Top

Published in:

01-06-2020 | Multiple Sclerosis | Original Paper

Mitochondrial DNA Copy Number in Peripheral Blood as a Potential Non-invasive Biomarker for Multiple Sclerosis

Authors: Ghada Al-Kafaji, Halla F. Bakheit, Maram A. Alharbi, Ahmad A. Farahat, Mohamed Jailani, Bashayer H. Ebrahin, Moiz Bakhiet

Published in: NeuroMolecular Medicine | Issue 2/2020

Abstract

The impaired mitochondrial function has been implicated in the pathogenicity of multiple sclerosis (MS), a chronic inflammatory, demyelinating, and neurodegenerative disease of the CNS. Circulating mtDNA copy number in body fluids has been proposed as an indicator for several neurodegenerative diseases, and the altered cerebrospinal fluid mtDNA has been shown as a promising marker for MS. The aim of this study was to determine changes and biomarker potential of circulating mtDNA in peripheral blood in MS. The mtDNA copy number was quantified by real-time PCR in blood samples from 60 patients with relapsing–remitting MS (RRMS) and 64 healthy controls. The RRMS patients had significantly lower circulating mtDNA copy number compared to controls. Subgroup analysis with stratification of RRMS patients based on disease duration under or over 10 years revealed that the mtDNA copy number was significantly lower in the group with longer disease duration. A negative correlation was observed between mtDNA copy number and disease duration. The ROC curve analysis indicated a significant ability of mtDNA copy number to separate RRMS patients from controls with an AUC of 0.859. This is the first study to measure peripheral blood mtDNA copy number in MS patients. Current data suggest that the reduction in peripheral blood mtDNA copy number may be an early event in MS and correlate with the disease progression. The findings of this study indicate that circulating blood-based mtDNA copy number may be a potential non-invasive candidate biomarker for mitochondria-mediated neurodegeneration and MS. This can put forward the clinical applicability over other invasive markers.

Al-Kafaji, G., & Golbahar, J. (2013). High glucose-induced oxidative stress increases the copy number of mitochondrial DNA in human mesangial cells. BioMed Research International,2013, 754946.PubMedPubMedCentralCrossRef

Al-Kafaji, G., Sabry, M. A., & Bakhiet, M. (2016a). Increased expression of mitochondrial DNA-encoded genes in human renal mesangial cells in response to high glucose-induced reactive oxygen species. Molecular Medicine Reports,13(2), 1774–1780.PubMedCrossRef

Al-Kafaji, G., Sabry, M. A., & Skrypnyk, C. (2016b). Time-course effect of high glucose-induced reactive oxygen species on mitochondrial biogenesis and function in human renal mesangial cells. Cell Biology International,40(1), 36–48.PubMedCrossRef

Al-Kafaji, G., AlJadaan, A., Kamal, A., & Bakhiet, M. (2018). Peripheral blood mitochondrial DNA copy number is a potential new biomarker for diabetic nephropathy in type 2 diabetes patients. Experimental and Therapeutic Medicine,16(2), 1483–1492.PubMedPubMedCentral

Andalib, S., Talebi, M., Sakhinia, E., Farhiudi, M., Sadeghi-Bazargani, H., Motavallian, A., et al. (2013). Multiple sclerosis and mitochondrial gene variations: A review. Journal of the Neurological Sciences,330(1–2), 10–15.PubMedCrossRef

Blokhin, A., Vyshkina, T., Komoly, S., & Kalman, B. (2008). Variations in mitochondrial DNA copy numbers in MS brains. Journal of Molecular Neuroscience,35(3), 283–287.PubMedCrossRef

Bohr, V. A. (2002). Repair of oxidative DNA damage in nuclear and mitochondrial DNA, and some changes with aging in mammalian cells. Free Radical Biology and Medicine,32(9), 804–812.PubMedCrossRef

Campbell, G. R., Ziabreva, I., Reeve, A. K., Krishnan, K. J., Reynolds, R., Howell, O., et al. (2011). Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Annals of Neurology,69(3), 481–492.PubMedCrossRef

Cerqueira, J. J., Compston, D. A. S., Geraldes, R., Rosa, M. M., Schmierer, K., Thompson, A., et al. (2018). Time matters in multiple sclerosis: Can early treatment and long-term follow-up ensure everyone benefits from the latest advances in multiple sclerosis? Journal of Neurology, Neurosurgery, and Psychiatry,89, 844–850.PubMedPubMedCentralCrossRef

Chen, S., Li, Z., He, Y., Zhang, F., Li, H., Liao, Y., et al. (2015). Elevated mitochondrial DNA copy number in peripheral blood cells is associated with childhood autism. BMC Psychiatry,15, 50.PubMedPubMedCentralCrossRef

Clay-Montier, L. L., Deng, J. J., Bai, Y., et al. (2009). Number matters: Control of mammalian mitochondrial DNA copy number. Journal of Genetics and Genomics,36, 125–131.PubMedPubMedCentralCrossRef

De Stefano, N., Stromillo, M. L., Giorgio, A., Bartolozzi, M. L., Battaglini, M., Baldini, M., et al. (2016). Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry,87, 93–99.PubMedCrossRef

Delbarba, A., Abate, G., Prandelli, C., Marziano, M., Buizza, L., Varas, N. A., et al. (2016). Mitochondrial Alterations in peripheral mononuclear blood cells from Alzheimer’s disease and mild cognitive impairment patients. Oxidative Medicine and Cellular Longevity,2016, 5923938.PubMedPubMedCentralCrossRef

Dutta, R., McDonough, J., Yin, X., Peterson, J., Chang, A., Torres, T., et al. (2006). Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Annals of Neurology,59, 478–489.PubMedCrossRef

Errea, O., Moreno, B., Conzalez-Franquesa, A., Garcia-Roves, P. M., & Villoslada, P. (2015). The disruption of mitochondrial axonal transport is an early event in neuroinflammation. J Neuroinflammation,12, 152.PubMedPubMedCentralCrossRef

Franco-Iborra, S., Vila, M., & Perier, C. (2018). Mitochondrial quality control in neurodegenerative diseases: Focus on Parkinson's disease and Huntington's disease. Frontiers in Neuroscience,12, 342.PubMedPubMedCentralCrossRef

Garcia, I., Jones, E., Ramos, M., Innis-Whitehouse, W., & Gilkerson, R. (2017). The little big genome: The organization of mitochondrial DNA. Frontiers in Bioscience,22, 710–721.CrossRef

Grunewald, A., Rygiel, K. A., Hepplewhite, P. D., Morris, C. M., Picard, M., Hom, D., et al. (2016). Mitochondrial DNA depletion in respiratory chain–deficient Parkinson disease neurons. Annals of Neurology,79(3), 366–378.PubMedPubMedCentralCrossRef

Hampel, H., O’Bryant, S. E., Molinuevo, J. L., Zetterberg, H., Masters, C. L., Lista, S., et al. (2018). Blood-based biomarkers for Alzheimer disease: Mapping the road to the clinic. Nature Reviews Neurology,14(11), 639–652.PubMedPubMedCentralCrossRef

Harris, V. K., Tuddenham, J. F., & Sadiq, S. A. (2017). Biomarkers of multiple sclerosis: Current findings. Degenerative Neurological and Neuromuscular Disease,7, 19–29.PubMedPubMedCentralCrossRef

Hernandez-Pedro, N. Y., Espinosa-Ramirez, G., de la Cruz, V. P., Pineda, B., & Sotelo, J. (2013). Initial immunopathogenesis of multiple sclerosis: Innate immune response. Clinical & Developmental Immunology,2013, 413465.CrossRef

Hu, L., Yao, X., & Shen, Y. (2016). Altered mitochondrial DNA copy number contributes to human cancer risk: Evidence from an updated meta-analysis. Scientific Reports,6, 35859.PubMedPubMedCentralCrossRef

Hulgan, T., Kallianpur, A. R., Guo, Y., Barnholtz, J. S., Gittleman, H., Brown, T. T., et al. (2019). Peripheral blood mitochondrial DNA copy number obtained from genome-wide genotype data is associated with neurocognitive impairment in persons with chronic HIV infection. Journal of Acquired Immune Deficiency Syndromes,80(4), e95–e102.PubMedCrossRef

Hurtado-Roca, Y., Ledesma, M., Gonzalez-Lazaro, M., Moreno-Loshuertos, R., Fernandez-Silva, P., Enriquez, J. A., et al. (2016). Adjusting mtDNA quantification in whole blood for peripheral blood platelet and leukocyte counts. PLoS ONE,11(10), e0163770.PubMedPubMedCentralCrossRef

Ide, T., Tsutsu, H., Hayashidani, S., Kang, D., Suematsu, N., Nakamura, K., et al. (2001). Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circulation Research,88, 529–535.PubMedCrossRef

Johri, A., & Beal, M. F. (2012). Mitochondrial dysfunction in neurodegenerative diseases. Journal of Pharmacology and Experimental Therapeutics,342(3), 619–630.PubMedCrossRef

Kilbaugh, T. J., Lvova, M., Karlsson, M., Zhang, Z., Leipzig, J., Wallace, D. C., et al. (2015). Peripheral blood mitochondrial DNA as a biomarker of cerebral mitochondrial dysfunction following traumatic brain injury in a porcine model. PLoS ONE,10(6), e0130927.PubMedPubMedCentralCrossRef

Lee, H. C., & Wei, Y. H. (2005). Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. The International Journal of Biochemistry & Cell Biology,37, 822–834.CrossRef

Lee, H., Song, J. H., Shine, C. S., Park, D. J., Park, K. S., Lee, K. U., et al. (1998). Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus. Diabetes Research and Clinical Practice,42, 161–167.PubMedCrossRef

Leurs, C. E., Podlesniy, P., Trullas, R., Balk, L., Steenwijk, M. D., Malekzadeh, A., et al. (2018). Cerebrospinal fluid mtDNA concentration is elevated in multiple sclerosis disease and responds to treatment. Multiple Sclerosis Journal,24(4), 472–480.PubMedCrossRef

Loma, I., & Heyman, R. (2011). Multiple sclerosis: Pathogenesis and treatment. Current Neuropharmacology,9, 409–416.PubMedPubMedCentralCrossRef

Lowes, H., Pyle, A., Duddy, M., & Hudson, G. (2008). Cell-free mitochondrial DNA in progressive multiple sclerosis. Journal of Molecular Neuroscience,35(3), 283–287.CrossRef

Mahad, D., Lassmann, H., & Turnbull, D. (2008). Review: Mitochondria and disease progression in multiple sclerosis. Neuropathology and Applied Neurobiology,34, 577–589.PubMedPubMedCentralCrossRef

Manuelidis, L. (2011). Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD. The Journal of NeuroVirology,17, 131–145.PubMedCrossRef

Mao, P., & Reddy, P. H. (2010). Is multiple sclerosis a mitochondrial disease? Biochimica et Biophysica Acta,1802, 66–79.PubMedCrossRef

Morais, V. A., & De Strooper, B. (2010). Mitochondria dysfunction and neurodegenerative disorders: Cause or consequence. Journal of Alzheimer's Disease,20, S255–S263.PubMedCrossRef

Noseworthy, J. H., Lucchinetti, C., Rodriguez, M., & Weinshenker, B. G. (2000). Multiple sclerosis. The New England Journal of Medicine,343, 938–952.PubMedCrossRef

O'Gorman, C., Lucas, R., & Taylor, B. (2012). Environmental risk factors for multiple sclerosis: A review with a focus on molecular mechanisms. International Journal of Molecular Sciences,13(9), 11718–11752.PubMedPubMedCentralCrossRef

Petersen, M. H., Budtz-Jorgensen, E., Sorensen, S. A., Nielsen, J. E., Hjermind, L. E., Vinther-Jensen, T., et al. (2014). Reduction in mitochondrial DNA copy number in peripheral leukocytes after onset of Huntington's disease. Mitochondrion,17, 14–21.PubMedCrossRef

Podlesniy, P., Figueiro-Silva, J., Llado, A., Sanchez-Valle, R., Alcolea, D., et al. (2013). Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease. Annals of Neurology,74(5), 655–668.PubMedCrossRef

Polman, C. H., Reingold, S. C., Banwell, B., Clanet, M., Cohen, J. A., Filippi, M., et al. (2011). Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology,69(2), 292–302.PubMedPubMedCentralCrossRef

Pyle, A., Brennan, R., Kurzawa-Akanbi, M., Yarnall, A., Thouin, A., Mollenhauer, B., et al. (2015). Reduced cerebrospinal fluid mitochondrial DNA is a biomarker for early stage Parkinson's disease. Annals of Neurology,78(6), 1000–1004.PubMedPubMedCentralCrossRef

Pyle, A., Anugrha, H., Kurzawa-Akanbi, M., Yarnall, A., Burn, D., & Hudson, G. (2016). Reduced mitochondrial DNA copy number is a biomarker of Parkinson's disease. Neurobiology Aging,38, 216.e7–216.e10.CrossRef

Rice, A. C., Keeney, P. M., Algarzae, N. K., Ladd, A. C., Thomas, R. R., & Bennett, J. P., Jr. (2014). Mitochondrial DNA copy numbers in pyramidal neurons are decreased and mitochondrial biogenesis transcriptome signaling is disrupted in Alzheimer's disease hippocampi. Journal of Alzheimer's Disease,40, 319–330.PubMedCrossRef

Rodriguez-Santiago, B., Casademont, J., & Nunes, V. (2001). Is mitochondrial DNA depletion involved in Alzheimer's disease? European Journal of Human Genetics,9, 279–285.PubMedCrossRef

Satoh, M., & Kuroiwa, T. (1991). Organization of multiple nucleoids and DNA molecules in mitochondria of a human cell. Experimental Cell Research,196, 137–140.PubMedCrossRef

Schwarzenbach, H., Hoon, D. S., & Pantel, K. (2011). Cell-free nucleic acids as biomarkers in cancer patients. Nature Reviews Cancer,11, 426–437.PubMedCrossRef

Shen, J., Gopalakrishnan, V., Lee, J. E., Fang, S., & Zhao, H. (2015). Mitochondrial DNA copy number in peripheral blood and melanoma risk. PLoS ONE,10(6), e0131649.PubMedPubMedCentralCrossRef

Silzer, T., Barber, R., Sun, J., Pathak, G., Johnson, L., O’Bryant, S., et al. (2019). Circulating mitochondrial DNA: New indices of type 2 diabetes-related cognitive impairment in Mexican Americans. PLoS ONE,14(3), e0213527.PubMedPubMedCentralCrossRef

Song, J., Oh, J. Y., Sung, Y.-A., Pak, Y. K., Park, K. S., & Lee, H. K. (2001). Peripheral blood mitochondrial DNA content is related to insulin sensitivity in offspring of type 2 diabetic patients. Diabetes Care,24(5), 865–869.PubMedCrossRef

Trojano, M., Paolicelli, D., Bellacosa, A., & Cataldo, S. (2003). The transition from relapsing–remitting MS to irreversible disability: Clinical evaluation. Neurological Sciences,24(Suppl. 5), S268–S270.PubMedCrossRef

Tsujii, N., Otsuka, I., Okazaki, S., Yanagi, M., Numata, S., Yamaki, N., et al. (2019). Mitochondrial DNA copy number raises the potential of left frontopolar hemodynamic response as a diagnostic marker for distinguishing bipolar disorder from major depressive disorder. Frontiers in Psychiatry,8(10), 312.CrossRef

Weinshenker, B. G., Bass, B., Rice, G. P., Noseworthy, J., Carriere, W., Baskerville, J., et al. (1989). The natural history of multiple sclerosis: A geographically based study I. Clinical course and disability. Brain,112(Pt 1), 133–146.PubMedCrossRef

Xia, P., An, H. X., Dang, C. X., Radpour, R., Kohler, C., Fokas, E., et al. (2009). Decreased mitochondrial DNA content in blood samples of patients with stage I breast cancer. BMC Cancer,9, 454.PubMedPubMedCentralCrossRef

Xia, C.-Y., Liu, Y., Yang, H. R., Yang, H. Y., Liu, J. X., & Qi, Y. (2017). Reference intervals of mitochondrial DNA copy number in peripheral blood for Chinese minors and adults. Chinese Medical Journal,130(20), 2435–2440.PubMedPubMedCentralCrossRef

Zhang, Q., Raoof, M., Chen, Y., Sumi, Y., Sursal, T., Junger, W., et al. (2010). Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature,464, 104–107.PubMedPubMedCentralCrossRef

Zhao, H., Chang, D., Ye, Y., Shen, J., Chow, W., Wu, X., et al. (2018). Associations of blood mitochondrial DNA copy number with social-demographics and cancer risk: Results from the Mano-AMano Mexican American Cohort. Oncotarget,9(39), 2549–25502.CrossRef

Zuvich, R. L., McCauley, J. L., Pericak-Vance, M. A., & Haines, J. L. (2009). Genetics and pathogenesis of multiple sclerosis. Seminars in Immunology,21(6), 328–333.PubMedPubMedCentralCrossRef

Title: Mitochondrial DNA Copy Number in Peripheral Blood as a Potential Non-invasive Biomarker for Multiple Sclerosis
Authors: Ghada Al-Kafaji
Halla F. Bakheit
Maram A. Alharbi
Ahmad A. Farahat
Mohamed Jailani
Bashayer H. Ebrahin
Moiz Bakhiet
Publication date: 01-06-2020
Publisher: Springer US
Keywords: Multiple Sclerosis
Biomarkers
Published in: NeuroMolecular Medicine / Issue 2/2020
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-019-08588-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Mitochondrial DNA Copy Number in Peripheral Blood as a Potential Non-invasive Biomarker for Multiple Sclerosis

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2020

A Transcriptomic Analysis of Neuropathic Pain in Rat Dorsal Root Ganglia Following Peripheral Nerve Injury

Correction to: High‑Mobility Group Box‑1‑Induced Angiogenesis After Indirect Bypass Surgery in a Chronic Cerebral Hypoperfusion Model

Dexmedetomidine Protects Against Oxygen–Glucose Deprivation-Induced Injury Through Inducing Astrocytes Autophagy via TSC2/mTOR Pathway

Naringin Exhibits Neuroprotection Against Rotenone-Induced Neurotoxicity in Experimental Rodents

Disregulation of Autophagy in the Transgenerational Cc2d1a Mouse Model of Autism

Harpagophytum procumbens Extract Ameliorates Allodynia and Modulates Oxidative and Antioxidant Stress Pathways in a Rat Model of Spinal Cord Injury