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Mitochondrial DNA Copy Number


Mitochondria, first described as far back as 1890, are double‐membrane organelles present in almost all eukaryotic cells. Most of the genetic information in mitochondria has been lost or transferred to the nucleus during their evolution. However, mitochondria have retained their own genome that is essential for the regulation of a wide variety of cellular processes, including ATP (energy) production by oxidative phosphorylation (OXPHOS), β‐oxidation of fatty acids, biogenesis of iron–sulfur clusters, metabolic regulation, calcium homeostasis, lipid metabolism, cell proliferation, and motility, as well as free radical generation. (Both the electron transport chain reactions of the inner membrane, as well as the oxidative deamination of biogenic amines in the outer membrane generate H2O2 that further reacts to generate the hydroxyl radical O2-). Other functions that are less commonly thought of as being associated with mitochondria are the roles in detoxifying ammonia in liver cells, regulating ferroptosis, building certain parts of the blood and various hormones like testosterone and estrogen, as well as its role in apoptosis, or programmed cell death.


We now know that mitochondrial DNA (mtDNA) is present at hundreds to thousands of copies per cell in a tissue-specific manner (2). Emerging evidence strongly suggests that the proportion of mutated mtDNA copies is not the only determinant of disease but that also the absolute copy number matters. Because of this finding, the need for novel diagnostic and prognostic biomarkers for neurodegenerative diseases has promoted significant research efforts to assess mtDNA copy number in peripheral blood and cerebrospinal fluid (CSF). (3). In fact, mtDNA copy number might be considered as a biomarker that mirrors alterations within the human body. (4).

Mitochondrial DNA copy number may be used as a proxy for mitochondrial function as it varies during aging and disease progression, as in, for example, Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Autism, and Cancer.  There is a clear correlation between reduction in mtDNA levels in neurodegeneration in AD (cell free), and PD (serum), that has been supported by a comprehensive in-depth analysis of mtDNA sequence variation and abundance in over 1000 human brains. (5).  In blood samples from PD patients, mtDNA levels were decreased when compared to healthy controls. (6, 7). Additionally, lower mtDNA copy number was more frequently observed in elderly PD subjects, suggesting that mtDNA content might even have a prognostic relevance in PD progression. (7)  Analyses performed on CSF, which often mirrors the pathological changes in brain metabolism, revealed a reduction in cell-free mtDNA in both AD and PD samples, suggesting that the levels of cell-free mtDNA may be used as biomarker for the early detection of both of these neurodegenerative diseases.


Additionally, studies have provided evidence that telomeres and mitochondria are co-regulated in humans. Shorter telomere length corresponds to decreased mitochondrial DNA copy number. This persisted in subgroups with a history of adversity and psychiatric disorder. These remained significant after controlling for age, smoking, and BMI. (8).

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