A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling
Name
Patterson-2015-A respiratory chain.pdf
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10.25 MB
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Checksum (MD5)
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Author(s)
Patterson, Heide Christine
Gerbeth, Carolin
Thiru, Prathapan
Vogtle, Nora F.
Knoll, Marko
Shahsafaei, Aliakbar
Samocha, Kaitlin E.
Huang, Cher X.
Song, Rui
Chen, Cynthia
Date Issued
October 2015
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Patterson, Heide Christine, Carolin Gerbeth, Prathapan Thiru, Nora F. Vogtle, Marko Knoll, Aliakbar Shahsafaei, Kaitlin E. Samocha, et al. “A Respiratory Chain Controlled Signal Transduction Cascade in the Mitochondrial Intermembrane Space Mediates Hydrogen Peroxide Signaling.” Proc Natl Acad Sci USA 112, no. 42 (October 5, 2015): E5679–E5688.
Version
Final published version
Abstract
Reactive oxygen species (ROS) such as hydrogen peroxide (H[subscript 2]O[subscript 2]) govern cellular homeostasis by inducing signaling. H[subscript 2]O[subscript 2] modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H[subscript 2]O[subscript 2] signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H[subscript 2]O[subscript 2] signaling colocalize as H[subscript 2]O[subscript 2] induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H[subscript 2]O[subscript 2] as the respiratory chain, Lyn, and Syk were similarly required for H[subscript 2]O[subscript 2] signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H[subscript 2]O[subscript 2] signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1073/pnas.1517932112
