Research Papers: Autophagy and Cell Death:

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 and Ming-Fu Chiang

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Oncotarget. 2017; 8:73627-73639. https://doi.org/10.18632/oncotarget.20617

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Dar-Shong Lin1,2, Shu-Huei Kao3, Che-Sheng Ho1, Yau-Huei Wei2,10, Pi-Lien Hung4, Mei-Hsin Hsu4, Tsu-Yen Wu5, Tuan-Jen Wang6, Yuan-Ren Jian5, Tsung-Han Lee5 and Ming-Fu Chiang7,8,9

1 Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan

2 Department of Medicine, Institute of Biomedical Sciences, Mackay Medical College, New Taipei, Taiwan

3 School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan

4 Department of Pediatric Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan

5 Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan

6 Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei, Taiwan

7 Department of Neurosurgery, Mackay Memorial Hospital, Taipei, Taiwan

8 Mackay Medicine, Nursing and Management College, Taipei, Taiwan

9 Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei, Taiwan

10 Center for Mitochondrial Medicine and Free Radical Research, Changhua Christian Hospital, Changhua, Taiwan

Correspondence to:

Dar-Shong Lin, email:

Ming-Fu Chiang, email:

Keywords: mitochondrial diseases, oxidative phosphorylation, bioenergetics, AMPK, metabolic inflexibility, Autophagy

Received: June 08, 2017 Accepted: August 17, 2017 Published: September 01, 2017


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 AMP-activated 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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