Mitochondria are the power plants of the cell, responsible for packaging energy store molecules used to power cellular processes. There are hundreds of them in any given cell, the descendants of ancient symbiotic bacteria. They replicate by fission, like bacteria, and carry a remnant of their original DNA. Mitochondrial function declines with age, a problem that appears to stem from an imbalance in mitochondrial fission that in turn impairs the ability of the cell to clear out worn and malfunctioning mitochondria via the process of autophagy. Exactly why this imbalance arises is poorly understood, but it can be added to the long, long list of maladaptive processes that emerge in response to the underlying molecular damage of aging.
Researchers here focus on another maladaptive aspect of mitochondrial function in aging cells: they exhibit altered calcium transport, which may initially compensate for other shortfalls, but then ultimately further contributes to the faltering of mitochondrial function. This is very much a downstream consequence of deeper problems.
Sometimes the more a person tries to fix a seemingly minor problem, the worse things become. Cells are no different, it turns out, though attempting to compensate for what begins as a minor deficiency or dysfunction can be dire. In the case of Alzheimer's disease, researchers now show that mitochondrial calcium transport remodeling - what appears to be an attempt by cells to compensate for flagging energy production and metabolic dysfunction - while initially beneficial, ultimately becomes maladaptive, fueling declines in mitochondrial function, memory, and learning.
Altered calcium regulation and metabolic dysfunction have been suspected of contributing to neuronal dysfunction and Alzheimer's development. Calcium transport into mitochondria plays an important part in many cellular functions and requires the involvement of multiple proteins to be carried out effectively. Among the key regulators of this process is a protein known as NCLX, which previously was discovered to mediate calcium efflux from heart cells. NCLX expression is also important in mitochondrial calcium efflux in neurons.
In a new study, researchers examined the role of mitochondrial calcium uptake by neurons in Alzheimer's disease. To do so, the team used a mouse model of familial Alzheimer's disease in which animals harbored three gene mutations that give rise to age-progressive pathology comparable to Alzheimer's progression in human patients. As mice carrying the three mutations aged, the researchers observed a steady reduction in NCLX expression. This reduction was accompanied by decreases in the expression of proteins that limit mitochondrial calcium uptake, resulting in damaging calcium overload. NCLX loss was further linked to increases in the production of cell-damaging oxidants. When NCLX expression was restored, levels of harmful protein aggregates declined, neuronal mitochondrial calcium homeostasis was reestablished, and mice were rescued from cognitive decline.
"Our findings indicate that maladaptive remodeling of pathways to compensate for abnormalities in calcium regulation, which perhaps are meant to maintain energy production in cells, lead to neuronal dysfunction and Alzheimer's pathology. Moreover, our data suggest that amyloid beta and tau pathology actually lie downstream of mitochondrial dysfunction in the progression of Alzheimer's disease, which opens up a new therapeutic angle."