Tissue‐specific regulation of cytochrome c by post‐translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis

Abstract

Cytochrome c (Cytc) plays a vital role in the mitochondrial electron transport chain (ETC). In addition, it is a key regulator of apoptosis. Cytc has multiple other functions including ROS production and scavenging, cardiolipin peroxidation, and mitochondrial protein import. Cytc is tightly regulated by allosteric mechanisms, tissue‐specific isoforms, and post‐translational modifications (PTMs). Distinct residues of Cytc are modified by PTMs, primarily phosphorylations, in a highly tissue‐specific manner. These modifications downregulate mitochondrial ETC flux and adjust the mitochondrial membrane potential (ΔΨm), to minimize reactive oxygen species (ROS) production under normal conditions. In pathologic and acute stress conditions, such as ischemia–reperfusion, phosphorylations are lost, leading to maximum ETC flux, ΔΨm hyperpolarization, excessive ROS generation, and the release of Cytc. It is also the dephosphorylated form of the protein that leads to maximum caspase activation. We discuss the complex regulation of Cytc and propose that it is a central regulatory step of the mammalian ETC that can be rate limiting in normal conditions. This regulation is important because it maintains optimal intermediate ΔΨm, limiting ROS generation. We examine the role of Cytc PTMs, including phosphorylation, acetylation, methylation, nitration, nitrosylation, and sulfoxidation and consider their potential biological significance by evaluating their stoichiometry.—Kalpage, H. A., Bazylianska, V., Recanati, M. A., Fite, A., Liu, J., Wan, J., Mantena, N., Malek, M. H., Podgorski, I., Heath, E. I., Vaishnav, A., Edwards, B. F., Grossman, L. I., Sanderson, T. H., Lee, I., Hüttemann, M. Tissue‐specific regulation of cytochrome c by post‐translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis. FASEB J. 33, 1540–1553 (2019). http://www.fasebj.org

Stress-mediated generation of deleterious ROS in healthy individuals - role of cytochrome c oxidase

“…In addition to ATP inhibition of COX activity by the phosphorylated enzyme (postulated phosphorylation site: Ser-441 in subunit I [68]), COX activity is also inhibited by its substrate cytochrome c when it is phosphorylated at serine-47. After dephosphorylation of cytochrome c during ischemia, this attenuation of COX activity is abolished [71].…”

New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

“…Recently, it has been proposed that C c and the cytochrome bc 1 complex could use long‐distance electron transfer through the solution to keep high turnover rates in the crowded environment of cells . On the other hand, the functionality of the mitochondrial electron transport chain fully relies on C c , as shown by the observation that C c knockout mice die at mid‐gestation, when the fetal metabolism switches from glycolysis to oxidative phosphorylation .…”

Can All Major ROS Forming Sites of the Respiratory Chain Be Activated By High FADH2/NADH Ratios?

“…That a sudden large membrane potential (Δp) shift, especially in conjunction with high F/N ratio substrates, would lead to intense ROS formation is reflected in further adaptations to the ETC in high ATP consuming tissues, such as liver, kidney, and heart, which use varying catabolic substrates. In these organs, different residues of cytochrome c can be phosphorylated at high levels, leading to reductions in Complex IV activity and, thus, Δp, which would lower ROS formation . There are indications that AMPK, mentioned above, might be involved .…”

“…In these organs, different residues of cytochrome c can be phosphorylated at high levels, leading to reductions in Complex IV activity and, thus, Δp, which would lower ROS formation . There are indications that AMPK, mentioned above, might be involved . This would make sense, because a strong induction of catabolism to heighten ATP production would give rise to the danger of ROS formation.…”