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Nitric Oxide-Dependent Oxidative Stress Induced Mitochondrial DNA Overproliferation and Deletion in the Context of Cancer and Alzheimer Disease

Gjumrakch Aliev1 and George E. Barreto2*
  • 1 GALLY International Biomedical Research Consulting LLC, 7733 Louis Pasteur Drive, #330, United States
  • 2 Pontificia Universidad Javeriana, Colombia

Oxidative stress initiates mitochondrial DNA overproliferation and/or deletion of the organ and/or tissues, especially the mitochondrial energy demands, have been implicated in the pathogenesis of several diseases, including Alzheimer disease (AD), tumor growth, and metastasis. The present study has determined if an intimate, i.e. causal, relationship between oxidative stress and mitochondrial damage and/or vascular lesions occurs before the development of human AD, in animal models that mimic human neurodegenerative diseases and human colorectal carcinoid cancer or primary malignant brain cancer. In situ hybridization and ultrastructural analysis of the mitochondria (mitochondria with electron dense matrix, mitochondrial-derived lysosomes) showed that mitochondria with the abnormal structures and lipofuscin appear to be features of hippocampal damaged neurons in human AD, aged Tg (+) mice, 2 and 3 vessel occlusion model of the brain hypoperfusion, and malignant primary and metastatic cancer. The abnormal mitochondria appeared to be a permanent feature in all cellular compartments; in situ hybridization analysis with mouse and human mtDNA probes found a large amount of deleted mtDNA in human AD and in all models that mimic human AD (mice, rats etc.) hippocampus and cancer tissues compared to aged controls. The majority of these mtDNA deletions were found in mitochondrial-derived lysosomes in regions closely associated with lipofuscin and/or tumor growth regions. In situ hybridization with a chimeric cDNA probe for the 5kb common deletion indicated that the 5kb mtDNA is increased at least 3 and 4 fold respectively in AD and malignant tumor cases as compared to controls. Only hippocampal and cortical vulnerable neurons as well as malignant cancer tissues showed immunopositive staining for RNA oxidation markers visualized by using 8-OHG-staining, NOSs, and all oxidative stress markers. The mitochondrial DNA overproliferation and deletion detected by using cytological techniques suggests that successful dysregulation of the cell cycle is also the hallmark of neoplasm; early mitochondrial dependent cell-cycle pathophysiology in AD may recruit oncogenic signal transduction mechanisms and hence, can be viewed as an abortive neoplastic transformation. The common features on the mitochondrial abnormality were seen on the brain during tumorigenesis and AD indicating that mitochondrial DNA overproliferation and/or deletion are the key initiating factors for development, maturation, and progression of neurodegeneration as well as tumor growth and/or metastases. Materials presented in this work indicate that the Nitric oxide- (NO-) dependent oxidative stress results in mitochondrial ultrastructural alterations and DNA damage in cases of Alzheimer disease (AD). However, little is known about these pathways in human cancers, especially during the development as well as the progression of primary brain tumors and metastatic colorectal cancer. One of the key features of tumors is the deficiency in tissue energy that accompanies mitochondrial lesions and formation of the hypoxic smaller sized mitochondria with ultrastructural abnormalities. We theorize that mitochondrial involvement may play a significant role in the etiopathogenesis of cancer. Moreover, our study also demonstrates a potential link between AD and cancer, and anticancer drugs are being explored for the inhibition of AD-like pathology in transgenic mice. Severity of the cancer growth, metastasis, and brain pathology in AD (in animal models that mimic human AD) correlate with the degree of mitochondrial ultrastructural abnormalities. Recent advances in the cell-cycle reentry of the terminally differentiated neuronal cells indicate that NO-dependent mitochondrial abnormal activities and mitotic cell division are not the only important pathogenic factors in pathogenesis of cancer and AD, but open a new window for the development of novel treatment strategies for these devastating diseases.

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References

1. Aliev G., Li Y., Palacios H., and Obrenovich M.E. Oxidative Stress Induced Mitochondrial DNA Deletion as a Hallmark for the Drug Development in the Context of the Cerebrovascular Diseases. Recent Patents on Cardiovascular Drug Discovery, 2011, 6, 222-241.

2. Aliev G. Oxidative stress induced-metabolic imbalance, mitochondrial failure, and cellular hypoperfusion as primary pathogenetic factors for the development of Alzheimer disease which can be used as a alternate and successful drug treatment strategy: past, present and future. CNS & Neurological Disorders – Drug Targets, 2011;10(2):147-8.

3. Palacios H.H., Yendluri B.B., Parvathaneni K. , Shadlinski V. B. , Obrenovich M. E., Leszek J., Gokhman D. , Gąsiorowski K. Bragin V. and Aliev G. Mitochondrion-Specific Antioxidants as Drug Treatments for Alzheimer Disease. CNS & Neurological Disorders – Drug Targets, 2011;10(2):149-62.

4. Aliev, G. Palacios H.H., Cacabelos P., Cacabelos R., Burzynski G., and S.R. Burzynski. Mitochondria Specific Antioxidants and their Derivatives in the Context of the Drug Development for Neurodegeneration and Cancer. Drug Des 2012, 2: 103, doi: 10.4172/2169-0138.1000103.

5. Aliev, G., Obrenovich M.E., Tabrez S., Jabir N.R., Reddy V.P., Li Y., Burnstock G., Cacabelos R. and Kamal M.A. Link between Cancer and Alzheimer Disease via Oxidative Stress Induced by Nitric Oxide-Dependent Mitochondrial DNA Overproliferation and Deletion. Oxidative Medicine and Cellular Longevity. vol. 2013, Article ID 962984, 19 pages, 2013. doi:10.1155/2013/962984.

6. Aliev, G. “The Role of Oxidative Stress, Mitochondria Failure, and Cellular Hypoperfusion in the Context of Alzheimer Disease: Past, Present and Future”. Monograph Book: Nova Science Publishers, Inc., New York, 2013, ISBN: 978-1-61942-878-2. PP. 1-426. https://www.novapublishers.com/catalog/product_info.php?products_id=31801.

7. Aliev G., K. Shahida, C.K. Hua Gan S.K. Firoz, A. Khan, A.M. Abuzenadah, W. Kamal, M.A. Kamal, Tan Y., Qu X and M. Reale. Alzheimer disease and type 2 diabetes mellitus: the link to tyrosine hydroxylase and probable nutritional strategies. CNS & Neurological Disorders-Drug Targets. 2014, 13 (3), 467-477.

8. Aliev G., Priyadarshini M., Reddy V.P., Grieg N.H., Kaminsky Y., Cacabelos R. Ashraf G.Md., Jabir, N.R. , Kamal M.A., Nikolenko V.N., Zamyatnin Jr. A.A., Benberin V.V., and S. O. Bachurin. Oxidative Stress Mediated Mitochondrial and Vascular Lesions as Markers in the Pathogenesis of Alzheimer Disease. Current Medicinal Chemistry, 2014, 21, 2208-2217.

9. V.P. Reddy, J. Mehta and Aliev G. Role of α-Lipoic Acid and Acetyl-L-Carnitine in Dementia. In: Diet and Nutrition in Dementia and Cognitive Decline, 1st Edition (Eds. Colin R. Martin and Victor R. Preedy). Academic Press (Imprint of Elsevier). Print Book ISBN :9780124078246, eBook ISBN :9780124079397. Release Date: 18 Nov 2014 (2015), part V, Chapter 88, PP. 955-962. http://store.elsevier.com/product.jsp?isbn=9780124078246.

10. Shevtsova E.F., Vinogradova D.V., Kireeva E.G., V. Prakash Reddy, Aliev G. and Bachurin S.O. Dimebon Attenuates the Rat-Brain Mitochondrial Permeabilization. Curr Alzheimer Res. 2014;11(5):422-429.

11. Kosenko E. A., Beloushko E.E., Tikhonova L.A., V. P. Reddy, Aliev G., and Kaminsky Y.G. Differential Up-Regulation of Ammonia Detoxifying Enzymes in Cerebral Cortex, Cerebellum, Hippocampus, Striatum and Liver in Hyperammonemia. CNS Neurol Disord Drug Targets. 2014, 13(6):1089-1095.

12. Tikhonova L. A., Kaminsky Y. G., Li Y., Reddy V.P., Solomadin I. N., Kosenko E. A. and Aliev G. Impacts of Аβ25–35 on membrane stability, energy metabolic and antioxidant enzymes in erythrocytes of different ages. Am J Alzheimers Dis Other Demen. 2014, Vol. 29(8): 685-695 [Epub ahead of print, 2014 May 16. pii: 1533317514534757. ].

Keywords: Alzheimer Disease, mtDNA, Oxidative Stress, Nitric Oxide, Cancer

Conference: Latin-American School on glial cells in the diseased brain (IBRO), Bogotá, Colombia, 13 Jul - 17 Jul, 2015.

Presentation Type: Oral Presentation

Topic: Neurodegenerative diseases

Citation: Aliev G and Barreto G (2015). Nitric Oxide-Dependent Oxidative Stress Induced Mitochondrial DNA Overproliferation and Deletion in the Context of Cancer and Alzheimer Disease. Conference Abstract: Latin-American School on glial cells in the diseased brain (IBRO). doi: 10.3389/conf.fncel.2015.35.00015

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Received: 21 Mar 2015; Published Online: 11 Jun 2015.

* Correspondence: Prof. George E. Barreto, Pontificia Universidad Javeriana, Bogotá, Colombia, gesbarreto@gmail.com