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ccf-mtDNA as a Potential Link Between the Brain and Immune System in Neuro-Immunological Disorders
Open accessAbstract
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.
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“Assessing the presence of extracellular mitochondria or their fragments by measuring ccf-mtDNA levels could allow on-flight direct estimation of cellular stress to take preventive measures of cumulative damage196,199–206.”
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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)
- 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
- gold
- doi.org
- 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
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