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Cytochrome c (Cc) underwent accelerated evolution from the stem of the anthropoid primates to humans. Of the 11 amino acid changes that occurred from horse Cc to human Cc, five were at Cc residues near the binding site of the Cc:CcO complex. Single-point mutants of horse and human Cc were made at each of these positions. The Cc:CcO dissociation constant KD of the horse mutants decreased in the order: T89E > native horse Cc > V11I Cc > Q12M > D50A > A83V > native human. The largest effect was observed for the mutants at residue 50, where the horse Cc D50A mutant decreased KD from 28.4 to 11.8 μM, and the human Cc A50D increased KD from 4.7 to 15.7 μM. To investigate the role of Cc phosphorylation in regulating the reaction with CcO, phosphomimetic human Cc mutants were prepared. The Cc T28E, S47E, and Y48E mutants increased the dissociation rate constant kd, decreased the formation rate constant kf, and increased the equilibrium dissociation constant KD of the Cc:CcO complex. These studies indicate that phosphorylation of these residues plays an important role in regulating mitochondrial electron transport and membrane potential ΔΨ.

The endoplasmic reticulum (ER) is an intracellular organelle consisting of a continuous network of membranes. In the liver, the ER is highly active in protein modification, lipid metabolism, and xenobiotic detoxification. Maintaining these complicated processes requires elaborate control of the ER lumen environment as well as the ER volume. Increasing evidence suggests that autophagy plays a critical role in regulating the homeostasis of hepatic ER contents and levels of cytochrome P450 (CYP) enzymes via selective ER-phagy. This review will provide an overview of ER-phagy, summarizing the possible roles of recently identified ER-phagy receptor proteins in regulating the homeostasis of hepatic ER and CYP enzymes as well as outlining the various implications of ER-phagy in ER-related liver diseases. Keywords: Alcoholic liver disease, Endoplasmic reticulum (ER)-phagy, Endoplasmic reticulum (ER) stress, Cytochrome P450 (CYP) enzymes, Liver diseases, Non-alcoholic fatty liver disease (NAFLD), Non-alcoholic steatohepatitis (NASH)