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

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.

Merging the Multi-Target Effects of Phytochemicals in Neurodegeneration: From Oxidative Stress to Protein Aggregation and Inflammation

“…Mitochondria are the best-known adenosine triphosphate (ATP)-producing organelles at baseline while representing the main intracellular source of ROS and pro-apoptotic caspases when damaged or impaired. Oxidative stress resulting from an increased rate of ROS production and lipid peroxidation leads to mitochondrial dysfunctions while promoting mutations and deletions of mtDNA, which occurs in various age-related and neurodegenerative disorders [ 4 , 45 , 171 ]. In detail, the high amount of ROS being generated around mtDNA during oxidative phosphorylation contributes to mtDNA damage and fragmentation.…”

“…In detail, the high amount of ROS being generated around mtDNA during oxidative phosphorylation contributes to mtDNA damage and fragmentation. Once released extracellularly as cell-free circulating mtDNA fragments (ccf-mtDNA), these may act as pro-inflammatory mediators in the neuronal milieu [ 45 ], which will be dealt with in Section 6 .…”

“…Inflammation is critically involved in the pathogenesis of neurodegenerative disorders and it is tightly liked to oxidative stress, as well as abnormal DAMPs accumulation and their extracellular spreading [ 10 , 33 , 41 , 45 ]. Intriguingly, a paucity of studies exists investigating the effects of phytochemicals in the prion-like, cell-to-cell spreading of potentially toxic, and pro-inflammatory proteins.…”

“…Prionoid release occurs mostly when these proteins accumulate in the cell being oxidized/aggregated and glycated [ 38 , 39 , 40 ]. If this occurs in the presence of a failure in the cell-clearing systems, and mostly the autophagy-lysosome pathway, the extracellular release is the unconventional solution to overcome danger-associated molecular patterns (DAMPs), including advanced glycation end products (AGE), AGE-modified proteins, high mobility group box 1 (HMGB1), depolarized mitochondria leaking ROS, and also fragments of mitochondrial DNA (mtDNA) [ 10 , 38 , 41 , 42 , 43 , 44 , 45 ]. The irreversible glycation and oxidation of proteins and lipids produce AGEs which, similar to fragments of mtDNA and HMGB1, are released extracellularly either as free compounds or via exosomes that derive from the fusion of autophagy-lysosome vacuoles with the plasma membrane [ 10 , 38 , 45 ].…”

“…If this occurs in the presence of a failure in the cell-clearing systems, and mostly the autophagy-lysosome pathway, the extracellular release is the unconventional solution to overcome danger-associated molecular patterns (DAMPs), including advanced glycation end products (AGE), AGE-modified proteins, high mobility group box 1 (HMGB1), depolarized mitochondria leaking ROS, and also fragments of mitochondrial DNA (mtDNA) [ 10 , 38 , 41 , 42 , 43 , 44 , 45 ]. The irreversible glycation and oxidation of proteins and lipids produce AGEs which, similar to fragments of mtDNA and HMGB1, are released extracellularly either as free compounds or via exosomes that derive from the fusion of autophagy-lysosome vacuoles with the plasma membrane [ 10 , 38 , 45 ]. In neighboring cells, including neurons and glia, these DAMPs bind to toll-like receptors (TLRs) and AGE receptors (RAGEs), thus activating downstream oxidative and inflammatory signaling pathways which converge in altering cell-clearing systems, such as nuclear factor (NF)-κB, JAK/STAT, protein kinase C (PKC), and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) [ 28 , 44 , 46 , 47 , 48 ].…”