Special Issue "Mitochondrial Genetics"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Organelle Function".

Deadline for manuscript submissions: closed (28 February 2019)

Special Issue Editor

Guest Editor
Prof. Dr. Maria Cristina Kenney

Gavin Herbert Eye Institute, University of California, Irvine, 843 Health Science Road, Irvine, CA 92697, USA
Website | E-Mail
Interests: age-related macular degeneration; AMD; mitochondrial genetics; Keratoconus; KC

Special Issue Information

Dear Colleagues,

Mitochondria originated from free-living, aerobic bacteria that were incorporated into the early, ancestral eukaryotic cells.  Over time, this symbiotic relationship resulted in increased levels of energy production that allowed progression from single-cell eukaryotes to multi-cellular organisms, tissues and the diversity of species found worldwide.  Cells possess the nuclear DNA (nDNA) inherited from both the father and mother, along with the maternally inherited mitochondrial (mt) DNA, which can be classified based upon their single nucleotide polymorphism (SNP) patterns into haplogroups representing ancestral geographic regions. 

There is increased interest to understand the role of the mtDNA in human disease pathologies because in addition to energy production and redox status, the mtDNA plays an important role in retrograde signaling that modulates the nuclear genome.  The influences of mtDNA upon disease processes can be separated into three categories. First, some human diseases are caused by specific mutations within the mtDNA genome.  Secondly, other studies show that mtDNA haplogroups representing different ethnic/racial populations may also be associated with specific diseases, because some haplogroup-defining SNPs cause changes in amino acids (nonsynonymous), modify replication/transcription levels and alter retrograde signaling profiles.  Finally, the mtDNA damage due to aging can lower mitochondrial efficiency, elevate levels of reactive oxygen species (ROS) causing cellular impairment and contribute to many age-related diseases.  Techniques for in-depth sequencing and characterization of mtDNA have lagged behind the advancements that nDNA analyses have taken.  However, it is vital to gain greater understanding of the contribution that the mitochondrial genome has on the development and progression of human diseases. 

The aim of this Special Issue is to provide a comprehensive overview of various aspects of the mtDNA, including (a) methods available for sequencing, classifying haplogroups and identifying low level heteroplasmy variants, (b) cell culture and animal models to determine the functional consequences of having mtDNA variants, and (c) potential treatments to regulate and restore the dysfunctional mtDNA associated with human diseases.  We hope that the experts in the mitochondrial medicine community will contribute creative, practical information that moves our field forward and provides open communication amongst our colleagues.

Prof. Dr. Maria Cristina Kenney
Guest Editor

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Keywords

  • mitochondria
  • mitochondrial DNA
  • haplogroups
  • mitochondrial derived peptides
  • sequencing
  • retrograde signaling

Published Papers (10 papers)

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Research

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Open AccessArticle
Mitochondrial Transcriptome Control and Intercompartment Cross-Talk During Plant Development
Cells 2019, 8(6), 583; https://doi.org/10.3390/cells8060583 (registering DOI)
Received: 21 March 2019 / Revised: 3 June 2019 / Accepted: 11 June 2019 / Published: 13 June 2019
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Abstract
We address here organellar genetic regulation and intercompartment genome coordination. We developed earlier a strategy relying on a tRNA-like shuttle to mediate import of nuclear transgene-encoded custom RNAs into mitochondria in plants. In the present work, we used this strategy to drive trans [...] Read more.
We address here organellar genetic regulation and intercompartment genome coordination. We developed earlier a strategy relying on a tRNA-like shuttle to mediate import of nuclear transgene-encoded custom RNAs into mitochondria in plants. In the present work, we used this strategy to drive trans-cleaving hammerhead ribozymes into the organelles, to knock down specific mitochondrial RNAs and analyze the regulatory impact. In a similar approach, the tRNA mimic was used to import into mitochondria in Arabidopsis thaliana the orf77, an RNA associated with cytoplasmic male sterility in maize and possessing sequence identities with the atp9 mitochondrial RNA. In both cases, inducible expression of the transgenes allowed to characterise early regulation and signaling responses triggered by these respective manipulations of the organellar transcriptome. The results imply that the mitochondrial transcriptome is tightly controlled by a “buffering” mechanism at the early and intermediate stages of plant development, a control that is released at later stages. On the other hand, high throughput analyses showed that knocking down a specific mitochondrial mRNA triggered a retrograde signaling and an anterograde nuclear transcriptome response involving a series of transcription factor genes and small RNAs. Our results strongly support transcriptome coordination mechanisms within the organelles and between the organelles and the nucleus. Full article
(This article belongs to the Special Issue Mitochondrial Genetics)
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Open AccessArticle
Alterations of Mitochondrial Biology in the Oral Mucosa of Chilean Children with Autism Spectrum Disorder (ASD)
Received: 18 February 2019 / Revised: 15 April 2019 / Accepted: 21 April 2019 / Published: 23 April 2019
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Abstract
Autistic Spectrum Disorder (ASD) is characterized by the impairment of socio-communicative skills and the presence of restricted and stereotyped behavior patterns. Recent researches have revealed the influence of mitochondrial physiology on the development of ASD. Several research groups have identified defects in respiratory [...] Read more.
Autistic Spectrum Disorder (ASD) is characterized by the impairment of socio-communicative skills and the presence of restricted and stereotyped behavior patterns. Recent researches have revealed the influence of mitochondrial physiology on the development of ASD. Several research groups have identified defects in respiratory complexes, coenzyme-Q10 deficiency, increased oxidative damage, decreased of superoxide dismutase (SOD2). A study on the influence of mitochondrial physiology on the development of ASD can provide new alternatives and challenges. That is why we set ourselves the general objective to initiate studies of mitochondrial physiology in Chilean children with ASD. A sample of oral mucosa was collected in a group of 12 children diagnosed with ASD and 12 children without ASD. In children with ASD, we found a significant increase in mitochondrial DNA levels. Likewise, in these children, an increase in the protein oxidation was observed. Finally, a downward trend in the expression of the HIGD2A and SOD2 genes was observed, while DRP1, FIS1, MFN1, MFN2, and OPA1 gene expression show an upward trend. The increment of mitochondrial DNA, high oxidative stress, and high expression of the MFN2 gene could help as a scanner of the mitochondrial function in children with ASD. Full article
(This article belongs to the Special Issue Mitochondrial Genetics)
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Open AccessFeature PaperArticle
Comparing the Utility of Mitochondrial and Nuclear DNA to Adjust for Genetic Ancestry in Association Studies
Received: 1 March 2019 / Revised: 26 March 2019 / Accepted: 29 March 2019 / Published: 3 April 2019
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Abstract
Mitochondrial genome-wide association studies identify mitochondrial single nucleotide polymorphisms (mtSNPs) that associate with disease or disease-related phenotypes. Most mitochondrial and nuclear genome-wide association studies adjust for genetic ancestry by including principal components derived from nuclear DNA, but not from mitochondrial DNA, as covariates [...] Read more.
Mitochondrial genome-wide association studies identify mitochondrial single nucleotide polymorphisms (mtSNPs) that associate with disease or disease-related phenotypes. Most mitochondrial and nuclear genome-wide association studies adjust for genetic ancestry by including principal components derived from nuclear DNA, but not from mitochondrial DNA, as covariates in statistical regression analyses. Furthermore, there is no standard when controlling for genetic ancestry during mitochondrial and nuclear genetic interaction association scans, especially across ethnicities with substantial mitochondrial genetic heterogeneity. The purpose of this study is to (1) compare the degree of ethnic variation captured by principal components calculated from microarray-defined nuclear and mitochondrial DNA and (2) assess the utility of mitochondrial principal components for association studies. Analytic techniques used in this study include a principal component analysis for genetic ancestry, decision-tree classification for self-reported ethnicity, and linear regression for association tests. Data from the Health and Retirement Study, which includes self-reported White, Black, and Hispanic Americans, was used for all analyses. We report that (1) mitochondrial principal component analysis (PCA) captures ethnic variation to a similar or slightly greater degree than nuclear PCA in Blacks and Hispanics, (2) nuclear and mitochondrial DNA classify self-reported ethnicity to a high degree but with a similar level of error, and 3) mitochondrial principal components can be used as covariates to adjust for population stratification in association studies with complex traits, as demonstrated by our analysis of height—a phenotype with a high heritability. Overall, genetic association studies might reveal true and robust mtSNP associations when including mitochondrial principal components as regression covariates. Full article
(This article belongs to the Special Issue Mitochondrial Genetics)
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Open AccessArticle
Molecular Phylogeny and Historical Biogeography of the Butterfly Tribe Aeromachini Tutt (Lepidoptera: Hesperiidae) from China
Received: 4 March 2019 / Revised: 22 March 2019 / Accepted: 23 March 2019 / Published: 29 March 2019
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Abstract
The butterfly tribe Aeromachini Tutt, 1906 is a large group of skippers. In this study, a total of 10 genera and 45 species of putative members of this tribe, which represent most of the generic diversity and nearly all the species diversity of [...] Read more.
The butterfly tribe Aeromachini Tutt, 1906 is a large group of skippers. In this study, a total of 10 genera and 45 species of putative members of this tribe, which represent most of the generic diversity and nearly all the species diversity of the group in China, were sequenced for two mitochondrial genes and three nuclear genes (2093 bp). The combined dataset was analyzed with maximum likelihood inference using IQtree. We found strong support for monophyly of Aeromachini from China and support for the most recent accepted species in the tribe. Two paraphyletic genera within Aeromachini are presented and discussed. The divergence time estimates with BEAST and ancestral-area reconstructions with RASP provide a detailed description about the historical biogeography of the Aeromachini from China. The tribe very likely originated from the Hengduan Mountains in the late Ecocene and expanded to the Himalaya Mountains and Central China Regions. A dispersal-vicariance analysis suggests that dispersal events have played essential roles in the distribution of extant species, and geological and climatic changes have been important factors driving current distribution patterns. Full article
(This article belongs to the Special Issue Mitochondrial Genetics)
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Open AccessArticle
Adaptations in Mitochondrial Enzymatic Activity Occurs Independent of Genomic Dosage in Response to Aerobic Exercise Training and Deconditioning in Human Skeletal Muscle
Received: 25 February 2019 / Revised: 8 March 2019 / Accepted: 9 March 2019 / Published: 12 March 2019
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Abstract
Mitochondrial DNA (mtDNA) replication is thought to be an integral part of exercise-training-induced mitochondrial adaptations. Thus, mtDNA level is often used as an index of mitochondrial adaptations in training studies. We investigated the hypothesis that endurance exercise training-induced mitochondrial enzymatic changes are independent [...] Read more.
Mitochondrial DNA (mtDNA) replication is thought to be an integral part of exercise-training-induced mitochondrial adaptations. Thus, mtDNA level is often used as an index of mitochondrial adaptations in training studies. We investigated the hypothesis that endurance exercise training-induced mitochondrial enzymatic changes are independent of genomic dosage by studying mtDNA content in skeletal muscle in response to six weeks of knee-extensor exercise training followed by four weeks of deconditioning in one leg, comparing results to the contralateral untrained leg, in 10 healthy, untrained male volunteers. Findings were compared to citrate synthase activity, mitochondrial complex activities, and content of mitochondrial membrane markers (porin and cardiolipin). One-legged knee-extensor exercise increased endurance performance by 120%, which was accompanied by increases in power output and peak oxygen uptake of 49% and 33%, respectively (p < 0.01). Citrate synthase and mitochondrial respiratory chain complex I–IV activities were increased by 51% and 46–61%, respectively, in the trained leg (p < 0.001). Despite a substantial training-induced increase in mitochondrial activity of TCA and ETC enzymes, there was no change in mtDNA and mitochondrial inner and outer membrane markers (i.e., cardiolipin and porin). Conversely, deconditioning reduced endurance capacity by 41%, muscle citrate synthase activity by 32%, and mitochondrial complex I–IV activities by 29–36% (p < 0.05), without any change in mtDNA and porin and cardiolipin content in the previously trained leg. The findings demonstrate that the adaptations in mitochondrial enzymatic activity after aerobic endurance exercise training and the opposite effects of deconditioning are independent of changes in the number of mitochondrial genomes, and likely relate to changes in the rate of transcription of mtDNA. Full article
(This article belongs to the Special Issue Mitochondrial Genetics)
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Review

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Open AccessReview
Mitochondrial DNA Variants and Common Diseases: A Mathematical Model for the Diversity of Age-Related mtDNA Mutations
Received: 25 March 2019 / Revised: 30 May 2019 / Accepted: 14 June 2019 / Published: 18 June 2019
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Abstract
The mitochondrion is the only organelle in the human cell, besides the nucleus, with its own DNA (mtDNA). Since the mitochondrion is critical to the energy metabolism of the eukaryotic cell, it should be unsurprising, then, that a primary driver of cellular aging [...] Read more.
The mitochondrion is the only organelle in the human cell, besides the nucleus, with its own DNA (mtDNA). Since the mitochondrion is critical to the energy metabolism of the eukaryotic cell, it should be unsurprising, then, that a primary driver of cellular aging and related diseases is mtDNA instability over the life of an individual. The mutation rate of mammalian mtDNA is significantly higher than the mutation rate observed for nuclear DNA, due to the poor fidelity of DNA polymerase and the ROS-saturated environment present within the mitochondrion. In this review, we will discuss the current literature showing that mitochondrial dysfunction can contribute to age-related common diseases such as cancer, diabetes, and other commonly occurring diseases. We will then turn our attention to the likely role that mtDNA mutation plays in aging and senescence. Finally, we will use this context to develop a mathematical formula for estimating for the accumulation of somatic mtDNA mutations with age. This resulting model shows that almost 90% of non-proliferating cells would be expected to have at least 100 mutations per cell by the age of 70, and almost no cells would have fewer than 10 mutations, suggesting that mtDNA mutations may contribute significantly to many adult onset diseases. Full article
(This article belongs to the Special Issue Mitochondrial Genetics)
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Open AccessReview
Mitochondrial DNA, a Powerful Tool to Decipher Ancient Human Civilization from Domestication to Music, and to Uncover Historical Murder Cases
Received: 27 February 2019 / Revised: 17 April 2019 / Accepted: 7 May 2019 / Published: 9 May 2019
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Abstract
Mitochondria are unique organelles carrying their own genetic material, independent from that in the nucleus. This review will discuss the nature of mitochondrial DNA (mtDNA) and its levels in the cell, which are the key elements to consider when trying to achieve molecular [...] Read more.
Mitochondria are unique organelles carrying their own genetic material, independent from that in the nucleus. This review will discuss the nature of mitochondrial DNA (mtDNA) and its levels in the cell, which are the key elements to consider when trying to achieve molecular identification in ancient and degraded samples. mtDNA sequence analysis has been appropriately validated and is a consistent molecular target for the examination of biological evidence encountered in forensic cases—and profiling, in certain conditions—especially for burnt bodies and degraded samples of all types. Exceptional cases and samples will be discussed in this review, such as mtDNA from leather in Beethoven’s grand piano, mtDNA in mummies, and solving famous historical criminal cases. In addition, this review will be discussing the use of ancient mtDNA to understand past human diet, to trace historical civilizations and ancient trade routes, and to uncover geographical domestication origins and lineage relationships. In each topic, we will present the power of mtDNA and how, in many cases, no nuclear DNA was left, leaving mitochondrial DNA analysis as a powerful alternative. Exploring this powerful tool further will be extremely useful to modern science and researchers, due to its capabilities in providing us with previously unattainable knowledge. Full article
(This article belongs to the Special Issue Mitochondrial Genetics)
Open AccessReview
Mitochondrial DNA: Distribution, Mutations, and Elimination
Received: 1 April 2019 / Revised: 17 April 2019 / Accepted: 20 April 2019 / Published: 25 April 2019
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Abstract
Mitochondrion harbors its own DNA (mtDNA), which encodes many critical proteins for the assembly and activity of mitochondrial respiratory complexes. mtDNA is packed by many proteins to form a nucleoid that uniformly distributes within the mitochondrial matrix, which is essential for mitochondrial functions. [...] Read more.
Mitochondrion harbors its own DNA (mtDNA), which encodes many critical proteins for the assembly and activity of mitochondrial respiratory complexes. mtDNA is packed by many proteins to form a nucleoid that uniformly distributes within the mitochondrial matrix, which is essential for mitochondrial functions. Defects or mutations of mtDNA result in a range of diseases. Damaged mtDNA could be eliminated by mitophagy, and all paternal mtDNA are degraded by endonuclease G or mitophagy during fertilization. In this review, we describe the role and mechanism of mtDNA distribution and elimination. In particular, we focus on the regulation of paternal mtDNA elimination in the process of fertilization. Full article
(This article belongs to the Special Issue Mitochondrial Genetics)
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Open AccessReview
Import of Non-Coding RNAs into Human Mitochondria: A Critical Review and Emerging Approaches
Received: 6 March 2019 / Revised: 19 March 2019 / Accepted: 23 March 2019 / Published: 26 March 2019
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Abstract
Mitochondria harbor their own genetic system, yet critically depend on the import of a number of nuclear-encoded macromolecules to ensure their expression. In all eukaryotes, selected non-coding RNAs produced from the nuclear genome are partially redirected into the mitochondria, where they participate in [...] Read more.
Mitochondria harbor their own genetic system, yet critically depend on the import of a number of nuclear-encoded macromolecules to ensure their expression. In all eukaryotes, selected non-coding RNAs produced from the nuclear genome are partially redirected into the mitochondria, where they participate in gene expression. Therefore, the mitochondrial RNome represents an intricate mixture of the intrinsic transcriptome and the extrinsic RNA importome. In this review, we summarize and critically analyze data on the nuclear-encoded transcripts detected in human mitochondria and outline the proposed molecular mechanisms of their mitochondrial import. Special attention is given to the various experimental approaches used to study the mitochondrial RNome, including some recently developed genome-wide and in situ techniques. Full article
(This article belongs to the Special Issue Mitochondrial Genetics)
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Other

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Open AccessBrief Report
From Normal to Obesity and Back: The Associations between Mitochondrial DNA Copy Number, Gender, and Body Mass Index
Received: 28 February 2019 / Revised: 23 April 2019 / Accepted: 8 May 2019 / Published: 9 May 2019
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Abstract
Mitochondrial DNA (mtDNA) encodes core subunits of oxidative phosphorylation complexes and, as a result of intricate regulatory crosstalk between nuclear and mitochondrial genomes, the total number of mtDNA copies fits the requirements of each cell type. Deviations from the physiological number of mtDNA [...] Read more.
Mitochondrial DNA (mtDNA) encodes core subunits of oxidative phosphorylation complexes and, as a result of intricate regulatory crosstalk between nuclear and mitochondrial genomes, the total number of mtDNA copies fits the requirements of each cell type. Deviations from the physiological number of mtDNA copies are expected to be deleterious and might cause some inherited diseases and normal ageing. We studied 46 obese patients with type 2 diabetes (T2DM) one year after a laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB). The results were compared with normal-weight patients without T2DM (control group 1) (body mass index (BMI) = 22.5 ± 3.01 kg/m2) and patients with obesity without T2DM (control group 2) (BMI = 36 ± 3.45 kg/m2). We detected an increase of mtDNA copy number in the cells of the buffy coat obtained from peripheral blood, sampled one year after bariatric surgery. We also found that average mtDNA copy number as well as its dynamics (before and after the surgery) are gender-specific. To the best of our knowledge, this is the first evidence for the restoration of mtDNA copy number in obese patients after LSG and RYGB. Full article
(This article belongs to the Special Issue Mitochondrial Genetics)
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