Mitochondrial diseases are a result of a signaling problem in the cells, according to researchers at Melbourne's LaTrobe University, as opposed to the commonly held belief that a failure to produce ATP causes these diseases.
"This research gives us a completely novel understanding of the causal mechanisms of mitochondrial disease, demonstrating that such conditions may result from a signaling disorder in the cells, rather than a fundamental energy insufficiency as was previously thought," notes Paul Fisher, Ph.D., lead investigator and chair in microbiology at LaTrobe University.
"Like a smoke alarm that activates at the first sign of trouble, AMPK is an energy-sensing alarm protein that averts an impending energy crisis in the cell by activating before the situation becomes critical," explains Dr. Fisher. "When triggered, AMPK temporarily shuts down a variety of activities and initiates energy production within the cell. In a healthy cell this returns ATP supplies to normal and allows the cell to return to regular functioning.
"What we found is that in a mitochondrially diseased cell, the AMPK alarm is permanently activated," Dr. Fisher said. "Many of the cellular outcomes of mitochondrial dysfunction are known also to be associated with AMPK signaling, but this is the first time the alarm protein has itself been implicated in mitochondrial disease causation."
Dr. Fisher and his team believe that these results can be used to develop drugs to treat not only various types of the mitochondrial disease but also most major neurodegenerative disorders where mitochondrial dysfunction plays a central role.
Using the slime mold dictyostelium discoideum as a model for mitochondrial disease, the scientists genetically manipulated the signaling pathways that control cellular functions thought to be involved in mitochondrial disease. Overproduction of an active form of AMPK was shown to create the same symptoms as mitochondrial disease, while decreasing the supply of AMPK completely suppressed those symptoms.