDNA-based disorders. Full article
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21 pages, 680 KiB  
Review
Secondary Mitochondrial Dysfunction as a Cause of Neurodegenerative Dysfunction in Lysosomal Storage Diseases and an Overview of Potential Therapies
by Karolina M. Stepien, Neve Cufflin, Aimee Donald, Simon Jones, Heather Church and Iain P. Hargreaves
Int. J. Mol. Sci. 2022, 23(18), 10573; https://doi.org/10.3390/ijms231810573 - 12 Sep 2022
Cited by 7 | Viewed by 2232
Abstract
Mitochondrial dysfunction has been recognised a major contributory factor to the pathophysiology of a number of lysosomal storage disorders (LSDs). The cause of mitochondrial dysfunction in LSDs is as yet uncertain, but appears to be triggered by a number of different factors, although [...] Read more.
Mitochondrial dysfunction has been recognised a major contributory factor to the pathophysiology of a number of lysosomal storage disorders (LSDs). The cause of mitochondrial dysfunction in LSDs is as yet uncertain, but appears to be triggered by a number of different factors, although oxidative stress and impaired mitophagy appear to be common inhibitory mechanisms shared amongst this group of disorders, including Gaucher’s disease, Niemann–Pick disease, type C, and mucopolysaccharidosis. Many LSDs resulting from defects in lysosomal hydrolase activity show neurodegeneration, which remains challenging to treat. Currently available curative therapies are not sufficient to meet patients’ needs. In view of the documented evidence of mitochondrial dysfunction in the neurodegeneration of LSDs, along with the reciprocal interaction between the mitochondrion and the lysosome, novel therapeutic strategies that target the impairment in both of these organelles could be considered in the clinical management of the long-term neurodegenerative complications of these diseases. The purpose of this review is to outline the putative mechanisms that may be responsible for the reported mitochondrial dysfunction in LSDs and to discuss the new potential therapeutic developments. Full article
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