QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 18, Issue 5, 1874-1886, May 2007

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: E06-09-0881v1 E06-09-0881v2 18/5/1874    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bokko, P. B. Articles by Fisher, P. R. Search for Related Content PubMed PubMed Citation Articles by Bokko, P. B. Articles by Fisher, P. R.

Diverse Cytopathologies in Mitochondrial Disease Are Caused by AMP-activated Protein Kinase Signaling

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

*Department of Microbiology, La Trobe University, Melbourne, Victoria 3086, Australia; and National Institutes of Health, Bethesda, MD 20892

Submitted October 2, 2006; Revised January 16, 2007; Accepted February 16, 2007
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 subunit (AMPKT). The aberrant phenotypes in mitochondrially diseased strains were suppressed completely by antisense-inhibiting AMPK expression. Phagocytosis and macropinocytosis, although energy consuming, were unaffected by mitochondrial disease and AMPK expression levels. Consistent with the role of AMPK in energy homeostasis, mitochondrial "mass" and ATP levels were reduced by AMPK antisense inhibition and increased by AMPKT overexpression, but they were near normal in mitochondrially diseased cells. We also found that 5-aminoimidazole-4-carboxamide-1--D-ribofuranoside, a pharmacological AMPK activator in mammalian cells, mimics mitochondrial disease in impairing Dictyostelium phototaxis and that AMPK 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.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

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

This article has been cited by other articles:

				F. M. Sansom, P. Riedmaier, H. J. Newton, M. A. Dunstone, C. E. Muller, H. Stephan, E. Byres, T. Beddoe, J. Rossjohn, P. J. Cowan, et al. Enzymatic Properties of an Ecto-nucleoside Triphosphate Diphosphohydrolase from Legionella pneumophila: SUBSTRATE SPECIFICITY AND REQUIREMENT FOR VIRULENCE J. Biol. Chem., May 9, 2008; 283(19): 12909 - 12918. [Abstract] [Full Text] [PDF]