BioWorld International Correspondent

MELBOURNE, Australia - It is only in the recent past that the broad range of inherited disorders caused by defects in mitochondrial genes have been recognized as having a single root.

Attempts to redress the cellular energy shortages that occur in mitochondrial diseases by boosting adenosine tri-phosphate (ATP) levels, have had no success to date, and as yet the only treatment is high-energy food and vitamin supplements

Now, Australian researchers have discovered a single target that may be relevant to all these diseases, and to diseases of aging, including Alzheimer's disease and Parkinson's disease, in which accumulating mitochondrial damage is implicated.

Although at a very preliminary stage, research by Paul Fisher and colleagues at La Trobe University in Melbourne indicated that the cellular signalling protein, AMP-activated protein kinase (AMPK), which is responsible for warning mitochondria of impending energy shortages - prompting them to generate ATP - could provide a target for treating mitochondrial diseases.

Fisher's work focuses on the soil-living amoeba Dictyostelium discoideum, or Dicty, as it is paraphrased. The mitochondria in this eukaryote share many of the same genes as those in humans, making it a good model organism for mitochondrial diseases. Dicty is one of the species chosen by the U.S. National Institutes of Health as part of its model organisms initiative, and a global community of some 600 researchers is working with this amoeba.

By selectively disrupting Dicty's mitochondrial genes, Fisher has created a model for mitochondrial diseases. The technique used makes it possible to vary the severity of the disease, by inhibiting or overexpressing the target gene.

Dicty with these genetic modifications exhibits a range of symptoms. Unlike normal counterparts, it no longer orients toward the light. While some continue to grow normally, others exhibit much slower growth. And in the reproductive phase, the cells of genetically modified Dicty are directed into the incorrect pathways, so for example, there are too many spore cells and not enough cells to form the stalk on which the spores are held aloft.

Fisher postulated that those symptoms of mitochondrial disease in Dicty are caused by overproduction of AMPK. And indeed, reducing levels of the signalling protein restores normal light orientation or phototaxis, in genetically modified Dicty.

"The same thing happens with growth," Fisher told BioWorld International. "High levels of AMPK inhibit growth; reduced levels accelerate it." The same is true of the distribution of cells types during reproduction.

"That is, the three major symptoms of mitochondrial disease are all corrected by turning down levels [of AMPK] in diseased cells, and mimicked by turning it up in normal cell," Fisher said.

The symptoms exhibited by Dicty are the same regardless of which mitochondrial gene is manipulated. "Should this prove to be the case in human cells, then this is a whole new way of looking at mitochondrial disease," said Fisher.

In effect, it means that the downstream pathology is initiated by defects in cell signalling, and is activated well before ATP levels become too low.

Although AMPK is known to be involved in the regulation of cholesterol and fat levels, and is widely studied in relation to its role in metabolic diseases, exercise physiology and energy homeostasis, a possible role in mitochondrial diseases has not been considered previously, according to Fisher.

AMPK is currently the subject of drug discovery programs. For example, in June 2005, Metabasis Therapeutics Inc., of San Diego, signed a collaboration worth a potential $74 million with Merck & Co Inc., of Whitehouse Station, N.J., to develop small molecules to activate production of AMPK in the liver, for treating diabetes and hyperlipidemia.

One company, Edison Pharmaceuticals Inc., of San Jose, Calif., specializes in the development of treatments for mitochondrial diseases, targeting the interruptions to the electron flow through mitochondria that are caused by the genetic defects.

Fisher is eager to move the work forward and will be presenting his research at the Biotechnology Industrial Organization annual conference in Boston next week, in the hope of finding collaborators. "The first moves would be to analyze the pathways in more detail, and see if the findings can be replicated in animal models or human tissues. "This is a good example of how simple model organisms can create breakthroughs in the understanding of complex human diseases," he said.