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Phosphorylations and Acetylations of Cytochrome c Control Mitochondrial Respiration, Mitochondrial Membrane Potential, Energy, ROS, and Apoptosis.

Paul T MorseTasnim ArroumJunmei WanLucynda PhamAsmita VaishnavJamie BellLauren PavelichMoh H MalekThomas H SandersonBrian F P EdwardsMaik Hüttemann
Published in: Cells (2024)
Cytochrome c (Cyt c ) has both life-sustaining and cellular death-related functions, depending on subcellular localization. Within mitochondria, Cyt c acts as a single electron carrier as part of the electron transport chain (ETC). When released into the cytosol after cellular insult, Cyt c triggers the assembly of the apoptosome, committing the cell to intrinsic apoptosis. Due to these dual natures, Cyt c requires strong regulation by the cell, including post-translational modifications, such as phosphorylation and acetylation. Six phosphorylation sites and three acetylation sites have been detected on Cyt c in vivo. Phosphorylations at T28, S47, Y48, T49, T58, and Y97 tend to be present under basal conditions in a tissue-specific manner. In contrast, the acetylations at K8, K39, and K53 tend to be present in specific pathophysiological conditions. All of the phosphorylation sites and two of the three acetylation sites partially inhibit respiration, which we propose serves to maintain an optimal, intermediate mitochondrial membrane potential (ΔΨ m ) to minimize reactive oxygen species (ROS) production. Cyt c phosphorylations are lost during ischemia, which drives ETC hyperactivity and ΔΨ m hyperpolarization, resulting in exponential ROS production thus causing reperfusion injury following ischemia. One of the acetylation sites, K39, shows a unique behavior in that it is gained during ischemia, stimulating respiration while blocking apoptosis, demonstrating that skeletal muscle, which is particularly resilient to ischemia-reperfusion injury compared to other organs, possesses a different metabolic strategy to handle ischemic stress. The regulation of Cyt c by these post-translational modifications underscores the importance of Cyt c for the ETC, ΔΨ m , ROS production, apoptosis, and the cell as a whole.
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