A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

Heide Christine Patterson*, Carolin Gerbeth, Prathapan Thiru, Nora F. Vögtle, Marko Knoll, Aliakbar Shahsafaei, Kaitlin E. Samocha, Cher X. Huang, Mark Michael Harden, Rui Song, Cynthia Chen, Jennifer Kao, Jiahai Shi, Wendy Salmon, Yoav D. Shaul, Matthew P. Stokes, Jeffrey C. Silva, George W. Bell, Daniel G. MacArthur, Jürgen RulandChris Meisinger, Harvey F. Lodish

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by inducing signaling. H2O2 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 H2O2 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 H2O2 signaling colocalize as H2O2 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 H2O2 as the respiratory chain, Lyn, and Syk were similarly required for H2O2 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 H2O2 signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane spacelocalized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.

Original languageAmerican English
Pages (from-to)E5679-E5688
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number42
StatePublished - 20 Oct 2015
Externally publishedYes


  • Btk
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  • Fostamatinib
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  • Rotenone


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