Mitochondrial Genetic Variation in Health and Disease

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 3870

Special Issue Editor

Vascular Biology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
Interests: mitochondria; mitochondrial DNA; tobacco smoking; e-cigarettes; tobacco regulatory science; vascular endothelium

Special Issue Information

Dear Colleagues,

Mitochondria are central to cellular function, providing not only the ATP needed to sustain life, but also serving as central regulators of cellular phenotype. Oxidative phosphorylation is the mitochondrial process that generates energy for most cellular activities with alterations in oxidative phosphorylation driving changes in upstream metabolic pathways. The oxidative phosphorylation complexes are encoded by both the mitochondrial and nuclear genomes with the nuclear genome also encoding assembly factors and chaperones required for oxidative phosphorylation complex assembly.

Defects in mitochondrial genes result in a spectrum of diseases in humans, ranging from severe pediatric syndromes to aging-related diseases. Multiple copies of the mitochondrial genome are present within a mitochondrion; hence, hundreds to thousands of mitochondrial DNA copies exist per cell. Consequently, mitochondrial DNA copies carrying different mitochondrial variants may co-exist, a condition termed heteroplasmy. Prior technologies were unable to detect low-level, heteroplasmic mitochondrial DNA variants but advances in next-generation sequencing have provided new opportunities to advance our understanding of the contribution of mitochondrial genetic variation in health and disease. The goal of this Special Issue is to provide an overview of the current state of our understanding of mitochondrial genetic variation in health and disease and the opportunities and challenges provided by advances in next-generation sequencing, multiomics, gene editing techniques, and stem cell biology.

Dr. Jessica L. Fetterman
Guest Editor

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Keywords

  • mitochondrial DNA
  • mitochondrial genes
  • mitochondrial mutations
  • mitochondrial variants
  • heteroplasmy
  • oxidative phosphorylation
  • mitochondrial disease

Published Papers (2 papers)

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Research

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15 pages, 3298 KiB  
Article
Mitochondrial Diabetes Is Associated with the ND4 G11696A Mutation
Biomolecules 2023, 13(6), 907; https://doi.org/10.3390/biom13060907 - 30 May 2023
Cited by 1 | Viewed by 1199
Abstract
Type 2 diabetes mellitus (T2DM) is a common endocrine disorder which remains a large challenge for clinicians. Previous studies have suggested that mitochondrial dysfunction plays an active role in T2DM progression, but a detailed mechanism is still elusive. In the current study, two [...] Read more.
Type 2 diabetes mellitus (T2DM) is a common endocrine disorder which remains a large challenge for clinicians. Previous studies have suggested that mitochondrial dysfunction plays an active role in T2DM progression, but a detailed mechanism is still elusive. In the current study, two Han Chinese families with maternally inherited T2DM were evaluated using clinical, genetic, molecular, and biochemical analyses. The mitochondrial genomes were PCR amplified and sequenced. Phylogenetic and bioinformatic analyses were used to assess the potential pathogenicity of mitochondrial DNA (mtDNA) mutations. Interestingly, the matrilineal relatives of these pedigrees exhibited variable severity of T2DM, in particular, the age at onset of T2DM varied from 26 to 65 years, with an average of 49 years. Sequence analysis revealed the presence of ND4 G11696A mutation, which resulted in the substitution of an isoleucine for valine at amino acid (AA) position 312. Indeed, this mutation was present in homoplasmy only in the maternal lineage, not in other members of these families, as well as 200 controls. Furthermore, the m.C5601T in the tRNAAla and novel m.T5813C in the tRNACys, showing high evolutional conservation, may contribute to the phenotypic expression of ND4 G11696A mutation. In addition, biochemical analysis revealed that cells with ND4 G11696A mutation exhibited higher levels of reactive oxygen species (ROS) productions than the controls. In contrast, the levels of mitochondrial membrane potential (MMP), ATP, mtDNA copy number (mtDNA-CN), Complex I activity, and NAD+/NADH ratio significantly decreased in cell lines carrying the m.G11696A and tRNA mutations, suggesting that these mutations affected the respiratory chain function and led to mitochondrial dysfunction that was involved in T2DM. Thus, our study broadened the clinical phenotypes of m.G11696A mutation. Full article
(This article belongs to the Special Issue Mitochondrial Genetic Variation in Health and Disease)
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Review

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11 pages, 2238 KiB  
Review
The Mighty NUMT: Mitochondrial DNA Flexing Its Code in the Nuclear Genome
Biomolecules 2023, 13(5), 753; https://doi.org/10.3390/biom13050753 - 27 Apr 2023
Cited by 4 | Viewed by 1843
Abstract
Nuclear-mitochondrial DNA segments (NUMTs) are mitochondrial DNA (mtDNA) fragments that have been inserted into the nuclear genome. Some NUMTs are common within the human population but most NUMTs are rare and specific to individuals. NUMTs range in size from 24 base pairs to [...] Read more.
Nuclear-mitochondrial DNA segments (NUMTs) are mitochondrial DNA (mtDNA) fragments that have been inserted into the nuclear genome. Some NUMTs are common within the human population but most NUMTs are rare and specific to individuals. NUMTs range in size from 24 base pairs to encompassing nearly the entire mtDNA and are found throughout the nuclear genome. Emerging evidence suggests that the formation of NUMTs is an ongoing process in humans. NUMTs contaminate sequencing results of the mtDNA by introducing false positive variants, particularly heteroplasmic variants present at a low variant allele frequency (VAF). In our review, we discuss the prevalence of NUMTs in the human population, the potential mechanisms of de novo NUMT insertion via DNA repair mechanisms, and provide an overview of the existing approaches for minimizing NUMT contamination. Apart from filtering known NUMTs, both wet lab-based and computational methods can be used to minimize the contamination of NUMTs in analyses of human mtDNA. Current approaches include: (1) isolating mitochondria to enrich for mtDNA; (2) applying basic local alignment to identify NUMTs for subsequent filtering; (3) bioinformatic pipelines for NUMT detection; (4) k-mer-based NUMT detection; and (5) filtering candidate false positive variants by mtDNA copy number, VAF, or sequence quality score. Multiple approaches must be applied in order to effectively identify NUMTs in samples. Although next-generation sequencing is revolutionizing our understanding of heteroplasmic mtDNA, it also raises new challenges with the high prevalence and individual-specific NUMTs that need to be handled with care in studies of mitochondrial genetics. Full article
(This article belongs to the Special Issue Mitochondrial Genetic Variation in Health and Disease)
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