Journal
FASEB JOURNAL
Volume 33, Issue 12, Pages 13503-13514Publisher
WILEY
DOI: 10.1096/fj.201901120R
Keywords
apoptosis; electron transport chain; ischemia; respiration; signaling
Categories
Funding
- U.S. National Institutes of Health (NIH) National Institute of General Medical Sciences [R01 GM116807, R01 GM113908]
- NIH National Institute of Neurological Disorders and Stroke [R01 NS091242, R42 NS105238]
- Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program [W81XWH-16-1-0175]
- Department of Defense or the NIH
- U.S. Department of Energy Office of Science User Facility operated for the Department of Energy Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
- Michigan Economic Development Corp.
- Michigan Technology Tri-Corridor [085P1000817]
- Wayne State University Office of the Vice-President for Research
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Cytochrome c (Cytc) is a multifunctional protein that operates as an electron carrier in the mitochondrial electron transport chain and plays a key role in apoptosis. We have previously shown that tissue-specific phosphorylations of Cytc in the heart, liver, and kidney play an important role in the regulation of cellular respiration and cell death. Here, we report that Cytc purified from mammalian brain is phosphorylated on S47 and that this phosphorylation is lost during ischemia. We have characterized the functional effects in vitro using phosphorylated Cytc purified from pig brain tissue and a recombinant phosphomimetic mutant (S47E). We crystallized S47E phosphomimetic Cytc at 1.55 angstrom and suggest that it spatially matches S47-phosphorylated Cytc, making it a good model system. Both S47-phosphorylated and phosphomimetic Cytc showed a lower oxygen consumption rate in reaction with isolated Cytc oxidase, which we propose maintains intermediate mitochondrial membrane potentials under physiologic conditions, thus minimizing production of reactive oxygen species. S47-phosphorylated and phosphomimetic Cytc showed lower caspase-3 activity. Furthermore, phosphomimetic Cytc had decreased cardiolipin peroxidase activity and is more stable in the presence of H2O2. Our data suggest that S47 phosphorylation of Cytc is tissue protective and promotes cell survival in the brain.
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