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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 46279

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Dr. Carlo Vascotto

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Department of Medicine, University of Udine, 33100 Udine, Italy
Interests: DNA repair; mitochondrial RNA processing; protein trafficking; role of mitochondria in tumor biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria are the primary sites of ATP production and are also involved in several other important cellular processes such as programmed cell death and cell signaling. Mitochondria are surrounded by a double-membrane system consisting of inner and outer mitochondrial membranes separated by an intermembrane space. The inner membrane delimitates the innermost compartment, the matrix, where mitochondrial DNA (mtDNA) resides. Human mtDNA is circular, 16 kbp long molecule that encodes 13 proteins, two ribosomal RNAs, and 22 tRNAs. Once transcribed, mitochondrial RNA (mtRNA) is processed, mitoribosomes are assembled, and mtDNA-encoded proteins belonging to the respiratory chain are synthesized. All these processes require the coordinated spatiotemporal action of several enzymes, and many different factors are involved in the regulation and control of protein synthesis and in the stability and turnover of mitochondrial DNA and RNA.

The goal of this Special Issue is to present the current knowledge on mtDNA replication and repair mechanisms, processing of mitochondrial RNA transcripts, and how alteration of these processes may affect cell physiology in pathological conditions.

The formats for submissions include original research reports, reviews, perspectives/opinions, and methodology articles.

Dr. Carlo Vascotto
Guest Editor

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Keywords

mitochondria
DNA repair and replication
RNA processing
mitochondrial transcription
nucleoids

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Published Papers (10 papers)

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Research

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16 pages, 1571 KiB

Open AccessArticle

Helena’s Many Daughters: More Mitogenome Diversity behind the Most Common West Eurasian mtDNA Control Region Haplotype in an Extended Italian Population Sample

by Martin Bodner, Christina Amory, Anna Olivieri, Francesca Gandini, Irene Cardinali, Hovirag Lancioni, Gabriela Huber, Catarina Xavier, Maria Pala, Alessandro Fichera, Lisa Schnaller, Mario Gysi, Stefania Sarno, Davide Pettener, Donata Luiselli, Martin B. Richards, Ornella Semino, Alessandro Achilli, Antonio Torroni and Walther Parson

Int. J. Mol. Sci. 2022, 23(12), 6725; https://doi.org/10.3390/ijms23126725 - 16 Jun 2022

Cited by 4 | Viewed by 3271

Abstract

The high number of matching haplotypes of the most common mitochondrial (mt)DNA lineages are considered to be the greatest limitation for forensic applications. This study investigates the potential to solve this constraint by massively parallel sequencing a large number of mitogenomes that share the most common West Eurasian mtDNA control region (CR) haplotype motif (263G 315.1C 16519C). We augmented a pilot study on 29 to a total of 216 Italian mitogenomes that represents the largest set of the most common CR haplotype compiled from a single country. The extended population sample confirmed and extended the huge coding region diversity behind the most common CR motif. Complete mitogenome sequencing allowed for the detection of 163 distinct haplotypes, raising the power of discrimination from 0 (CR) to 99.6% (mitogenome). The mtDNAs were clustered into 61 named clades of haplogroup H and did not reveal phylogeographic trends within Italy. Rapid individualization approaches for investigative purposes are limited to the most frequent H clades of the dataset, viz. H1, H3, and H7. Full article

(This article belongs to the Special Issue Mitochondrial DNA and RNA)

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20 pages, 2110 KiB

Open AccessArticle

Mitochondrial DNA Consensus Calling and Quality Filtering for Constructing Ancient Human Mitogenomes: Comparison of Two Widely Applied Methods

by Alexandros Heraclides and Eva Fernández-Domínguez

Int. J. Mol. Sci. 2022, 23(9), 4651; https://doi.org/10.3390/ijms23094651 - 22 Apr 2022

Viewed by 3116

Abstract

Retrieving high-quality endogenous ancient DNA (aDNA) poses several challenges, including low molecular copy number, high rates of fragmentation, damage at read termini, and potential presence of exogenous contaminant DNA. All these factors complicate a reliable reconstruction of consensus aDNA sequences in reads from high-throughput sequencing platforms. Here, we report findings from a thorough evaluation of two alternative tools (ANGSD and schmutzi) aimed at overcoming these issues and constructing high-quality ancient mitogenomes. Raw genomic data (BAM/FASTQ) from a total of 17 previously published whole ancient human genomes ranging from the 14th to the 7th millennium BCE were retrieved and mitochondrial consensus sequences were reconstructed using different quality filters, with their accuracy measured and compared. Moreover, the influence of different sequence parameters (number of reads, sequenced bases, mean coverage, and rate of deamination and contamination) as predictors of derived sequence quality was evaluated. Complete mitogenomes were successfully reconstructed for all ancient samples, and for the majority of them, filtering substantially improved mtDNA consensus calling and haplogroup prediction. Overall, the schmutzi pipeline, which estimates and takes into consideration exogenous contamination, appeared to have the edge over the much faster and user-friendly alternative method (ANGSD) in moderate to high coverage samples (>1,000,000 reads). ANGSD, however, through its read termini trimming filter, showed better capabilities in calling the consensus sequence from low-quality samples. Among all the predictors of overall sample quality examined, the strongest correlation was found for the available number of sequence reads and bases. In the process, we report a previously unassigned haplogroup (U3b) for an Early Chalcolithic individual from Southern Anatolia/Northern Levant. Full article

(This article belongs to the Special Issue Mitochondrial DNA and RNA)

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15 pages, 3146 KiB

Open AccessArticle

T1121G Point Mutation in the Mitochondrial Gene COX1 Suppresses a Null Mutation in ATP23 Required for the Assembly of Yeast Mitochondrial ATP Synthase

by Guangying Yang, Tong Zhao, Shan Lu, Jun Weng and Xiaomei Zeng

Int. J. Mol. Sci. 2022, 23(4), 2327; https://doi.org/10.3390/ijms23042327 - 19 Feb 2022

Cited by 2 | Viewed by 2594

Abstract

Nuclear-encoded Atp23 was previously shown to have dual functions, including processing the yeast Atp6 precursor and assisting the assembly of yeast mitochondrial ATP synthase. However, it remains unknown whether there are genes functionally complementary to ATP23 to rescue atp23 null mutant. In the present paper, we screen and characterize three revertants of atp23 null mutant and reveal a T1121G point mutation in the mitochondrial gene COX1 coding sequence, which leads to Val374Gly mutation in Cox1, the suppressor in the revertants. This was verified further by the partial restoration of mitochondrial ATP synthase assembly in atp23 null mutant transformed with exogenous hybrid COX1 T1121G mutant plasmid. The predicted tertiary structure of the Cox1 p.Val374Gly mutation showed no obvious difference from wild-type Cox1. By further chase labeling with isotope [³⁵S]-methionine, we found that the stability of Atp6 of ATP synthase increased in the revertants compared with the atp23 null mutant. Taking all the data together, we revealed that the T1121G point mutation of mitochondrial gene COX1 could partially restore the unassembly of mitochondrial ATP synthase in atp23 null mutant by increasing the stability of Atp6. Therefore, this study uncovers a gene that is partially functionally complementary to ATP23 to rescue ATP23 deficiency, broadening our understanding of the relationship between yeast the cytochrome c oxidase complex and mitochondrial ATP synthase complex. Full article

(This article belongs to the Special Issue Mitochondrial DNA and RNA)

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20 pages, 1193 KiB

Open AccessArticle

The Value of Whole-Genome Sequencing for Mitochondrial DNA Population Studies: Strategies and Criteria for Extracting High-Quality Mitogenome Haplotypes

by Kimberly Sturk-Andreaggi, Joseph D. Ring, Adam Ameur, Ulf Gyllensten, Martin Bodner, Walther Parson, Charla Marshall and Marie Allen

Int. J. Mol. Sci. 2022, 23(4), 2244; https://doi.org/10.3390/ijms23042244 - 17 Feb 2022

Cited by 5 | Viewed by 3789

Abstract

Whole-genome sequencing (WGS) data present a readily available resource for mitochondrial genome (mitogenome) haplotypes that can be utilized for genetics research including population studies. However, the reconstruction of the mitogenome is complicated by nuclear mitochondrial DNA (mtDNA) segments (NUMTs) that co-align with the mtDNA sequences and mimic authentic heteroplasmy. Two minimum variant detection thresholds, 5% and 10%, were assessed for the ability to produce authentic mitogenome haplotypes from a previously generated WGS dataset. Variants associated with NUMTs were detected in the mtDNA alignments for 91 of 917 (~8%) Swedish samples when the 5% frequency threshold was applied. The 413 observed NUMT variants were predominantly detected in two regions (nps 12,612–13,105 and 16,390–16,527), which were consistent with previously documented NUMTs. The number of NUMT variants was reduced by ~97% (400) using a 10% frequency threshold. Furthermore, the 5% frequency data were inconsistent with a platinum-quality mitogenome dataset with respect to observed heteroplasmy. These analyses illustrate that a 10% variant detection threshold may be necessary to ensure the generation of reliable mitogenome haplotypes from WGS data resources. Full article

(This article belongs to the Special Issue Mitochondrial DNA and RNA)

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8 pages, 230 KiB

Open AccessArticle

Fine-Tuning Phylogenetic Alignment and Haplogrouping of mtDNA Sequences

by Arne Dür, Nicole Huber and Walther Parson

Int. J. Mol. Sci. 2021, 22(11), 5747; https://doi.org/10.3390/ijms22115747 - 27 May 2021

Cited by 29 | Viewed by 4246

Abstract

In this paper, we present a new algorithm for alignment and haplogroup estimation of mitochondrial DNA (mtDNA) sequences. Based on 26,011 vetted full mitogenome sequences, we refined the 5435 original haplogroup motifs of Phylotree Build 17 without changing the haplogroup nomenclature. We adapted 430 motifs (about 8%) and added 966 motifs for yet undetermined subclades. In summary, this led to an 18% increase of haplogroup defining motifs for full mitogenomes and a 30% increase for the mtDNA control region that is of interest for a variety of scientific disciplines, such as medical, population and forensic genetics. The new algorithm is implemented in the EMPOP mtDNA database and is freely accessible. Full article

(This article belongs to the Special Issue Mitochondrial DNA and RNA)

20 pages, 6697 KiB

Open AccessArticle

Characterization and Comparative Analyses of Mitochondrial Genomes in Single-Celled Eukaryotes to Shed Light on the Diversity and Evolution of Linear Molecular Architecture

by Tengteng Zhang, Chao Li, Xue Zhang, Chundi Wang, Andrew J. Roger and Feng Gao

Int. J. Mol. Sci. 2021, 22(5), 2546; https://doi.org/10.3390/ijms22052546 - 3 Mar 2021

Cited by 13 | Viewed by 3653

Abstract

Determination and comparisons of complete mitochondrial genomes (mitogenomes) are important to understand the origin and evolution of mitochondria. Mitogenomes of unicellular protists are particularly informative in this regard because they are gene-rich and display high structural diversity. Ciliates are a highly diverse assemblage of protists and their mitogenomes (linear structure with high A+T content in general) were amongst the first from protists to be characterized and have provided important insights into mitogenome evolution. Here, we report novel mitogenome sequences from three representatives (Strombidium sp., Strombidium cf. sulcatum, and Halteria grandinella) in two dominant ciliate lineages. Comparative and phylogenetic analyses of newly sequenced and previously published ciliate mitogenomes were performed and revealed a number of important insights. We found that the mitogenomes of these three species are linear molecules capped with telomeric repeats that differ greatly among known species. The genomes studied here are highly syntenic, but larger in size and more gene-rich than those of other groups. They also all share an AT-rich tandem repeat region which may serve as the replication origin and modulate initiation of bidirectional transcription. More generally we identified a split version of ccmf, a cytochrome c maturation-related gene that might be a derived character uniting taxa in the subclasses Hypotrichia and Euplotia. Finally, our mitogenome comparisons and phylogenetic analyses support to reclassify Halteria grandinella from the subclass Oligotrichia to the subclass Hypotrichia. These results add to the growing literature on the unique features of ciliate mitogenomes, shedding light on the diversity and evolution of their linear molecular architecture. Full article

(This article belongs to the Special Issue Mitochondrial DNA and RNA)

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Review

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13 pages, 275 KiB

Open AccessReview

Mitochondrial DNA and MitomiR Variations in Pancreatic Cancer: Potential Diagnostic and Prognostic Biomarkers

by Loredana Moro

Int. J. Mol. Sci. 2021, 22(18), 9692; https://doi.org/10.3390/ijms22189692 - 7 Sep 2021

Cited by 11 | Viewed by 3487

Abstract

Pancreatic cancer is an aggressive disease with poor prognosis. Only about 15–20% of patients diagnosed with pancreatic cancer can undergo surgical resection, while the remaining 80% are diagnosed with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). In these cases, chemotherapy and radiotherapy only confer marginal survival benefit. Recent progress has been made in understanding the pathobiology of pancreatic cancer, with a particular effort in discovering new diagnostic and prognostic biomarkers, novel therapeutic targets, and biomarkers that can predict response to chemo- and/or radiotherapy. Mitochondria have become a focus in pancreatic cancer research due to their roles as powerhouses of the cell, important subcellular biosynthetic factories, and crucial determinants of cell survival and response to chemotherapy. Changes in the mitochondrial genome (mtDNA) have been implicated in chemoresistance and metastatic progression in some cancer types. There is also growing evidence that changes in microRNAs that regulate the expression of mtDNA-encoded mitochondrial proteins (mitomiRs) or nuclear-encoded mitochondrial proteins (mitochondria-related miRs) could serve as diagnostic and prognostic cancer biomarkers. This review discusses the current knowledge on the clinical significance of changes of mtDNA, mitomiRs, and mitochondria-related miRs in pancreatic cancer and their potential role as predictors of cancer risk, as diagnostic and prognostic biomarkers, and as molecular targets for personalized cancer therapy. Full article

(This article belongs to the Special Issue Mitochondrial DNA and RNA)

18 pages, 3435 KiB

Open AccessReview

The Role of Mitochondrial Dysfunction in Atrial Fibrillation: Translation to Druggable Target and Biomarker Discovery

by Lisa Pool, Leonoor F. J. M. Wijdeveld, Natasja M. S. de Groot and Bianca J. J. M. Brundel

Int. J. Mol. Sci. 2021, 22(16), 8463; https://doi.org/10.3390/ijms22168463 - 6 Aug 2021

Cited by 27 | Viewed by 4301

Abstract

Atrial fibrillation (AF) is the most prevalent and progressive cardiac arrhythmia worldwide and is associated with serious complications such as heart failure and ischemic stroke. Current treatment modalities attenuate AF symptoms and are only moderately effective in halting the arrhythmia. Therefore, there is an urgent need to dissect molecular mechanisms that drive AF. As AF is characterized by a rapid atrial activation rate, which requires a high energy metabolism, a role of mitochondrial dysfunction in AF pathophysiology is plausible. It is well known that mitochondria play a central role in cardiomyocyte function, as they produce energy to support the mechanical and electrical function of the heart. Details on the molecular mechanisms underlying mitochondrial dysfunction are increasingly being uncovered as a contributing factor in the loss of cardiomyocyte function and AF. Considering the high prevalence of AF, investigating the role of mitochondrial impairment in AF may guide the path towards new therapeutic and diagnostic targets. In this review, the latest evidence on the role of mitochondria dysfunction in AF is presented. We highlight the key modulators of mitochondrial dysfunction that drive AF and discuss whether they represent potential targets for therapeutic interventions and diagnostics in clinical AF. Full article

(This article belongs to the Special Issue Mitochondrial DNA and RNA)

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23 pages, 1434 KiB

Open AccessReview

Human Mitochondrial RNA Processing and Modifications: Overview

by Marta Jedynak-Slyvka, Agata Jabczynska and Roman J. Szczesny

Int. J. Mol. Sci. 2021, 22(15), 7999; https://doi.org/10.3390/ijms22157999 - 27 Jul 2021

Cited by 30 | Viewed by 9455

Abstract

Mitochondria, often referred to as the powerhouses of cells, are vital organelles that are present in almost all eukaryotic organisms, including humans. They are the key energy suppliers as the site of adenosine triphosphate production, and are involved in apoptosis, calcium homeostasis, and regulation of the innate immune response. Abnormalities occurring in mitochondria, such as mitochondrial DNA (mtDNA) mutations and disturbances at any stage of mitochondrial RNA (mtRNA) processing and translation, usually lead to severe mitochondrial diseases. A fundamental line of investigation is to understand the processes that occur in these organelles and their physiological consequences. Despite substantial progress that has been made in the field of mtRNA processing and its regulation, many unknowns and controversies remain. The present review discusses the current state of knowledge of RNA processing in human mitochondria and sheds some light on the unresolved issues. Full article

(This article belongs to the Special Issue Mitochondrial DNA and RNA)

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13 pages, 691 KiB

Open AccessReview

Mitochondrial DNA Copy Number and Developmental Origins of Health and Disease (DOHaD)

by Hisanori Fukunaga

Int. J. Mol. Sci. 2021, 22(12), 6634; https://doi.org/10.3390/ijms22126634 - 21 Jun 2021

Cited by 19 | Viewed by 6119

Abstract

Mitochondrial dysfunction is known to contribute to mitochondrial diseases, as well as to a variety of aging-based pathologies. Mitochondria have their own genomes (mitochondrial DNA (mtDNA)) and the abnormalities, such as point mutations, deletions, and copy number variations, are involved in mitochondrial dysfunction. In recent years, several epidemiological studies and animal experiments have supported the Developmental Origin of Health and Disease (DOHaD) theory, which states that the environment during fetal life influences the predisposition to disease and the risk of morbidity in adulthood. Mitochondria play a central role in energy production, as well as in various cellular functions, such as apoptosis, lipid metabolism, and calcium metabolism. In terms of the DOHaD theory, mtDNA copy number may be a mediator of health and disease. This paper summarizes the results of recent epidemiological studies on the relationship between environmental factors and mtDNA copy number during pregnancy from the perspective of DOHaD theory. The results of these studies suggest a hypothesis that mtDNA copy number may reflect environmental influences during fetal life and possibly serve as a surrogate marker of health risks in adulthood. Full article

(This article belongs to the Special Issue Mitochondrial DNA and RNA)

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