Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease

Dar Shong Lin, Shu Huei Kao, Che Sheng Ho, Yau Huei Wei, Pi Lien Hung, Mei Hsin Hsu, Tsu Yen Wu, Tuan Jen Wang, Yuan Ren Jian, Tsung Han Lee, Ming Fu Chiang

研究成果: 雜誌貢獻文章

4 引文 (Scopus)

摘要

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is most commonly caused by the A3243G mutation of mitochondrial DNA. The capacity to utilize fatty acid or glucose as a fuel source and how such dynamic switches of metabolic fuel preferences and transcriptional modulation of adaptive mechanism in response to energy deficiency in MELAS syndrome have not been fully elucidated. The fibroblasts from patients with MELAS syndrome demonstrated a remarkable deficiency of electron transport chain complexes I and IV, an impaired cellular biogenesis under glucose deprivation, and a decreased ATP synthesis. In situ analysis of the bioenergetic properties of MELAS cells demonstrated an attenuated fatty acid oxidation that concomitantly occurred with impaired mitochondrial respiration, while energy production was mostly dependent on glycolysis. Furthermore, the transcriptional modulation was mediated by the AMPactivated protein kinase (AMPK) signaling pathway, which activated its downstream modulators leading to a subsequent increase in glycolytic flux through activation of pyruvate dehydrogenase. In contrast, the activities of carnitine palmitoyltransferase for fatty acid oxidation and acetyl-CoA carboxylase-1 for fatty acid synthesis were reduced and transcriptional regulation factors for biogenesis were not altered. These results provide novel information that MELAS cells lack the adaptive mechanism to switch fuel source from glucose to fatty acid, as glycolysis rates increase in response to energy deficiency. The aberrant secondary cellular responses to disrupted metabolic homeostasis mediated by AMPK signaling pathway may contribute to the development of the clinical phenotype.
原文英語
頁(從 - 到)73627-73639
頁數13
期刊Oncotarget
8
發行號43
DOIs
出版狀態已發佈 - 2017

指紋

MELAS Syndrome
Mitochondrial Diseases
Protein Kinases
Fatty Acids
Glycolysis
Glucose
Carnitine O-Palmitoyltransferase
Electron Transport Complex I
Acetyl-CoA Carboxylase
Electron Transport Complex IV
Pyruvic Acid
Mitochondrial DNA
Energy Metabolism
Oxidoreductases
Respiration
Homeostasis
Fibroblasts
Adenosine Triphosphate
Phenotype
Mutation

ASJC Scopus subject areas

  • Oncology

引用此文

Lin, D. S., Kao, S. H., Ho, C. S., Wei, Y. H., Hung, P. L., Hsu, M. H., ... Chiang, M. F. (2017). Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease. Oncotarget, 8(43), 73627-73639. https://doi.org/10.18632/oncotarget.20617

Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease. / Lin, Dar Shong; Kao, Shu Huei; Ho, Che Sheng; Wei, Yau Huei; Hung, Pi Lien; Hsu, Mei Hsin; Wu, Tsu Yen; Wang, Tuan Jen; Jian, Yuan Ren; Lee, Tsung Han; Chiang, Ming Fu.

於: Oncotarget, 卷 8, 編號 43, 2017, p. 73627-73639.

研究成果: 雜誌貢獻文章

Lin, DS, Kao, SH, Ho, CS, Wei, YH, Hung, PL, Hsu, MH, Wu, TY, Wang, TJ, Jian, YR, Lee, TH & Chiang, MF 2017, 'Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease', Oncotarget, 卷 8, 編號 43, 頁 73627-73639. https://doi.org/10.18632/oncotarget.20617
Lin, Dar Shong ; Kao, Shu Huei ; Ho, Che Sheng ; Wei, Yau Huei ; Hung, Pi Lien ; Hsu, Mei Hsin ; Wu, Tsu Yen ; Wang, Tuan Jen ; Jian, Yuan Ren ; Lee, Tsung Han ; Chiang, Ming Fu. / Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease. 於: Oncotarget. 2017 ; 卷 8, 編號 43. 頁 73627-73639.
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abstract = "Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is most commonly caused by the A3243G mutation of mitochondrial DNA. The capacity to utilize fatty acid or glucose as a fuel source and how such dynamic switches of metabolic fuel preferences and transcriptional modulation of adaptive mechanism in response to energy deficiency in MELAS syndrome have not been fully elucidated. The fibroblasts from patients with MELAS syndrome demonstrated a remarkable deficiency of electron transport chain complexes I and IV, an impaired cellular biogenesis under glucose deprivation, and a decreased ATP synthesis. In situ analysis of the bioenergetic properties of MELAS cells demonstrated an attenuated fatty acid oxidation that concomitantly occurred with impaired mitochondrial respiration, while energy production was mostly dependent on glycolysis. Furthermore, the transcriptional modulation was mediated by the AMPactivated protein kinase (AMPK) signaling pathway, which activated its downstream modulators leading to a subsequent increase in glycolytic flux through activation of pyruvate dehydrogenase. In contrast, the activities of carnitine palmitoyltransferase for fatty acid oxidation and acetyl-CoA carboxylase-1 for fatty acid synthesis were reduced and transcriptional regulation factors for biogenesis were not altered. These results provide novel information that MELAS cells lack the adaptive mechanism to switch fuel source from glucose to fatty acid, as glycolysis rates increase in response to energy deficiency. The aberrant secondary cellular responses to disrupted metabolic homeostasis mediated by AMPK signaling pathway may contribute to the development of the clinical phenotype.",
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AU - Hsu, Mei Hsin

AU - Wu, Tsu Yen

AU - Wang, Tuan Jen

AU - Jian, Yuan Ren

AU - Lee, Tsung Han

AU - Chiang, Ming Fu

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AB - Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is most commonly caused by the A3243G mutation of mitochondrial DNA. The capacity to utilize fatty acid or glucose as a fuel source and how such dynamic switches of metabolic fuel preferences and transcriptional modulation of adaptive mechanism in response to energy deficiency in MELAS syndrome have not been fully elucidated. The fibroblasts from patients with MELAS syndrome demonstrated a remarkable deficiency of electron transport chain complexes I and IV, an impaired cellular biogenesis under glucose deprivation, and a decreased ATP synthesis. In situ analysis of the bioenergetic properties of MELAS cells demonstrated an attenuated fatty acid oxidation that concomitantly occurred with impaired mitochondrial respiration, while energy production was mostly dependent on glycolysis. Furthermore, the transcriptional modulation was mediated by the AMPactivated protein kinase (AMPK) signaling pathway, which activated its downstream modulators leading to a subsequent increase in glycolytic flux through activation of pyruvate dehydrogenase. In contrast, the activities of carnitine palmitoyltransferase for fatty acid oxidation and acetyl-CoA carboxylase-1 for fatty acid synthesis were reduced and transcriptional regulation factors for biogenesis were not altered. These results provide novel information that MELAS cells lack the adaptive mechanism to switch fuel source from glucose to fatty acid, as glycolysis rates increase in response to energy deficiency. The aberrant secondary cellular responses to disrupted metabolic homeostasis mediated by AMPK signaling pathway may contribute to the development of the clinical phenotype.

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