The chicken or the egg: mitochondrial dysfunction as a cause or consequence of toxicity in Huntington's disease

- MT are dysfunctional in late stage disease.
- Discrepancies exist as to whether mitochondrial dysfunction is a primary cause of early onset of symptoms or is a consequence of disease toxicity.
- Discussed are key questions that are relevant to resolving the discrepancies.
- A detailed Table is presented as a reference.

Mitochondrial dysfunction and ensuing oxidative damage is typically thought to be a primary cause of Huntington's disease, Alzheimer's disease, and Parkinson disease. There is little doubt that mitochondria (MT) become defective as neurons die, yet whether MT defects are the primary cause or a detrimental consequence of toxicity remains unanswered. Oxygen consumption rate (OCR) and glycolysis provide sensitive and informative measures of the functional status MT and the cells metabolic regulation, yet these measures differ depending on the sample source; species, tissue type, age at measurement, and whether MT are measured in purified form or in a cell. The effects of these various parameters are difficult to quantify and not fully understood, but clearly have an impact on interpreting the bioenergetics of MT or their failure in disease states. A major goal of the review is to discuss issues and coalesce detailed information into a reference table to help in assessing mitochondrial dysfunction as a cause or consequence of Huntington's disease.

Death of neurons in Huntington's and other neurodegenerative diseases is intimately involved with failing mitochondria. Oxidative damage can modify the membranes, proteins, and DNA in mitochondria and in the nucleus, all of which are measureable deleterious changes in the HD brain. Despite the widespread acceptance that MT dysfunction is involved with disease progression, there is substantial controversy as to whether or when energy-producing pathways of glycolysis and oxygen consumption are altered in the disease state. It remains speculative whether dysfunction of MT energy production is a cause or a consequence of toxicity. Depicted is a neuron with oxygen radicals emanating from malfunctions (red circles) that may affect ATP production.157