Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1874 - 1886 |
| Number of pages | 13 |
| Journal | Molecular Biology of the Cell |
| Volume | 18 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2007 |
| Externally published | Yes |
Cite this
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Diverse cytopathologies in mitochondrial disease are caused by AMP-activated protein kinase signaling. / Bokko, Paul; Francione, Lisa; Bandala-Sanchez, Esther; Ahmed, Afsar; Annesley, Sarah; Huang, Xiuli; Khurana, Taruna; Kimmel, Alan; Fisher, Paul.
In: Molecular Biology of the Cell, Vol. 18, No. 5, 2007, p. 1874 - 1886.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Diverse cytopathologies in mitochondrial disease are caused by AMP-activated protein kinase signaling
AU - Bokko, Paul
AU - Francione, Lisa
AU - Bandala-Sanchez, Esther
AU - Ahmed, Afsar
AU - Annesley, Sarah
AU - Huang, Xiuli
AU - Khurana, Taruna
AU - Kimmel, Alan
AU - Fisher, Paul
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17332500
U2 - 10.1091/mbc.E06-09-0881
DO - 10.1091/mbc.E06-09-0881
M3 - Article
VL - 18
SP - 1874
EP - 1886
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
SN - 1059-1524
IS - 5
ER -