Российская академия наук

Oxidative Stress Induced Cellular Hypoperfusion, Mitochondrial DNA Overproliferation and Deletion in Context of Neurodegeneration and Cancer

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Oxidative Stress Induced Cellular Hypoperfusion, Mitochondrial DNA Overproliferation and Deletion in Context of Neurodegeneration and Cancer

1,2Aliev Gjumrakch, MD&PhD

1GALLY” International Biomedical Research Consulting LLC, San Antonio, TX, USA

2Department of Health Science and Healthcare Administration, University of Atlanta, Atlanta, GA USA, aliev03@gmail.com, GAliev@uofa.edu, Phone: 440-263-7461
Neurodegeneration [Stroke and Alzheimer disease (AD)] and cancer are fast becoming one of the leading causes of age-associated disability, dementia, and death. In addition, the Centers for Disease Control and Prevention (CDC) and the National Center for Health Statistics recently reported that AD has surpassed diabetes as a leading cause of death and is now considered the sixth-leading cause of death in the United States

Oxidative stress induced mitochondrial DNA over-proliferation and/or deletion of the organ and/or tissues, especially the mitochondrial energy demands, have been implicated in the pathogenesis of several diseases, including AD, tumor growth, and metastasis. Decline in mitochondrial function during the development and maturation of the neurodegeneration, tumor growth, and metastases characterizing the tissue oxygen deficiency may lead to cellular energy defects, which will compensate vital cellular components and regulators. The overexpression of the enzymes such as NOS induce the production of unwanted large amounts of free radicals that cause the oxidative stress, cellular change, and particularly the concomitant mitochondrial lesions and decline in normal organ function. 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 neurodegeneration and human colorectal carcinoid cancer or 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 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, and suggests that proliferation, deletion, and duplication of mtDNA occurs in mitochondria, many of which have been fused with lysosomes in human AD, Tg(+) mice, and malignant tumors. Moreover, the biopsy and perfused brain samples from AD and the animals’ models that mimics human AD as well as cancer patients were dominated by abnormal mitochondria as compared to a control group. 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. In quantitative analysis of the mtDNA deletion and 8OHG in the same cases, we found a strong significant positive correlation (r=0.934). 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. This

observation indicates that the oxidative stress markers seen in the AD brain and malignant cancer selectively affects the population of vulnerable neurons, vascular EC, and perivascular cells, suggesting that oxidative stress induced mitochondrial DNA overproliferation and/or deletion plays a key role in the pathogenesis of AD and cancer. 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.

By using electron microscopic techniques we have found that the mitochondrial lesions appeared to be the primary hallmark of the glioblastoma. Vessel endothelium from tumor tissues shows the damage of mitochondrion cristae. The mitochondria derived lysosomes appeared to be permanent feature of the glial cells derived tumor cells. The lipid laden tumor cells and surrounding cells often show a different degree of mitochondria abnormality (such as mitochondria with broken cristae, presence of edema in their matrix, disruption of inner and external mitochondrial membrane). Moreover, giant mitochondria also appeared to be permanent features of tumor growth and metastases. Comparative characteristics of marginal and central portion of tumor tissues obtained from patients undergoing surgery with diagnosis of the primary glioblastoma showed that distance area of tumor tissue characterized heterogeneous distribution of damage in the structure of the mitochondria. Central regions of tumor tissues in almost all of area shows astrocytes with clusters of mitochondria derived lysosomes. The same patterns of cellular and subcellular damage were seen in spinal cord tumor.

One of the big challenges for treatment of neurodegenerative diseases and cancer appeared to be delivering drugs into the injury affected tissues. Our future studies are aimed to show that injection of silver nanoparticles in the brain lead to leaking on the inter endothelial contact and luminal plasma membrane, and therefore elucidate the possibility of penetrating into the cerebrovascular, neuronal, and glial cell which are especially damaged in AD and/or brain cancer.

Our clinical study showed the preservation and improvement of cognitive tasks in depressed and demented patients after 24, 36 and 60 month follow up of combined pharmacological (especially the combination of the diseases and mitochondrion specific compounds) and non- pharmacological treatment. The study group consisted of 156 medically ill and physically disabled patients with mild to moderate dementia and depression. Patients were treated with antidepressants, cholinesterase inhibitors, and NMDA antagonists, along with their regular medication regimen. Non-pharmacological intervention was centered on a home-based program of physical and cognitive exercises as well as with vitamins and supplements (multivitamins, vitamin E, L-methylfolate, alpha-lipoic acid, acetyl-L-carnitine, omega-3, and coenzyme Q-10) and diet modification. Cognitive assessments were performed yearly. After 60 months of treatment, performance of all tasks remained at or above baseline. The MMSE, Cognistat–Attention, Cognistat–Judgment, and RFFT - Total Unique Designs demonstrated significant improvement. Our results also demonstrate the arrest in cognitive decline in demented/depressed patients with multiple medical co-morbidities for 60 months.

Our study, for the first time, demonstrated the pattern of oxidative stress induced mitochondrial DNA overproliferation and/or deletion as well as mitochondrial enzyme activities during the development of human AD, and animals that mimic human AD, colorectal cancer in liver metastasis, and malignant brain cancers. We conclude that mitochondrial lesions, especially mitochondrial DNA abnormalities, are responsible for cell viability which can be used as new diagnostic tools and/or criteria for the earlier detection of diseases and future considerations for this approach will enable us to open new pathways, not only for the better understanding of BBB homeostasis which most likely plays a key role in the development of AD, but also for the development of new and more specific treatment strategies that will be more powerful and effective in bringing a cure for this devastating disease. Thus, our research involving the conjugation of the silver nanoparticles with mitochondrially-specific drugs would help to diminish the lesions that occur in AD and/or tumor tissues. Future investigations addressing the application of a combined, integrative treatment models in clinical practices are warranted.

Acknowledgements: This study was partially supported by “GALLY” International Biomedical Research Consulting LLC, San Antonio, TX, USA.

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