Plasma circulating cell-free mitochondrial DNA in the assessment of Friedreich's ataxia

Dantham, Subrahamanyam; Srivastava, Achal K.; Gulati, Sheffali; Rajeswari, Moganty R.

doi:10.1016/j.jns.2016.04.016

Cited by 17 publications

(16 citation statements)

References 35 publications

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“…Several studies have associated cell-free mtDNA (cfmtDNA) with human disease [11][12][13][14][15][16][17][18][19][20][21][22][23] , particularly neurodegenerative disease (NDD) 26,28,37 . Whilst these studies were typically aimed at identifying biomarkers of disease, they were unable to link cfmtDNA levels to pathology.…”

Section: Discussionmentioning

confidence: 99%

Post-mortem ventricular cerebrospinal fluid cell-free-mtDNA in neurodegenerative disease

Lowes

Kurzawa‐Akanbi

Pyle

et al. 2020

Sci Rep

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Cell-free mitochondrial DNA (cfmtDNA) is detectable in almost all human body fluids and has been associated with the onset and progression of several complex traits. In-life assessments indicate that reduced cfmtDNA is a feature of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and multiple sclerosis. However, whether this feature is conserved across all neurodegenerative diseases and how it relates to the neurodegenerative processes remains unclear. In this study, we assessed the levels of ventricular cerebrospinal fluid-cfmtDNA (vCSF-cfmtDNA) in a diverse group of neurodegenerative diseases (NDDs) to determine if the in-life observations of reduced cfmtDNA seen in lumbar CSF translated to the post-mortem ventricular CSF. To investigate further, we compared vCSF-cfmtDNA levels to known protein markers of neurodegeneration, synaptic vesicles and mitochondrial integrity. Our data indicate that reduced vCSF-cfmtDNA is a feature specific to Parkinson’s and appears consistent throughout the disease course. Interestingly, we observed increased vCSF-cfmtDNA in the more neuropathologically severe NDD cases, but no association to protein markers of neurodegeneration, suggesting that vCSF-cfmtDNA release is more complex than mere cellular debris produced following neuronal death. We conclude that vCSF-cfmtDNA is reduced in PD, but not other NDDs, and appears to correlate to pathology. Although its utility as a prognostic biomarker is limited, our data indicate that higher levels of vCSF-cfmtDNA is associated with more severe clinical presentations; suggesting that it is associated with the neurodegenerative process. However, as vCSF-cfmtDNA does not appear to correlate to established indicators of neurodegeneration or indeed indicators of mitochondrial mass, further work to elucidate its exact role is needed.

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Section: Discussionmentioning

confidence: 99%

Post-mortem ventricular cerebrospinal fluid cell-free-mtDNA in neurodegenerative disease

Lowes

Kurzawa‐Akanbi

Pyle

et al. 2020

Sci Rep

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“…The identification of circulating cell-free mitochondrial DNA (ccf-mtDNA) in 2000 [1], prompted a wave of studies assessing the utility of ccf-mtDNA as a biomarker of disease [2][3][4][5][6][7], detection of cancers [8][9][10][11][12] and susceptibility to comorbidities during HIV infection [13,14].…”

mentioning

confidence: 99%

Circulating cell-free mitochondrial DNA levels in Parkinson’s disease are influenced by treatment

Lowes

Pyle

Santibanez‐Koref

et al. 2020

Mol Neurodegeneration

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Several studies have linked circulating cell-free mitochondrial DNA (ccf-mtDNA) to human disease. In particular, reduced ccf-mtDNA levels in the cerebrospinal fluid (CSF) of both Alzheimer's and Parkinson's disease (PD) patients have raised the hypothesis that ccf-mtDNA could be used as a biomarker for neurodegenerative disease onset and progression. However, how a reduction of CSF ccf-mtDNA levels relates to neurodegeneration remains unclear. Many factors are likely to influence ccf-mtDNA levels, such as concomitant therapeutic treatment and comorbidities. In this study we aimed to investigate these factors, quantifying CSF ccf-mtDNA from the Parkinson's Progression Markers Initiative in 372 PD patients and 159 matched controls at two time points. We found that ccf-mtDNA levels appear significantly reduced in PD cases when compared to matched controls and are associated with cognitive impairment. However, our data indicate that this reduction in ccf-mtDNA is also associated with the commencement, type and duration of treatment. Additionally, we found that ccf-mtDNA levels are associated with comorbidities such as depression and insomnia, however this was only significant if measured in the absence of treatment. We conclude that in PD, similar to reports in HIV and sepsis, comorbidities and treatment can both influence ccf-mtDNA homeostasis, raising the possibility that ccf-mtDNA may be useful as a biomarker for treatment response or the development of secondary phenotypes. Given that, clinically, PD manifests often decades after neurodegeneration begins, predicting who will develop disease is important. Also, identifying patients who will respond to existing treatments or develop secondary phenotypes will have increased clinical importance as PD incidence rises.

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“…Furthermore, Dantham et al . [ 12 ] have shown that mutations in the mitochondrial protein-coding genes decreased the ratio of cf-mtDNA to nuclear cfDNA and that nutritional intervention using omega-3 fatty acids helped restore the ratio. From these reports, it may be hypothesized that mitochondrial dynamics in oocytes and embryos, affect the level of cf-mtDNA in circulation as well as in the cultural milieu.…”

mentioning

confidence: 99%

Mitochondrial dysfunction in cumulus-oocyte complexes increases cell-free mitochondrial DNA

Kansaku

Munakata

Itami

et al. 2018

Journal of Reproduction and Development

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This study examined the concentration of cell-free mitochondrial DNA (cf-mtDNA) in porcine follicular fluid (FF) and explored whether the cfDNA level in the culture medium could reflect mitochondrial dysfunction in cumulus cell-oocyte complexes (COCs). cfDNA concentration was higher in the fluid of small-sized follicles, compared to that in larger follicles. The length of cfDNA ranged from short (152 bp) to long (1,914 bp) mtDNA in FF, detected by polymerase chain reaction (PCR). cfDNA concentration in FF significantly correlated with the mtDNA copy number in FF but not with the number of one-copy gene (nuclear DNA) in FF. When the COCs were treated with the mitochondrial uncoupler, namely carbonyl cyanide m-chlorophenyl hydrazone (CCCP), for 2 h and incubated for 42 h, subsequent real-time PCR detected significantly higher amount of cf-mtDNA, compared to nuclear cfDNA, in the spent culture medium. The mtDNA number and viability of cumulus cells and oocytes remained unchanged. When the oocytes were denuded from the cumulus cells following CCCP treatment, PCR detected very low levels of cfDNA in the spent culture medium of the denuded oocytes. In contrast, CCCP treatment of granulosa cells significantly increased the amount of cf-mtDNA in the spent culture medium, without any effect on other markers, including survival rate, apoptosis of cumulus cells, and lactate dehydrogenase levels. Thus, cf-mtDNA was present in FF in a wide range of length, and mitochondrial dysfunction in COCs increased the active secretion of cf-mtDNA in the cultural milieu.

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Plasma circulating cell-free mitochondrial DNA in the assessment of Friedreich's ataxia

Cited by 17 publications

References 35 publications

Post-mortem ventricular cerebrospinal fluid cell-free-mtDNA in neurodegenerative disease

Post-mortem ventricular cerebrospinal fluid cell-free-mtDNA in neurodegenerative disease

Circulating cell-free mitochondrial DNA levels in Parkinson’s disease are influenced by treatment

Mitochondrial dysfunction in cumulus-oocyte complexes increases cell-free mitochondrial DNA

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