CoChat
Sign Up
Cited by 141Mitochondrial Function and PathologyNeuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research Studies

The DOI matches its Crossref record; 87 of the 87 references it cites were found in a registry or an index.

ccf-mtDNA as a Potential Link Between the Brain and Immune System in Neuro-Immunological Disorders

Open access
Gambardella, Stefano, Limanaqi, Fiona, Ferese, Rosangela, Biagioni, Francesca, Campopiano, Rosa, Centonze, Diego, Fornai, Francesco·2019·Frontiers in Immunology
DOI 10.3389/fimmu.2019.01064PMC PMC6520662
Open this paper in CoChat — free accountOpen PDF

Abstract

Fragments of mitochondrial DNA (mtDNA) are released outside the cell and they appear to persist in extracellular fluids as circulating, cell-free, mtDNA (ccf-mtDNA). When compared to nuclear DNA, such a double stranded mtDNA is more resistant to nuclease degradation. In fact, it is stable extracellularly where it can be detected in both plasma and cerebrospinal fluid (CSF), here acting as a potential biomarker in various disorders. In neurological diseases (Alzheimer's disease, Parkinson's disease and end-stage progressive Multiple Sclerosis), a decreased amount of CSF ccf-mtDNA is related with progressive cell dysfunction. This suggests an alteration in neuronal mtDNA levels (mtDNA replication, degradation and depletion) in vulnerable brain regions at early stages of neurodegeneration leading to reduced mtDNA release, which takes place before actual cell death occurs. On the other hand, elevated CSF ccf-mtDNA levels are reported in acute phases of relapsing-remitting Multiple Sclerosis (RRMS). This occurs during acute inflammation, which anticipates the neurodegenerative process. Thus, an increase in inflammatory cells in the affected regions is expected to add on mtDNA release into the CSF. In addition, similarly to bacterial DNA, the non-methylated CpG sites of mtDNA, which activate innate immunity and inflammation, are likely to participate in the molecular mechanisms of disease. Thus, ccf-mtDNA may represent a powerful biomarker for disease screening and prognosis at early stage, although its biological role may extend to generating the neurobiology of disease. The present manuscript discusses recent experimental findings in relationship with clinical evidence comparing neuro-immunological features of neurodegenerative disorders with frankly neuro-infectious diseases.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fimmu.2019.01064

Cites

87 of 87 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 An overview of mtDNA fragments life: from their generation to spreading and their role as DAMPs in inflammation. Following cellular stress/injury (1) mitochondria are compromised due to either a direct damage or an increased attempt to cope with metabolic cell demand. Thus, an increased amount of ROS in the three complexes of the respiratory chain, directly affects mtDNA integrity (2). This leads to the accumulation of oxidized mtDNA fragments, which along with ROS, are released in the cytosol as free molecules or engulfed into mitochondrial derived vesicles (MDV). The accumulation of mtDNA within a highly oxidative environment is likely to overcome the attempt of autophagy to digest damaged mitochondria and mtDNA fragments (3). This leads to the spreading of free- or exosomes/MDV engulfed- mtDNA fragments in the extracellular space (4). At the same time, intracellular mtDNA fragments trigger an inflammatory response already within the cytosol. In fact, mtDNA behave as DAMPs to activate TLR9 on the endo-lysosomal membrane (5). This promotes the activation of NFkB and the transcription of pro-inflammatory genes such as interferons (INFs) and pro-interleukines (ILs). Such an effect is magnified by an mtDNA-depended activation of two other components (6, 7), the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing-3 (NLRP3) (inflammasome) and the stimulator of interferon genes (STING) system. In this way, cytokines including IFN3/7 and IL-1β are produced and released extracellularly along with cell-free mtDNA. ccf-mtDNAs are spread into the bloodstream where they add on IL-1β activity to recruit and activate leucocytes while promoting tissue leukocyte infiltration (8a). Within blood leucocytes, ccf-mtDNA behave as DAMPs to promote inflammatory reaction, which favors cytokines release from the blood (9a). Again, ccf-mtDNA are spread within neighboring cells (such as tissue resident macrophages), either via exosome endocytosis or via binding to receptors for advanced glycated end-products (RAGEs) (8b). This is key to activate macrophages and fuel mtDNA-TLR9 dependent inflammation (9b). The result of such a domino-like cascade promoted by ccf-mtDNA is a vicious inflammatory cycle, which fosters tissue and cell injury along with progressive mitochondrial damage (1).
Figure 1 An overview of mtDNA fragments life: from their generation to spreading and their role as DAMPs in inflammation. Following cellular stress/injury (1) mitochondria are compromised due to either a direct damage or an increased attempt to cope with metabolic cell demand. Thus, an increased amount of ROS in the three complexes of the respiratory chain, directly affects mtDNA integrity (2). This leads to the accumulation of oxidized mtDNA fragments, which along with ROS, are released in the cytosol as free molecules or engulfed into mitochondrial derived vesicles (MDV). The accumulation of mtDNA within a highly oxidative environment is likely to overcome the attempt of autophagy to digest damaged mitochondria and mtDNA fragments (3). This leads to the spreading of free- or exosomes/MDV engulfed- mtDNA fragments in the extracellular space (4). At the same time, intracellular mtDNA fragments trigger an inflammatory response already within the cytosol. In fact, mtDNA behave as DAMPs to activate TLR9 on the endo-lysosomal membrane (5). This promotes the activation of NFkB and the transcription of pro-inflammatory genes such as interferons (INFs) and pro-interleukines (ILs). Such an effect is magnified by an mtDNA-depended activation of two other components (6, 7), the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing-3 (NLRP3) (inflammasome) and the stimulator of interferon genes (STING) system. In this way, cytokines including IFN3/7 and IL-1β are produced and released extracellularly along with cell-free mtDNA. ccf-mtDNAs are spread into the bloodstream where they add on IL-1β activity to recruit and activate leucocytes while promoting tissue leukocyte infiltration (8a). Within blood leucocytes, ccf-mtDNA behave as DAMPs to promote inflammatory reaction, which favors cytokines release from the blood (9a). Again, ccf-mtDNA are spread within neighboring cells (such as tissue resident macrophages), either via exosome endocytosis or via binding to receptors for advanced glycated end-products (RAGEs) (8b). This is key to activate macrophages and fuel mtDNA-TLR9 dependent inflammation (9b). The result of such a domino-like cascade promoted by ccf-mtDNA is a vicious inflammatory cycle, which fosters tissue and cell injury along with progressive mitochondrial damage (1).CC BY · PubMed Central
Figure 2 The crosstalk between mtDNA and miRNA in neuro-inflammation. The cartoon provides a schematic description of how mtDNA and mitomiR may behave as a single entity to promote neuro-inflammation. mitomiRs may derive either from cytosolic miRNA/pre-miRNA exported and processed within mitochondria (1a) or directly from mtDNA (1b). mitomiRs disrupt the respiratory chain complexes (2) and increase ROS production (3) thus producing mitochondrial damage, mitomiR dysregulation (4a), mtDNA fragmentation (4b) and spreading in the cytosol and further, in the extracellular space (5a). In the cytosol, mitomiRs repress a wide array of genes, among which those encoding for mitophagy (5b), thus exacerbating mitochondrial damage and cell stress. This enhances the extracellular release of mitomiRs and mtDNA (5a). In addition, both mitomiR and mtDNA behave as DAMPs to initiate an inflammatory response already within neurons and promote the release of pro-inflammatory cytokines (5c). In the extracellular space, mitomiRs and ccf-mtDNA spread into microglia (6a) to activate inflammation and again, to promote mitochondrial damage. This translates into fragmentation of mtDNA within glial cells and further release of cff-mtDNA and mitomiRs. Thus, these fragments along with pro-inflammatory molecules exacerbate the inflammatory response at the level of tissue stroma, which is magnified by the massive leucocyte infiltration and cytokines release fostered by the leakage of blood brain barrier (BBB). At the same time, ccf-mtDNA and mitomiRs cross the ependymal wall to reach the CSF (6b) and then the blood, where they are detectable as biomarkers of neuro-inflammation.
Figure 2 The crosstalk between mtDNA and miRNA in neuro-inflammation. The cartoon provides a schematic description of how mtDNA and mitomiR may behave as a single entity to promote neuro-inflammation. mitomiRs may derive either from cytosolic miRNA/pre-miRNA exported and processed within mitochondria (1a) or directly from mtDNA (1b). mitomiRs disrupt the respiratory chain complexes (2) and increase ROS production (3) thus producing mitochondrial damage, mitomiR dysregulation (4a), mtDNA fragmentation (4b) and spreading in the cytosol and further, in the extracellular space (5a). In the cytosol, mitomiRs repress a wide array of genes, among which those encoding for mitophagy (5b), thus exacerbating mitochondrial damage and cell stress. This enhances the extracellular release of mitomiRs and mtDNA (5a). In addition, both mitomiR and mtDNA behave as DAMPs to initiate an inflammatory response already within neurons and promote the release of pro-inflammatory cytokines (5c). In the extracellular space, mitomiRs and ccf-mtDNA spread into microglia (6a) to activate inflammation and again, to promote mitochondrial damage. This translates into fragmentation of mtDNA within glial cells and further release of cff-mtDNA and mitomiRs. Thus, these fragments along with pro-inflammatory molecules exacerbate the inflammatory response at the level of tissue stroma, which is magnified by the massive leucocyte infiltration and cytokines release fostered by the leakage of blood brain barrier (BBB). At the same time, ccf-mtDNA and mitomiRs cross the ependymal wall to reach the CSF (6b) and then the blood, where they are detectable as biomarkers of neuro-inflammation.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 87 references

Cited by

Sorted by citations

Related

See all

Metadata

Authors
Gambardella, S., Limanaqi, F., Ferese, R., Biagioni, F., Campopiano, R., Centonze, D., & Fornai, F.
Affiliations
  • Istituto Neurologico Mediterraneo (IT)
  • University of Pisa (IT)
  • University of Rome Tor Vergata (IT)
Corresponding author
Gambardella, Stefano
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2019-05-09
Volume
10
Pages
1064-1064
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2019.01064
PMC
PMC6520662
OpenAlex
W2944647162
Cited by
141
References
87
Citations by year
2026: 12 · 2025: 22 · 2024: 22 · 2023: 27 · 2022: 22 · 2021: 21 · 2020: 13 · 2019: 1
FWCI
1.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
Funders
Ministero della Salute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
Keywords
circulating cell-free mitochondrial DNA, cerebrospinal fluid biomarkers, neuroinflammation, neurodegeneration, Alzheimer's disease, Parkinson's disease, multiple sclerosis, relapsing-remitting multiple sclerosis, mitochondrial DNA release, CpG sites, innate immunity, central nervous system infection
MeSH terms
Cell-Free Nucleic Acids, Animals, Brain, Disease Susceptibility, DNA, Mitochondrial, Gene Expression Regulation, Humans, Immune System, Mitochondria, Nervous System Diseases, Neuroimmunomodulation, Signal Transduction, Biomarkers, Neurodegenerative Diseases, MicroRNAs, Exosomes

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review