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MBC in Press, published online ahead of print March 7, 2007
Mol. Biol. Cell 10.1091/mbc.E06-09-0881

A more recent version of this article appeared on May 1, 2007 Originally published as MBC in Press, 10.1091/mbc.E06-09-0881 on March 1, 2007
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Submitted on October 2, 2006
Revised on January 16, 2007
Accepted on February 16, 2007

Diverse Cytopathologies in Mitochondrial Disease Are Caused by AMPK Signalling

Paul B. Bokko,* Lisa Francione,* Esther Bandala-Sanchez,* Afsar U. Ahmed,* Sarah J. Annesley,* Xiuli Huang,{dagger} Taruna Khurana,{dagger} Alan R. Kimmel,{dagger} and Paul R. Fisher*

*Department of Microbiology, La Trobe University, Victoria 3086, Australia; {dagger}National Institutes of Health, Bethesda, MD 20892

Monitoring Editor: Carole Parent

The complex cytopathology of mitochondrial diseases is usually attributed to insufficient ATP. AMP-activated protein kinase (AMPK) is a highly sensitive cellular energy sensor that is stimulated by ATP-depleting stresses. By antisense-inhibiting chaperonin 60 expression we produced mitochondrially diseased strains with gene dose-dependent defects in phototaxis, growth and multicellular morphogenesis. Mitochondrial disease was phenocopied in a gene dose-dependent manner by overexpressing a constitutively active AMPK {alpha} subunit (AMPK{alpha}T). The aberrant phenotypes in mitochondrially diseased strains were suppressed completely by antisense-inhibiting AMPK{alpha} expression. Phagocytosis and macropinocytosis, although energy-consuming, were unaffected by mitochondrial disease and AMPK{alpha} expression levels. Consistent with AMPK’s role in energy homeostasis, mitochondrial "mass" and ATP levels were reduced by AMPK{alpha} antisense inhibition and increased by AMPK{alpha}T overexpression, but near normal in mitochondrially diseased cells. We also found that AICAR, a pharmacological AMPK activator in mammalian cells, mimics mitochondrial disease in impairing Dictyostelium phototaxis and that AMPK{alpha} antisense-inhibited cells were resistant to this effect. The results show that diverse cytopathologies in Dictyostelium mitochondrial disease are caused by chronic AMPK signaling not by insufficient ATP.

Address correspondence to: Paul R. Fisher (P.Fisher{at}latrobe.edu.au)




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