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.
| Original language | English |
|---|---|
| Pages (from-to) | 73627-73639 |
| Number of pages | 13 |
| Journal | Oncotarget |
| Volume | 8 |
| Issue number | 43 |
| DOIs | |
| Publication status | Published - 2017 |
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Keywords
- AMPK
- Autophagy
- Bioenergetics
- Metabolic inflexibility
- Mitochondrial diseases
- Oxidative phosphorylation
ASJC Scopus subject areas
- Oncology
Cite this
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.
In: Oncotarget, Vol. 8, No. 43, 2017, p. 73627-73639.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease
AU - Lin, Dar Shong
AU - Kao, Shu Huei
AU - Ho, Che Sheng
AU - Wei, Yau Huei
AU - Hung, Pi Lien
AU - Hsu, Mei Hsin
AU - Wu, Tsu Yen
AU - Wang, Tuan Jen
AU - Jian, Yuan Ren
AU - Lee, Tsung Han
AU - Chiang, Ming Fu
PY - 2017
Y1 - 2017
N2 - 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.
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.
KW - AMPK
KW - Autophagy
KW - Bioenergetics
KW - Metabolic inflexibility
KW - Mitochondrial diseases
KW - Oxidative phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=85030095955&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030095955&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.20617
DO - 10.18632/oncotarget.20617
M3 - Article
AN - SCOPUS:85030095955
VL - 8
SP - 73627
EP - 73639
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 43
ER -