Tau Impairs Both Mitochondrial Function and Quality Control

Researchers here show that tau protein, a feature of late stage Alzheimer’s disease, causes issues with mitochondrial quality control mechanisms responsible for removing damaged or dysfunctional mitochondria. Since tau also harms the function of mitochondria, this is particularly pernicious, and may be a significant component of the cell death that follows tau aggregation. Mitochondrial dysfunction is a feature of most neurodegenerative diseases, causing cellular processes in the brain to falter for lack of energy, but the question of where it sits in the web of cause and consequence in relation to other disease mechanisms remains to be resolved. Is the case that Alzheimer’s tends to occur more readily in people with worse age-related mitochondrial dysfunction, or does one or more of the other aspects of Alzheimer’s, such as tau aggregation, produce the observed greater level of mitochondrial dysfunction as a downstream effect? Or both? This sort of question is surprisingly hard to answer in conditions that have many contributing causes.

Accumulation of clumps of tau is a well-established hallmark of Alzheimer’s disease and other neurodegenerative disorders, as is the aggregation of damaged mitochondria, the powerhouse of a cell. However, the interaction between tau and mitochondria is still being explored, and new research has found an additional disruptive function of tau in terms of mitochondrial health. “It has long been known that there is an accumulation of abnormal mitochondria in neurodegenerative diseases, including Alzheimer’s disease. More specifically, tau has previously been shown to impair different aspects of mitochondrial function, and here, we find that tau also impairs the degradation of mitochondria. This causes a toxic cycle whereby tau both damages mitochondria and then also prevents their removal.”

One of the ways by which tau causes cell damage is by preventing the removal of damaged mitochondria, a process referred to as mitophagy. Normally, damaged mitochondria are trafficked to the lysosome (the waste remover of the cell) for destruction, by a molecule called Parkin, which moves from the intracellular fluid to the impacted mitochondria to start the trafficking process. However, researchers found tau impaired this process by interacting “aberrantly” with the Parkin protein in the intracellular fluid before it could reach the mitochondria, thereby preventing the removal process, and with damaging consequences for the cell.


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