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

Area of Science:

• Biochemistry
• Cell Biology
• Metabolic Regulation

Background:

• Adenosine triphosphate (ATP) is known to regulate mitochondrial function primarily through the AMP-activated protein kinase (AMPK) signaling pathway.
• The AMPK-independent mechanisms by which ATP influences mitochondrial activity remain largely uncharacterized.

Purpose of the Study:

• To investigate the role of ATP surplus in the negative regulation of mitochondrial function.
• To elucidate the AMPK-independent pathways involved in ATP-mediated mitochondrial regulation, focusing on pyruvate dehydrogenase (PDH) phosphorylation and protein acetylation.

Main Methods:

• Induction of PDH phosphorylation and protein acetylation in hepatoma cells and mouse liver models.
• Assessment of mitochondrial oxygen consumption rates.
• In vitro experiments involving mitochondrial lysate, ATP, and acetyl-CoA.
• Inhibition of fatty acid beta-oxidation using etomoxir.

Main Results:

• High-fat diet and palmitate treatment in obese mice and hepatoma cells, respectively, led to elevated ATP levels and induced PDH phosphorylation.
• Palmitate treatment reduced mitochondrial oxygen consumption, an effect blocked by etomoxir, indicating dependence on ATP production via fatty acid oxidation.
• In vitro incubation with ATP or acetyl-CoA induced PDH phosphorylation and mitochondrial protein acetylation without altering PDK2/4 expression.

Conclusions:

• ATP elevation can inhibit mitochondrial function through inducing PDH phosphorylation and mitochondrial protein acetylation.
• These findings suggest a novel, AMPK-independent mechanism for ATP in regulating mitochondrial activity and cellular energy metabolism.