Indexed on: 02 Sep '16Published on: 02 Sep '16Published in: Mitochondrion
Neurodegeneration and mitochondrial dysfunction are closely linked across many clinical conditions. In genetic diseases that result from defects in mitochondrial DNA (mtDNA) synthesis or maintenance, neurodegeneration is a frequent and major component of the disease pathology. In sporadic neurodegenerative diseases such as Alzheimer's and Parkinson's disease, mtDNA defects have been observed clinically. Mitochondrial stress related to mtDNA dysregulation can produce neuronal dysfunction and death via impaired electron transport chain activity, which results in deficient ATP production and related increases in mitochondrial reactive oxygen species (ROS) production. However, mtDNA dysregulation in post-mitotic neurons may also produce disturbances in mitochondrial homeostasis that are known to impair neuronal function as well. In this study, we used sub-toxic doses of ethidium bromide (EtBr) to induce mtDNA-associated mitochondrial stress in primary cortical neurons and measured several aspects of mitochondrial homeostasis, mitochondrial function and cell death. We found that low-dose EtBr severely depletes mtDNA synthesis and mitochondrial mRNA levels. Furthermore, homeostatic processes are especially disrupted in toxin treated neurons while mitochondrial function is relatively preserved. Mitochondria become fragmented and motility is abolished, while respiration and mitochondrial polarization are partially maintained. Moreover at these doses, cells do not exhibit increased ROS production, clear neurite retraction or loss of viability. These results indicate that mitochondrial homeostasis is a sensitive marker of mtDNA associated stress compared to mitochondria-functional outputs or endpoints related to cellular toxicity. These homeostatic disruptions are expected to contribute to neuronal dysfunction and potentially drive neurodegenerative disease pathology.
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