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Mitochondrial Disorders: Biochemical and Molecular Basis of Disease
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Mitochondrial Disorders: Biochemical and Molecular Basis of Disease

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 (20 August 2023) | Viewed by 8636

Special Issue Editors

Dr. Charlotte L. Alston

E-Mail Website
Guest Editor
Wellcome Centre for Mitochondrial Research, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
Interests: rare diseases; paediatric mitochondrial disease; new genomic and functional technologies
Dr. Alison G. Compton

E-Mail Website
Guest Editor
Murdoch Children’s Research Institute, Melbourne, VIC 3052, Australia
Interests: mitochondrial disease gene discovery; rare diseases; new genomic and functional technologies

Special Issue Information

Dear Colleagues,

Mitochondrial disease is an umbrella term used to describe a collection of inborn errors of metabolism that manifest as mitochondrial dysfunction and impaired cellular ATP production. Mitochondrial diseases have a minimum birth prevalence of 1:4,300 and are challenging to diagnose both clinically and genetically. They can present at any age, affecting both adults and children alike, and due to the ubiquitous nature of mitochondria within nucleated eukaryotic cells can affect any organ or tissue, with symptom severity varying dramatically from fatal infantile lactic acidosis and Leigh syndrome in children to late-onset chronic progressive opthalmoplegia (CPEO) and isolated myopathy in adults. Most of the over 1100 proteins required for normal mitochondrial function are encoded by the nuclear genome and imported into the mitochondria. However, a small number of equally important proteins are encoded by the mitochondria’s own genome, mtDNA. As mtDNA has unique characteristics for replication and inheritance outside of the better known Mendelian laws of genetics (which include maternal inheritance, tissue specific heteroplasmy and threshold effects), these factors combine to complicate the diagnostic process.

This Special Issue aims to review and expand the molecular and biochemical basis of mitochondrial disease, along with any developments in clinical expansion and improvements in diagnostic processes which may aid in diagnosis. With improved understanding of the processes that underpin mitochondrial dysfunction, we hope to identify therapeutic targets and improve counselling and patient management in the interim.

Dr. Charlotte L. Alston
Dr. Alison G. Compton
Guest Editors

Manuscript Submission Information

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Keywords

  • mitochondrial disease genetics

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Published Papers (3 papers)

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27 pages, 13499 KiB  
Article
Single-Cell Transcriptional Landscape Reveals the Regulatory Network and Its Heterogeneity of Renal Mitochondrial Damages in Diabetic Kidney Disease
by Chenhua Wu, Yuhui Song, Yihong Yu, Qing Xu, Xu Cui, Yurong Wang, Jie Wu and Harvest F. Gu
Int. J. Mol. Sci. 2023, 24(17), 13502; https://doi.org/10.3390/ijms241713502 - 31 Aug 2023
Cited by 5 | Viewed by 2607
Abstract
Diabetic kidney disease (DKD) is one of the common chronic microvascular complications of diabetes in which mitochondrial disorder plays an important role in its pathogenesis. The current study delved into the single-cell level transcriptome heterogeneity of mitochondrial homeostasis in db/db mice, an animal [...] Read more.
Diabetic kidney disease (DKD) is one of the common chronic microvascular complications of diabetes in which mitochondrial disorder plays an important role in its pathogenesis. The current study delved into the single-cell level transcriptome heterogeneity of mitochondrial homeostasis in db/db mice, an animal model for study of type 2 diabetes and DKD, with single-cell RNA sequencing (scRNA-Seq) and bulk RNA-seq analyses. From the comprehensive dataset comprising 13 meticulously captured and authenticated renal cell types, an unsupervised cluster analysis of mitochondria-related genes within the descending loop of Henle, collecting duct principal cell, endothelial, B cells and macrophage, showed that they had two types of cell subsets, i.e., health-dominant and DKD-dominant clusters. Pseudotime analysis, cell communication and transcription factors forecast resulted in identification of the hub differentially expressed genes between these two clusters and unveiled that the hierarchical regulatory network of receptor-TF-target genes was triggered by mitochondrial degeneration. Furthermore, the collecting duct principal cells were found to be regulated by the decline of Fzd7, which contributed to the impaired cellular proliferation and development, apoptosis and inactive cell cycle, as well as diminished capacity for material transport. Thereby, both scRNA-Seq and bulk RNA-Seq data from the current study elucidate the heterogeneity of mitochondrial disorders among distinct cell types, particularly in the collecting duct principal cells and B cells during the DKD progression and drug administration, which provide novel insights for better understanding the pathogenesis of DKD. Full article
(This article belongs to the Special Issue Mitochondrial Disorders: Biochemical and Molecular Basis of Disease)
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18 pages, 7607 KiB  
Article
CDDO-Me Abrogates Aberrant Mitochondrial Elongation in Clasmatodendritic Degeneration by Regulating NF-κB-PDI-Mediated S-Nitrosylation of DRP1
by Duk-Shin Lee, Tae-Hyun Kim, Hana Park and Ji-Eun Kim
Int. J. Mol. Sci. 2023, 24(6), 5875; https://doi.org/10.3390/ijms24065875 - 20 Mar 2023
Cited by 2 | Viewed by 1774
Abstract
Clasmatodendrosis is a kind of astroglial degeneration pattern which facilitates excessive autophagy. Although abnormal mitochondrial elongation is relevant to this astroglial degeneration, the underlying mechanisms of aberrant mitochondrial dynamics are still incompletely understood. Protein disulfide isomerase (PDI) is an oxidoreductase in the endoplasmic [...] Read more.
Clasmatodendrosis is a kind of astroglial degeneration pattern which facilitates excessive autophagy. Although abnormal mitochondrial elongation is relevant to this astroglial degeneration, the underlying mechanisms of aberrant mitochondrial dynamics are still incompletely understood. Protein disulfide isomerase (PDI) is an oxidoreductase in the endoplasmic reticulum (ER). Since PDI expression is downregulated in clasmatodendritic astrocytes, PDI may be involved in aberrant mitochondrial elongation in clasmatodendritic astrocytes. In the present study, 26% of CA1 astrocytes showed clasmatodendritic degeneration in chronic epilepsy rats. 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me; bardoxolone methyl or RTA 402) and SN50 (a nuclear factor-κB (NF-κB) inhibitor) ameliorated the fraction of clasmatodendritic astrocytes to 6.8 and 8.1% in CA1 astrocytes, accompanied by the decreases in lysosomal-associated membrane protein 1 (LAMP1) expression and microtubule-associated protein 1A/1B light-chain 3 (LC3)-II/LC3-I ratio, indicating the reduced autophagy flux. Furthermore, CDDO-Me and SN50 reduced NF-κB S529 fluorescent intensity to 0.6- and 0.57-fold of vehicle-treated animal level, respectively. CDDO-Me and SN50 facilitated mitochondrial fission in CA1 astrocytes, independent of dynamin-related protein 1 (DRP1) S616 phosphorylation. In chronic epilepsy rats, total PDI protein, S-nitrosylated PDI (SNO-PDI), and SNO-DRP1 levels were 0.35-, 0.34- and 0.45-fold of control level, respectively, in the CA1 region and increased CDDO-Me and SN50. Furthermore, PDI knockdown resulted in mitochondrial elongation in intact CA1 astrocytes under physiological condition, while it did not evoke clasmatodendrosis. Therefore, our findings suggest that NF-κB-mediated PDI inhibition may play an important role in clasmatodendrosis via aberrant mitochondrial elongation. Full article
(This article belongs to the Special Issue Mitochondrial Disorders: Biochemical and Molecular Basis of Disease)
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14 pages, 4703 KiB  
Case Report
Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma
by Nicole J. Van Bergen, Karen Gunanayagam, Adam M. Bournazos, Adhish S. Walvekar, Marc O. Warmoes, Liana N. Semcesen, Sebastian Lunke, Shobhana Bommireddipalli, Tim Sikora, Myrto Patraskaki, Dean L. Jones, Denisse Garza, Dale Sebire, Samuel Gooley, Catriona A. McLean, Parm Naidoo, Mugil Rajasekaran, David A. Stroud, Carole L. Linster, Mathew Wallis, Sandra T. Cooper and John Christodoulouadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2023, 24(4), 3582; https://doi.org/10.3390/ijms24043582 - 10 Feb 2023
Cited by 6 | Viewed by 3471
Abstract
We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the [...] Read more.
We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this individual were likely triggered by mild head trauma. This patient had a novel homozygous NAXD variant [NM_001242882.1:c.441+3A>G:p.?] that induces the mis-splicing of the majority of NAXD transcripts, leaving only trace levels of canonically spliced NAXD mRNA, and protein levels below the detection threshold by proteomic analysis. Accumulation of damaged NADH, the substrate of NAXD, could be detected in the fibroblasts of the patient. In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient. The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of mitochondrial apoptotic pathways. Importantly, we highlight that head trauma in adults, in addition to paediatric fever or illness, may precipitate neurometabolic crises associated with pathogenic NAXD variants. Full article
(This article belongs to the Special Issue Mitochondrial Disorders: Biochemical and Molecular Basis of Disease)
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