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

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)


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 languageEnglish
Pages (from-to)73627-73639
Number of pages13
Issue number43
Publication statusPublished - 2017


  • AMPK
  • Autophagy
  • Bioenergetics
  • Metabolic inflexibility
  • Mitochondrial diseases
  • Oxidative phosphorylation

ASJC Scopus subject areas

  • Oncology


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