Diverse cytopathologies in mitochondrial disease are caused by AMP-activated protein kinase signaling.
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 (AMPKalphaT). The aberrant phenotypes in mitochondrially diseased strains were suppressed completely by antisense-inhibiting AMPKalpha expression. Phagocytosis and macropinocytosis, although energy consuming, were unaffected by mitochondrial disease and AMPKalpha expression levels. Consistent with the role of AMPK in energy homeostasis, mitochondrial "mass" and ATP levels were reduced by AMPKalpha antisense inhibition and increased by AMPKalphaT overexpression, but they were near normal in mitochondrially diseased cells. We also found that 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, a pharmacological AMPK activator in mammalian cells, mimics mitochondrial disease in impairing Dictyostelium phototaxis and that AMPKalpha 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.
Bokko
Paul B
PB
Department of Microbiology, La Trobe University, Melbourne, Victoria 3086, Australia.
Francione
Lisa
L
Bandala-Sanchez
Esther
E
Ahmed
Afsar U
AU
Annesley
Sarah J
SJ
Huang
Xiuli
X
Khurana
Taruna
T
Kimmel
Alan R
AR
Fisher
Paul R
PR
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016054:DNA, Protozoan / Q000235:genetics; D004023:Dictyostelium / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D018628:Gene Dosage; D017125:Genes, Protozoan; D006801:Humans; D028361:Mitochondrial Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis; D018462:Photobiology; D010873:Pinocytosis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D016054:DNA, Protozoan; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases