Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease
Dar-Shong Lin1,2, Shu-Huei Kao3, Che-Sheng Ho1
1Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan.
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 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.
Insights
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome cells struggle to switch fuel sources. Energy deficiency increases glycolysis, hindering fatty acid use and contributing to disease.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, often caused by the A3243G mitochondrial DNA mutation, involves complex metabolic dysregulation.
- The adaptive mechanisms for switching between glucose and fatty acid metabolism in response to energy deficits in MELAS syndrome are not fully understood.
Purpose of the Study:
- To investigate the metabolic fuel preferences and adaptive responses in MELAS syndrome fibroblasts under energy-deficient conditions.
- To elucidate the role of the AMP-activated protein kinase (AMPK) signaling pathway in regulating cellular metabolism and biogenesis in MELAS syndrome.
Main Methods:
- Analysis of electron transport chain complex activity, cellular biogenesis, ATP synthesis, and fatty acid oxidation in MELAS fibroblasts.
- Assessment of glycolytic flux, AMPK pathway activation, and transcriptional modulation of metabolic enzymes and biogenesis factors.
Main Results:
- MELAS fibroblasts exhibit deficiencies in electron transport chain complexes I and IV, impaired biogenesis under glucose deprivation, and reduced ATP synthesis.
- Fatty acid oxidation is attenuated, with energy production primarily relying on glycolysis, indicating an inability to adapt fuel sources.
- AMPK signaling is activated, increasing glycolytic flux via pyruvate dehydrogenase, while enzymes for fatty acid metabolism show reduced activity.
Conclusions:
- MELAS syndrome cells lack the adaptive mechanism to switch from glucose to fatty acid utilization during energy deficiency.
- The aberrant activation of the AMPK pathway and impaired fatty acid metabolism contribute to metabolic dyshomeostasis and the clinical phenotype of MELAS syndrome.
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