Characterisation of AMPK and Its Role in Mitochondrial Disease

The AMPK heterotrimer comprised of a catalytic ¿ and regulatory non-catalytic ¿ and ¿ subunits acts as an intracellular energy sensor in eukaryotic cells. The AMPK ¿ subunit gene, snfA, is encoded by a single gene that is highly conserved with identical APE and DFG motifs. Overexpression of the truncated catalytic domain, AMPK ¿380, caused dose dependant signalling defects, slow growth and prolonged generation times; a classical mitochondrial disease signs. AMPK sustained activation during mitochondrial dysfunction accounted for the pathological consequences of mitochondrial disease albeit with mitochondrial biogenesis. The attenuation of AMPK by antisense RNA rescued all the abnormal phenotypes in mitochondrial disease strains. This novel insight that AMPK activation is responsible for much of the cytopathology accompanying mitochondrial disease opens up a whole new panorama of therapeutic opportunities for the management of mitochondrial disease. In the rescued strains, growth rates, generation times, ATP levels and mitochondrial mass were comparable to the wild type (AX2).