Induction of Posttranslational Modifications of Mitochondrial Proteins by ATP Contributes to Negative Regulation of Mitochondrial Function

• Published in: PloS one Vol. 11; no. 3; p. e0150454
• Main Authors: Zhang, Yong, Zhao, Zhiyun, Ke, Bilun, Wan, Lin, Wang, Hui, Ye, Jianping
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.03.2016; Public Library of Science (PLoS)
• Subjects: Acetylation; Adenosine Triphosphate - metabolism; Adenosine Triphosphate - physiology; AMP-Activated Protein Kinases - metabolism; AMP-Activated Protein Kinases - physiology; Analysis; Animals; Antioxidants; ATP; ATPases; Biology and Life Sciences; Biomedical research; Cell Line, Tumor; Dehydrogenases; Diabetes; Diet; Diet, High-Fat; Down-regulation; Enzymes; Fatty acids; Glucose; Hepatoma; High fat diet; Incubation; Inflammation; Insulin resistance; Laboratories; Liver; Male; Medicine and Health Sciences; Metabolism; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondria; Mitochondria, Liver - metabolism; Mitochondria, Liver - physiology; Mitochondrial DNA; Mitochondrial Proteins - metabolism; Mitochondrial Proteins - physiology; Obesity; Oxidation; Oxygen; Oxygen consumption; Palmitic acid; Phosphorylation; Physical Sciences; Physiological aspects; Protein expression; Protein Processing, Post-Translational - physiology; Proteins; Pyruvate Dehydrogenase Complex - metabolism; Pyruvate Dehydrogenase Complex - physiology; Pyruvic acid; Research and Analysis Methods; Rodents; Signal transduction; Signal Transduction - physiology; Signaling
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0150454

It is generally accepted that ATP regulates mitochondrial function through the AMPK signaling pathway. However, the AMPK-independent pathway remains largely unknown. In this study, we investigated ATP surplus in the negative regulation of mitochondrial function with a focus on pyruvate dehydrogenase (PDH) phosphorylation and protein acetylation. PDH phosphorylation was induced by a high fat diet in the liver of obese mice, which was associated with ATP elevation. In 1c1c7 hepatoma cells, the phosphorylation was induced by palmitate treatment through induction of ATP production. The phosphorylation was associated with a reduction in mitochondria oxygen consumption after 4 h treatment. The palmitate effect was blocked by etomoxir, which inhibited ATP production through suppression of fatty acid β-oxidation. The PDH phosphorylation was induced by incubation of mitochondrial lysate with ATP in vitro without altering the expression of PDH kinase 2 (PDK2) and 4 (PDK4). In addition, acetylation of multiple mitochondrial proteins was induced by ATP in the same conditions. Acetyl-CoA exhibited a similar activity to ATP in induction of the phosphorylation and acetylation. These data suggest that ATP elevation may inhibit mitochondrial function through induction of the phosphorylation and acetylation of mitochondrial proteins. The results suggest an AMPK-independent mechanism for ATP regulation of mitochondrial function.