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Cells
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Circulating mtDNA and Diseases
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Circulating mtDNA and Diseases

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (15 October 2021) | Viewed by 21918

Special Issue Editor

Dr. Marcello Pinti

E-Mail Website
Guest Editor
Dept. of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
Interests: mtDNA; immunometabolism; mitochondrial Lonp1 protease

Special Issue Information

Dear Colleagues,

In the last 15 years, an increasing body of evidence has shown that mitochondrial DNA (mtDNA), the only extra-nuclear genome present in human cells, is also present as circulating, cell free DNA in body fluids, including plasma or serum. Because of its evolutive origin from an ancestral, endosymbiotic bacterium, mtDNA is sensed as a “foreign” molecule. Thus, cell free mtDNA is considered to be a proinflammatory molecule, which can trigger inflammatory responses in target immune and non-immune cells.  Circulating mtDNA levels are particularly elevated in trauma, sepsis, and myocardial infarction inflammatory diseases, as well as in several type of cancers and inflammatory diseases.

Different mechanisms have been hypothesized to explain its pro-inflammatory effects, including the activation of the Toll like receptor-9 downstream pathway, or the activation of the NLP3 inflammasome. However, much remains to be addressed concerning the mechanisms of action of mtDNA as a proinflammatory molecule, as well as its clinical significance as an inflammatory marker in a plethora of pathologies.

Therefore, the aim of this Special Issue is to assemble original data and reviews illustrating the physiopathological role(s) of circulating mtDNA, the molecular mechanisms underpinning its proinflammatory effect, the technical challenges related to the detection of mtDNA in body fluids, and the possible use of this molecule as a potential biomarker of inflammation in human diseases.

Dr. Marcello Pinti
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cell free mtDNA
  • inflammasome
  • Toll like receptors
  • cell free DNA
  • mitochondria
  • mitochondrial DNA
  • pro-inflammatory molecules

Published Papers (4 papers)

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Research

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19 pages, 4578 KiB  
Article
Extracellular Release of Mitochondrial DNA: Triggered by Cigarette Smoke and Detected in COPD
by Luca Giordano, Alyssa D. Gregory, Mireia Pérez Verdaguer, Sarah A. Ware, Hayley Harvey, Evan DeVallance, Tomasz Brzoska, Prithu Sundd, Yingze Zhang, Frank C. Sciurba, Steven D. Shapiro and Brett A. Kaufman
Cells 2022, 11(3), 369; https://doi.org/10.3390/cells11030369 - 22 Jan 2022
Cited by 22 | Viewed by 6245
Abstract
Cigarette smoke (CS) is the most common risk factor for chronic obstructive pulmonary disease (COPD). The present study aimed to elucidate whether mtDNA is released upon CS exposure and is detected in the plasma of former smokers affected by COPD as a possible [...] Read more.
Cigarette smoke (CS) is the most common risk factor for chronic obstructive pulmonary disease (COPD). The present study aimed to elucidate whether mtDNA is released upon CS exposure and is detected in the plasma of former smokers affected by COPD as a possible consequence of airway damage. We measured cell-free mtDNA (cf-mtDNA) and nuclear DNA (cf-nDNA) in COPD patient plasma and mouse serum with CS-induced emphysema. The plasma of patients with COPD and serum of mice with CS-induced emphysema showed increased cf-mtDNA levels. In cell culture, exposure to a sublethal dose of CSE decreased mitochondrial membrane potential, increased oxidative stress, dysregulated mitochondrial dynamics, and triggered mtDNA release in extracellular vesicles (EVs). Mitochondrial DNA release into EVs occurred concomitantly with increased expression of markers that associate with DNA damage responses, including DNase III, DNA-sensing receptors (cGAS and NLRP3), proinflammatory cytokines (IL-1β, IL-6, IL-8, IL-18, and CXCL2), and markers of senescence (p16 and p21); the majority of the responses are also triggered by cytosolic DNA delivery in vitro. Exposure to a lethal CSE dose preferentially induced mtDNA and nDNA release in the cell debris. Collectively, the results of this study associate markers of mitochondrial stress, inflammation, and senescence with mtDNA release induced by CSE exposure. Because high cf-mtDNA is detected in the plasma of COPD patients and serum of mice with emphysema, our findings support the future study of cf-mtDNA as a marker of mitochondrial stress in response to CS exposure and COPD pathology. Full article
(This article belongs to the Special Issue Circulating mtDNA and Diseases)
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Review

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22 pages, 1455 KiB  
Review
Circulating Mitochondrial DNA and Inter-Organelle Contact Sites in Aging and Associated Conditions
by Anna Picca, Flora Guerra, Riccardo Calvani, Roberta Romano, Hélio José Coelho-Junior, Francesco P. Damiano, Cecilia Bucci and Emanuele Marzetti
Cells 2022, 11(4), 675; https://doi.org/10.3390/cells11040675 - 15 Feb 2022
Cited by 9 | Viewed by 4252
Abstract
Mitochondria are primarily involved in cell bioenergetics, regulation of redox homeostasis, and cell death/survival signaling. An immunostimulatory property of mitochondria has also been recognized which is deployed through the extracellular release of entire or portioned organelle and/or mitochondrial DNA (mtDNA) unloading. Dynamic homo- [...] Read more.
Mitochondria are primarily involved in cell bioenergetics, regulation of redox homeostasis, and cell death/survival signaling. An immunostimulatory property of mitochondria has also been recognized which is deployed through the extracellular release of entire or portioned organelle and/or mitochondrial DNA (mtDNA) unloading. Dynamic homo- and heterotypic interactions involving mitochondria have been described. Each type of connection has functional implications that eventually optimize mitochondrial activity according to the bioenergetic demands of a specific cell/tissue. Inter-organelle communications may also serve as molecular platforms for the extracellular release of mitochondrial components and subsequent ignition of systemic inflammation. Age-related chronic inflammation (inflamm-aging) has been associated with mitochondrial dysfunction and increased extracellular release of mitochondrial components—in particular, cell-free mtDNA. The close relationship between mitochondrial dysfunction and cellular senescence further supports the central role of mitochondria in the aging process and its related conditions. Here, we provide an overview of (1) the mitochondrial genetic system and the potential routes for generating and releasing mtDNA intermediates; (2) the pro-inflammatory pathways elicited by circulating mtDNA; (3) the participation of inter-organelle contacts to mtDNA homeostasis; and (4) the link of these processes with senescence and age-associated conditions. Full article
(This article belongs to the Special Issue Circulating mtDNA and Diseases)
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21 pages, 1296 KiB  
Review
Molecular Mechanisms of mtDNA-Mediated Inflammation
by Anna De Gaetano, Kateryna Solodka, Giada Zanini, Valentina Selleri, Anna Vittoria Mattioli, Milena Nasi and Marcello Pinti
Cells 2021, 10(11), 2898; https://doi.org/10.3390/cells10112898 - 26 Oct 2021
Cited by 81 | Viewed by 7177
Abstract
Besides their role in cell metabolism, mitochondria display many other functions. Mitochondrial DNA (mtDNA), the own genome of the organelle, plays an important role in modulating the inflammatory immune response. When released from the mitochondrion to the cytosol, mtDNA is recognized by cGAS, [...] Read more.
Besides their role in cell metabolism, mitochondria display many other functions. Mitochondrial DNA (mtDNA), the own genome of the organelle, plays an important role in modulating the inflammatory immune response. When released from the mitochondrion to the cytosol, mtDNA is recognized by cGAS, a cGAMP which activates a pathway leading to enhanced expression of type I interferons, and by NLRP3 inflammasome, which promotes the activation of pro-inflammatory cytokines Interleukin-1beta and Interleukin-18. Furthermore, mtDNA can be bound by Toll-like receptor 9 in the endosome and activate a pathway that ultimately leads to the expression of pro-inflammatory cytokines. mtDNA is released in the extracellular space in different forms (free DNA, protein-bound DNA fragments) either as free circulating molecules or encapsulated in extracellular vesicles. In this review, we discussed the latest findings concerning the molecular mechanisms that regulate the release of mtDNA from mitochondria, and the mechanisms that connect mtDNA misplacement to the activation of inflammation in different pathophysiological conditions. Full article
(This article belongs to the Special Issue Circulating mtDNA and Diseases)
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17 pages, 1317 KiB  
Review
Mitochondrial DNA and Exercise: Implications for Health and Injuries in Sports
by Giada Zanini, Anna De Gaetano, Valentina Selleri, Gustavo Savino, Andrea Cossarizza, Marcello Pinti, Anna Vittoria Mattioli and Milena Nasi
Cells 2021, 10(10), 2575; https://doi.org/10.3390/cells10102575 - 28 Sep 2021
Cited by 12 | Viewed by 3373
Abstract
Recently, several studies have highlighted the tight connection between mitochondria and physical activity. Mitochondrial functions are important in high-demanding metabolic activities, such as endurance sports. Moreover, regular training positively affects metabolic health by increasing mitochondrial oxidative capacity and regulating glucose metabolism. Exercise could [...] Read more.
Recently, several studies have highlighted the tight connection between mitochondria and physical activity. Mitochondrial functions are important in high-demanding metabolic activities, such as endurance sports. Moreover, regular training positively affects metabolic health by increasing mitochondrial oxidative capacity and regulating glucose metabolism. Exercise could have multiple effects, also on the mitochondrial DNA (mtDNA) and vice versa; some studies have investigated how mtDNA polymorphisms can affect the performance of general athletes and mtDNA haplogroups seem to be related to the performance of elite endurance athletes. Along with several stimuli, including pathogens, stress, trauma, and reactive oxygen species, acute and intense exercise also seem to be responsible for mtDNA release into the cytoplasm and extracellular space, leading to the activation of the innate immune response. In addition, several sports are characterized by a higher frequency of injuries, including cranial trauma, associated with neurological consequences. However, with regular exercise, circulating cell-free mtDNA levels are kept low, perhaps promoting cf-mtDNA removal, acting as a protective factor against inflammation. Full article
(This article belongs to the Special Issue Circulating mtDNA and Diseases)
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