Diverse cytopathologies in mitochondrial disease are caused by AMP-activated protein kinase signaling

Paul Bokko, Lisa Francione, Esther Bandala-Sanchez, Afsar Ahmed, Sarah Annesley, Xiuli Huang, Taruna Khurana, Alan Kimmel, Paul Fisher

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)1874 - 1886
Number of pages13
JournalMolecular Biology of the Cell
Volume18
Issue number5
DOIs
Publication statusPublished - 2007
Externally publishedYes

Cite this

Bokko, Paul ; Francione, Lisa ; Bandala-Sanchez, Esther ; Ahmed, Afsar ; Annesley, Sarah ; Huang, Xiuli ; Khurana, Taruna ; Kimmel, Alan ; Fisher, Paul. / Diverse cytopathologies in mitochondrial disease are caused by AMP-activated protein kinase signaling. In: Molecular Biology of the Cell. 2007 ; Vol. 18, No. 5. pp. 1874 - 1886.
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abstract = "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.",
author = "Paul Bokko and Lisa Francione and Esther Bandala-Sanchez and Afsar Ahmed and Sarah Annesley and Xiuli Huang and Taruna Khurana and Alan Kimmel and Paul Fisher",
year = "2007",
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Bokko, P, Francione, L, Bandala-Sanchez, E, Ahmed, A, Annesley, S, Huang, X, Khurana, T, Kimmel, A & Fisher, P 2007, 'Diverse cytopathologies in mitochondrial disease are caused by AMP-activated protein kinase signaling' Molecular Biology of the Cell, vol. 18, no. 5, pp. 1874 - 1886. https://doi.org/10.1091/mbc.E06-09-0881

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 journalArticleResearchpeer-review

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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

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