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mtDNA and Mitochondrial Stress Signaling in Human Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2019) | Viewed by 71000

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Dr. Angela Maria Serena Lezza

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Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy
Interests: aging; mitochondrial biogenesis in aging; mitochondrial pathologies; pathologies with mitochondrial oxidative stress (age-related diseases, autoimmune and inflammatory pathologies, neurodegenerative diseases); calorie restriction and nutritional anti-aging interventions; mtDNA–TFAM relationships
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Dr. Vito Pesce

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Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy
Interests: mtDNA damage and deletions; mitochondrial oxidative stress and antioxidant defense; mitochondrial biogenesis and dynamics; mitochondrial quality control; mitochondrial dysfunction in aging and age-related degenerative disorders; nutritional anti-aging interventions
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since its discovery in 1963 by Nass, M.M. and Nass, S., mitochondrial DNA (mtDNA) has arisen a large interest as it is the only genome other than the nuclear one in animal cells, and its small molecule is present in multiple copies in the cell’s power plants. Sequencing of human mtDNA unveiled the coordinated expression of the two genomes and the related complex nuclear–mitochondrial crosstalk. The mitohormesis theory, which proposes a dual response originated by exposure to different levels of ROS, suggests that modest ROS amounts, released from mitochondria, can constitute a message inducing metabolic adaptations that can permit cell survival in altered conditions. Conversely, high ROS levels can drive oxidative stress, cellular damage, and eventually cell death. In fact, mitochondrial oxidative stress, commonly associated with aging and age-related pathologies (neurodegenerative syndromes, cardiovascular diseases, endocrine pathologies, diabetes, and cancer), leads to damage to mitochondrial DNA, proteins, and lipids. The increased ROS presence can also induce chronic inflammation, which often characterizes age-related diseases and autoimmune pathologies. Furthermore, a growing number of studies have been reporting the relevance of mtDNA as part of mitochondria-derived damage-associated molecular patterns (DAMPs) contributing to evoke an inflammatory response. Besides such pro-inflammatory action of the mitochondrial genome, mtDNA mutations (point mutations and deletions) can be the cause of mitochondrial electron transfer chain (ETC) dysfunctions involved in a large cohort of devastating diseases (mitochondrial pathologies). A high proportion of mutated molecules is focally concentrated also in aged tissue areas with overt mitochondrial ETC dysfunctions. Recently, the accumulation of mtDNA damages has been shown to regulate apoptosis and mitophagy, underscoring the role of mitochondria in cell decision-making between mitophagy-mediated survival and apoptosis.

This Special Issue aims to provide a broad and updated overview of the involvement of “mtDNA and Mitochondrial Stress Signaling in Human Diseases” that might shed light on model systems, diagnostic biomarkers, pathophysiological mechanisms, and novel therapeutic approaches. To progress in the knowledge of such intricate issues, contributions by experts in the field in the form of research papers and critical reviews are called for.

Prof. Dr. Angela Maria Serena Lezza
Prof. Dr. Vito Pesce
Guest Editors

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Keywords

mitochondrial oxidative stress in pathologies
mtDNA pathologies
mtDNA in age-related diseases
mitochondrial signaling via ROS in diseases
mitochondrial oxidative stress and inflammation
mtDNA damage and mitophagy/apoptosis
novel therapeutic approaches

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Editorial

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5 pages, 186 KiB

Open AccessEditorial

mtDNA and Mitochondrial Stress Signaling in Human Diseases: A Special Issue

by Vito Pesce and Angela Maria Serena Lezza

Int. J. Mol. Sci. 2020, 21(7), 2617; https://doi.org/10.3390/ijms21072617 - 9 Apr 2020

Cited by 1 | Viewed by 1854

Abstract

The completion of the Special Issue dedicated to “mtDNA and mitochondrial stress signaling in human diseases” requests a final overall look to highlight the most valuable findings among the many presented data [...] Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

Research

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13 pages, 1039 KiB

Open AccessArticle

The Detection and Partial Localisation of Heteroplasmic Mutations in the Mitochondrial Genome of Patients with Diabetic Retinopathy

by Afshan N. Malik, Hannah S. Rosa, Eliane S. de Menezes, Priyanka Tamang, Zaidi Hamid, Anita Naik, Chandani Kiran Parsade and Sobha Sivaprasad

Int. J. Mol. Sci. 2019, 20(24), 6259; https://doi.org/10.3390/ijms20246259 - 11 Dec 2019

Cited by 4 | Viewed by 3868

Abstract

Diabetic retinopathy (DR) is a common complication of diabetes and a major cause of acquired blindness in adults. Mitochondria are cellular organelles involved in energy production which contain mitochondrial DNA (mtDNA). We previously showed that levels of circulating mtDNA were dysregulated in DR patients, and there was some evidence of mtDNA damage. In the current project, our aim was to confirm the presence of, and determine the location and prevalence of, mtDNA mutation in DR. DNA isolated from peripheral blood from diabetes patients (n = 59) with and without DR was used to amplify specific mtDNA regions which were digested with surveyor nuclease S1 to determine the presence and location of heteroplasmic mtDNA mutations were present. An initial screen of the entire mtDNA genome of 6 DR patients detected a higher prevalence of mutations in amplicon P, covering nucleotides 14,443 to 1066 and spanning the control region. Further analysis of 42 subjects showed the presence of putative mutations in amplicon P in 36% (14/39) of DR subjects and in 10% (2/20) non-DR subjects. The prevalence of mutations in DR was not related to the severity of the disease. The detection of a high-prevalence of putative mtDNA mutations within a specific region of the mitochondrial genome supports the view that mtDNA damage contributes to DR. The exact location and functional impact of these mutations remains to be determined. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

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12 pages, 18151 KiB

Open AccessArticle

Increased mtDNA Abundance and Improved Function in Human Barth Syndrome Patient Fibroblasts Following AAV-TAZ Gene Delivery

by Silveli Suzuki-Hatano, Mughil Sriramvenugopal, Manash Ramanathan, Meghan Soustek, Barry J. Byrne, W. Todd Cade, Peter B. Kang and Christina A. Pacak

Int. J. Mol. Sci. 2019, 20(14), 3416; https://doi.org/10.3390/ijms20143416 - 11 Jul 2019

Cited by 10 | Viewed by 4359

Abstract

Barth syndrome (BTHS) is a rare, X-linked, mitochondrial disorder caused by mutations in the gene encoding tafazzin. BTHS results in cardiomyopathy, muscle fatigue, and neutropenia in patients. Tafazzin is responsible for remodeling cardiolipin, a key structural lipid of the inner mitochondrial membrane. As symptoms can vary in severity amongst BTHS patients, we sought to compare mtDNA copy numbers, mitochondrial fragmentation, and functional parameters between primary dermal BTHS fibroblasts isolated from patients with two different mutations in the TAZ locus. To confirm cause‒effect relationships and further support the development of gene therapy for BTHS, we also characterized the BTHS cells following adeno-associated virus (AAV)-TAZ transduction. Our data show that, in response to AAV-TAZ transduction, these remarkably dynamic organelles show recovery of mtDNA copy numbers, mitochondrial structure, and mitochondrial function, providing additional evidence to support the therapeutic potential of AAV-mediated gene delivery for BTHS. This study also demonstrates the direct relationship between healthy mitochondrial membrane structure and maintenance of proper levels of mtDNA copy numbers. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

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11 pages, 1027 KiB

Open AccessCommunication

Deletion of OGG1 Results in a Differential Signature of Oxidized Purine Base Damage in mtDNA Regions

by Guglielmina Chimienti, Vito Pesce, Flavio Fracasso, Francesco Russo, Nadja Cristhina de Souza-Pinto, Vilhelm A. Bohr and Angela Maria Serena Lezza

Int. J. Mol. Sci. 2019, 20(13), 3302; https://doi.org/10.3390/ijms20133302 - 5 Jul 2019

Cited by 8 | Viewed by 2965

Abstract

Mitochondrial oxidative stress accumulates with aging and age-related diseases and induces alterations in mitochondrial DNA (mtDNA) content. Since mtDNA qualitative alterations are also associated with aging, repair of mtDNA damage is of great importance. The most relevant form of DNA repair in this context is base excision repair (BER), which removes oxidized bases such as 8-oxoguanine (8-oxoG) and thymine glycol through the action of the mitochondrial isoform of the specific 8-oxoG DNA glycosylase/apurinic or apyrimidinic (AP) lyase (OGG1) or the endonuclease III homolog (NTH1). Mouse strains lacking OGG1 (OGG1^−/−) or NTH1 (NTH1^−/−) were analyzed for mtDNA alterations. Interestingly, both knockout strains presented a significant increase in mtDNA content, suggestive of a compensatory mtDNA replication. The mtDNA “common deletion” was not detected in either knockout mouse strain, likely because of the young age of the mice. Formamidopyrimidine DNA glycosylase (Fpg)-sensitive sites accumulated in mtDNA from OGG1^−/− but not from NTH1^−/− mice. Interestingly, the D-loop region was most severely affected by the absence of OGG1, suggesting that this region may be a hotspot for oxidative damage. Thus, we speculate that mtDNA alterations may send a stress message to evoke cell changes through a retrograde mitochondrial–nucleus communication. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

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9 pages, 214 KiB

Open AccessCommunication

Analysis of Mitochondrial DNA Polymorphisms in the Human Cell Lines HepaRG and SJCRH30

by Matthew J. Young, Anitha D. Jayaprakash and Carolyn K. J. Young

Int. J. Mol. Sci. 2019, 20(13), 3245; https://doi.org/10.3390/ijms20133245 - 2 Jul 2019

Cited by 4 | Viewed by 4266

Abstract

The mitochondrial DNA (mtDNA) sequences of two commonly used human cell lines, HepaRG and SJCRH30, were determined. HepaRG originates from a liver tumor obtained from a patient with hepatocarcinoma and hepatitis C while SJCRH30 originates from a rhabdomyosarcoma patient tumor. In comparison to the revised Cambridge Reference Sequence, HepaRG and SJCRH30 mtDNA each contain 14 nucleotide variations. In addition to an insertion of a cytosine at position 315 (315insC), the mtDNA sequences from both cell types share six common polymorphisms. Heteroplasmic variants were identified in both cell types and included the identification of the 315insC mtDNA variant at 42 and 75% heteroplasmy in HepaRG and SJCRH30, respectively. Additionally, a novel heteroplasmic G13633A substitution in the HepaRG ND5 gene was detected at 33%. Previously reported cancer-associated mtDNA variants T195C and T16519C were identified in SJCRH30, both at homoplasmy (100%), while HepaRG mtDNA harbors a known prostate cancer-associated T6253C substitution at near homoplasmy, 95%. Based on our sequencing analysis, HepaRG mtDNA is predicted to lie within haplogroup branch H15a1 while SJCRH30 mtDNA is predicted to localize to H27c. The catalog of polymorphisms and heteroplasmy reported here should prove useful for future investigations of mtDNA maintenance in HepaRG and SJCRH30 cell lines. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

20 pages, 5144 KiB

Open AccessArticle

Genetic Defects in Mitochondrial Dynamics in Caenorhabditis elegans Impact Ultraviolet C Radiation- and 6-hydroxydopamine-Induced Neurodegeneration

by Jessica H. Hartman, Claudia Gonzalez-Hunt, Samantha M. Hall, Ian T. Ryde, Kim A. Caldwell, Guy A. Caldwell and Joel N. Meyer

Int. J. Mol. Sci. 2019, 20(13), 3202; https://doi.org/10.3390/ijms20133202 - 29 Jun 2019

Cited by 18 | Viewed by 7205

Abstract

Background: Parkinson’s disease (PD) is one of the most common neurodegenerative disorders involving devastating loss of dopaminergic neurons in the substantia nigra. Early steps in PD pathogenesis include mitochondrial dysfunction, and mutations in mitochondrial genes have been linked to familial forms of the disease. However, low penetrance of mutations indicates a likely important role for environmental factors in PD risk through gene by environment interactions. Herein, we study how genetic deficiencies in mitochondrial dynamics processes including fission, fusion, and mitophagy interact with environmental exposures to impact neurodegeneration. Methods: We utilized the powerful model organism Caenorhabditis elegans to study ultraviolet C radiation (UVC)- and 6-hydroxydopamine-induced degeneration of fluorescently-tagged dopaminergic neurons in the background of fusion deficiency (MFN1/2 homolog, fzo-1), fission deficiency (DMN1L homolog, drp-1), and mitochondria-specific autophagy (mitophagy) deficiency (PINK1 and PRKN homologs, pink-1 and pdr-1). Results: Overall, we found that deficiency in either mitochondrial fusion or fission sensitizes nematodes to UVC exposure (used to model common environmental pollutants) but protects from 6-hydroxydopamine-induced neurodegeneration. By contrast, mitophagy deficiency makes animals more sensitive to these stressors with an interesting exception—pink-1 deficiency conferred remarkable protection from 6-hydroxydopamine. We found that this protection could not be explained by compensatory antioxidant gene expression in pink-1 mutants or by differences in mitochondrial morphology. Conclusions: Together, our results support a strong role for gene by environment interactions in driving dopaminergic neurodegeneration and suggest that genetic deficiency in mitochondrial processes can have complex effects on neurodegeneration. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

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13 pages, 5406 KiB

Open AccessArticle

Differences in Liver TFAM Binding to mtDNA and mtDNA Damage between Aged and Extremely Aged Rats

by Guglielmina Chimienti, Anna Picca, Flavio Fracasso, Emanuele Marzetti, Riccardo Calvani, Christiaan Leeuwenburgh, Francesco Russo, Angela Maria Serena Lezza and Vito Pesce

Int. J. Mol. Sci. 2019, 20(10), 2601; https://doi.org/10.3390/ijms20102601 - 27 May 2019

Cited by 19 | Viewed by 4257

Abstract

While mitochondrial dysfunction is acknowledged as a major feature of aging, much less is known about the role of mitochondria in extended longevity. Livers from aged (28-month-old) and extremely aged (32-month-old) rats were analyzed for citrate synthase activity, mitochondrial transcription factor A (TFAM) amount, mitochondrial DNA (mtDNA), and 4.8 Kb “common deletion” contents. None of the assayed parameters differed significantly between age groups. TFAM-binding to mtDNA and the incidence of 8-oxo-deoxyguanosine in specific mtDNA regions, encompassing the origins of mtDNA replication (D-loop and Ori-L) and the 16-bp long direct repeat 1 (DR1) of the 4.8 Kb deletion, were determined. A decrease in TFAM binding was unveiled at all regions in extremely aged in comparison with aged rats. Reduced incidence of oxidized purines at all assayed regions was detected in 32-month-old rats compared with the 28-month-old group. A significant positive correlation between the incidence of 8-oxo-deoxoguanosine and TFAM-bound mtDNA was found at D-Loop and Ori-L regions only in 28-month-old rats. The absence of such correlation in 32-month-old rats indicates a different, fine-tuned regulation of TFAM binding in the two age groups and supports the existence of two different paces in aging and extended aging. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

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15 pages, 1104 KiB

Open AccessArticle

A Natural mtDNA Polymorphism in Complex III Is a Modifier of Healthspan in Mice

by Misa Hirose, Axel Künstner, Paul Schilf, Anna Katharina Tietjen, Olaf Jöhren, Patricia Huebbe, Gerald Rimbach, Jan Rupp, Markus Schwaninger, Hauke Busch and Saleh M. Ibrahim

Int. J. Mol. Sci. 2019, 20(9), 2359; https://doi.org/10.3390/ijms20092359 - 13 May 2019

Cited by 12 | Viewed by 4646

Abstract

In this study, we provide experimental evidence that a maternally inherited polymorphism in the mitochondrial cytochrome b gene (mt-Cytb; m.15124A>G, Ile-Val) in mitochondrial complex III resulted in middle-aged obesity and higher susceptibility to diet-induced obesity, as well as age-related inflammatory disease, e.g., ulcerative dermatitis, in mice. As a consequence of the gene variation, we observed alterations in body composition, metabolism and mitochondrial functions, i.e., increased mitochondrial oxygen consumption rate and higher levels of reactive oxygen species, as well as in the commensal bacterial composition in the gut, with higher abundance of Proteobacteria in mice carrying the variant. These observations are in line with the previously described links of the mitochondrial complex III gene with obesity and metabolic diseases in humans. Given that these functional changes by the G variant at m.15124 in the mt-Cytb are already present in young mice that were kept under normal condition, it is plausible that the m.15124A>G variant is a disease susceptibility modifier to the diseases induced by additional stressors, i.e., dietary and/or aging stress, and that the variant results in the higher incidence of clinical diseases presentation in C57BL/6J-mt^129S1/SvlmJ than C57BL/6J mice. Thus, mtDNA variants could be potential biomarkers to evaluate the healthspan. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

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14 pages, 2021 KiB

Open AccessArticle

An In Vitro Study on Mitochondrial Compensatory Response Induced by Gliadin Peptides in Caco-2 Cells

by Antonella Orlando, Guglielmina Chimienti, Vito Pesce, Flavio Fracasso, Angela Maria Serena Lezza and Francesco Russo

Int. J. Mol. Sci. 2019, 20(8), 1862; https://doi.org/10.3390/ijms20081862 - 15 Apr 2019

Cited by 9 | Viewed by 3035

Abstract

Dietary gliadin may show a broad spectrum of toxicity. The interplay between mitochondria and gliadin-induced oxidative stress has not been thoroughly examined in the intestinal epithelium. In this kinetic study, Caco-2 cells were exposed for 24 h to pepsin-trypsin-digested gliadin, alone or in combination with the antioxidant 2,6-di-tbutyl-p-cresol (BHT), and the effects on mitochondrial biogenesis and mtDNA were studied. Cells ability to recover from stress was determined after 24 h and 48 h of incubation in the culture medium. Gliadin-induced oxidative stress evoked a compensatory response. The stressor triggered a rapid and significant increase of Peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α) and Peroxiredoxin III (PrxIII) proteins, and mtDNA amount. As for the effects of gliadin on mtDNA integrity, strand breaks, abasic sites, and modified bases were analyzed in three mtDNA regions. D-loop appeared a more fragile target than Ori-L and ND1/ND2. The temporal trend of the damage at D-loop paralleled that of the amount of mtDNA. Overall, a trend toward control values was shown 48 h after gliadin exposure. Finally, BHT was able to counteract the effects of gliadin. Results from this study highlighted the effects of gliadin-induced oxidative stress on mitochondria, providing valuable evidence that might improve the knowledge of the pathophysiology of gluten-related disorders. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

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16 pages, 3581 KiB

Open AccessArticle

Telomerase Impinges on the Cellular Response to Oxidative Stress Through Mitochondrial ROS-Mediated Regulation of Autophagy

by Paula D. Green, Nilesh K. Sharma and Janine Hertzog Santos

Int. J. Mol. Sci. 2019, 20(6), 1509; https://doi.org/10.3390/ijms20061509 - 26 Mar 2019

Cited by 39 | Viewed by 4851

Abstract

Telomerase has cellular functions beyond telomere stabilization, including a role in mitochondria. The function of the catalytic component—TERT—in mitochondria is still unknown, but it seems to play a role in the response to oxidative stress. Here, we interrogated the role of the subcellular localization of TERT to the response to hydrogen peroxide (H₂O₂) treatment. Using normal human fibroblasts (NHF) expressing non-tagged wild type (WT) human TERT (hTERT) or nuclear localization and function (_nuchTERT), a mutant that we previously described as being competent in telomere elongation, while not being able to localize to mitochondria, we found the differential activation of autophagy as a function of hTERT’s subcellular localization. Specifically, we found that only cells expressing the mutant had significant increases in autophagy markers as a response to H₂O₂ challenge. Either the reintroduction of the mitochondrial pool of hTERT or the expression of mitochondrially-targeted catalase in mutant cells blunted the autophagic response under oxidative stress. Interestingly, autophagy activation was also associated with decreased levels of mitochondrial DNA damage. Taken together, these results suggest that the loss of hTERT in mitochondria initiates a signaling cascade that allows for cells to adapt to and cope with the lack of mitochondrial telomerase. Such effects also influence the cellular response to oxidative damage. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

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Review

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20 pages, 3048 KiB

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Protective Effects of Euthyroidism Restoration on Mitochondria Function and Quality Control in Cardiac Pathophysiology

by Francesca Forini, Giuseppina Nicolini, Claudia Kusmic and Giorgio Iervasi

Int. J. Mol. Sci. 2019, 20(14), 3377; https://doi.org/10.3390/ijms20143377 - 10 Jul 2019

Cited by 24 | Viewed by 6545

Abstract

Mitochondrial dysfunctions are major contributors to heart disease onset and progression. Under ischemic injuries or cardiac overload, mitochondrial-derived oxidative stress, Ca²⁺ dis-homeostasis, and inflammation initiate cross-talking vicious cycles leading to defects of mitochondrial DNA, lipids, and proteins, concurrently resulting in fatal energy crisis and cell loss. Blunting such noxious stimuli and preserving mitochondrial homeostasis are essential to cell survival. In this context, mitochondrial quality control (MQC) represents an expanding research topic and therapeutic target in the field of cardiac physiology. MQC is a multi-tier surveillance system operating at the protein, organelle, and cell level to repair or eliminate damaged mitochondrial components and replace them by biogenesis. Novel evidence highlights the critical role of thyroid hormones (TH) in regulating multiple aspects of MQC, resulting in increased organelle turnover, improved mitochondrial bioenergetics, and the retention of cell function. In the present review, these emerging protective effects are discussed in the context of cardiac ischemia-reperfusion (IR) and heart failure, focusing on MQC as a strategy to blunt the propagation of connected dangerous signaling cascades and limit adverse remodeling. A better understanding of such TH-dependent signaling could provide insights into the development of mitochondria-targeted treatments in patients with cardiac disease. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

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18 pages, 2704 KiB

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Role of Mitochondrial DNA Damage in ROS-Mediated Pathogenesis of Age-Related Macular Degeneration (AMD)

by Kai Kaarniranta, Elzbieta Pawlowska, Joanna Szczepanska, Aleksandra Jablkowska and Janusz Blasiak

Int. J. Mol. Sci. 2019, 20(10), 2374; https://doi.org/10.3390/ijms20102374 - 14 May 2019

Cited by 141 | Viewed by 10278

Abstract

Age-related macular degeneration (AMD) is a complex eye disease that affects millions of people worldwide and is the main reason for legal blindness and vision loss in the elderly in developed countries. Although the cause of AMD pathogenesis is not known, oxidative stress-related damage to retinal pigment epithelium (RPE) is considered an early event in AMD induction. However, the precise cause of such damage and of the induction of oxidative stress, including related oxidative effects occurring in RPE and the onset and progression of AMD, are not well understood. Many results point to mitochondria as a source of elevated levels of reactive oxygen species (ROS) in AMD. This ROS increase can be associated with aging and effects induced by other AMD risk factors and is correlated with damage to mitochondrial DNA. Therefore, mitochondrial DNA (mtDNA) damage can be an essential element of AMD pathogenesis. This is supported by many studies that show a greater susceptibility of mtDNA than nuclear DNA to DNA-damaging agents in AMD. Therefore, the mitochondrial DNA damage reaction (mtDDR) is important in AMD prevention and in slowing down its progression as is ROS-targeting AMD therapy. However, we know far less about mtDNA than its nuclear counterparts. Further research should measure DNA damage in order to compare it in mitochondria and the nucleus, as current methods have serious disadvantages. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

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11 pages, 1751 KiB

Open AccessPerspective

A Brief History of Mitochondrial Pathologies

by Salvatore DiMauro

Int. J. Mol. Sci. 2019, 20(22), 5643; https://doi.org/10.3390/ijms20225643 - 12 Nov 2019

Cited by 17 | Viewed by 5437

Abstract

The history of “mitochondrial pathologies”, namely genetic pathologies affecting mitochondrial metabolism because of mutations in nuclear DNA-encoded genes for proteins active inside mitochondria or mutations in mitochondrial DNA-encoded genes, began in 1988. In that year, two different groups of researchers discovered, respectively, large-scale single deletions of mitochondrial DNA (mtDNA) in muscle biopsies from patients with “mitochondrial myopathies” and a point mutation in the mtDNA gene for subunit 4 of NADH dehydrogenase (MTND4), associated with maternally inherited Leber’s hereditary optic neuropathy (LHON). Henceforth, a novel conceptual “mitochondrial genetics”, separate from mendelian genetics, arose, based on three features of mtDNA: (1) polyplasmy; (2) maternal inheritance; and (3) mitotic segregation. Diagnosis of mtDNA-related diseases became possible through genetic analysis and experimental approaches involving histochemical staining of muscle or brain sections, single-fiber polymerase chain reaction (PCR) of mtDNA, and the creation of patient-derived “cybrid” (cytoplasmic hybrid) immortal fibroblast cell lines. The availability of the above-mentioned techniques along with the novel sensitivity of clinicians to such disorders led to the characterization of a constantly growing number of pathologies. Here is traced a brief historical perspective on the discovery of autonomous pathogenic mtDNA mutations and on the related mendelian pathology altering mtDNA integrity. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

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13 pages, 1175 KiB

Open AccessPerspective

Mitochondrial-Derived Vesicles as Candidate Biomarkers in Parkinson’s Disease: Rationale, Design and Methods of the EXosomes in PArkiNson Disease (EXPAND) Study

by Anna Picca, Flora Guerra, Riccardo Calvani, Cecilia Bucci, Maria Rita Lo Monaco, Anna Rita Bentivoglio, Francesco Landi, Roberto Bernabei and Emanuele Marzetti

Int. J. Mol. Sci. 2019, 20(10), 2373; https://doi.org/10.3390/ijms20102373 - 14 May 2019

Cited by 60 | Viewed by 6349

Abstract

The progressive loss of dopaminergic neurons in the nigro-striatal system is a major trait of Parkinson’s disease (PD), manifesting clinically as motor and non-motor symptoms. Mitochondrial dysfunction and oxidative stress are alleged pathogenic mechanisms underlying aggregation of misfolded α-synuclein that in turn triggers dopaminergic neurotoxicity. Peripheral processes, including inflammation, may precede and contribute to neurodegeneration. Whether mitochondrial dyshomeostasis in the central nervous system and systemic inflammation are linked to one another in PD is presently unclear. Extracellular vesicles (EVs) are delivery systems through which cells can communicate or unload noxious materials. EV trafficking also participates in mitochondrial quality control (MQC) by generating mitochondrial-derived vesicles to dispose damaged organelles. Disruption of MQC coupled with abnormal EV secretion may play a role in the pathogenesis of PD. Furthermore, due to its bacterial ancestry, circulating mitochondrial DNA can elicit an inflammatory response. Therefore, purification and characterisation of molecules packaged in, and secreted through, small EVs (sEVs)/exosomes in body fluids may provide meaningful insights into the association between mitochondrial dysfunction and systemic inflammation in PD. The EXosomes in PArkiNson Disease (EXPAND) study was designed to characterise the cargo of sEVs/exosomes isolated from the serum of PD patients and to identify candidate biomarkers for PD. Full article

(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)

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