Hydrogen peroxide induces signals that link the mitochondrial respiratory chain to specific cellular pathway

CAMBRIDGE, Mass. – Hydrogen peroxide does much more than bleach hair or disinfect wounds. In cells, it induces signaling that regulates homeostasis, aging, and myriad chronic diseases. Initiation of this signaling has long been thought to be broad and seemingly non-specific, but now Whitehead Institute scientists have discovered that this reactive oxygen species (ROS) in fact triggers a distinct signal cascade—the Syk pathway—that regulates much of the signaling response, including transcription, translation, metabolism, and the cell cycle. Surprisingly, it is the mitochondrial respiratory chain that launches activation of the Syk pathway by ROS.

“This is a major discovery that goes against the established paradigm,” says Whitehead Institute Founding Member Harvey Lodish, who is also a professor of biology and a professor of biological engineering at MIT. “Initially a lot of scientists may find this controversial, but Heide Christine Patterson in my lab has shown that this is what happens. She has put all of the pieces together.”  

Life evolved to interpret levels of hydrogen peroxide and other ROS species as response cues to cellular processes and environmental conditions. For example, an abundance of hydrogen peroxide generated as a byproduct of increased cellular respiration in the mitochondria triggers activation and differentiation in cells.

Hydrogen peroxide and other ROS also mediate cellular responses in aging and numerous common chronic diseases, including diabetes, heart disease, stroke, cancer, and neurodegeneration. Understanding how these signals function may point to new therapy targets for these conditions.

Hydrogen peroxide’s cellular targets are certain enzymes called phosphatases that counteract signaling by kinases. For a long time, this observation seemed to provide the perfect explanation of how hydrogen peroxide induces cellular signaling. Since then, dozens of diverse cellular targets have been identified that all were proposed to initiate signaling. But Patterson, a postdoctoral researcher in the Lodish lab, reasoned that the cellular response to ROS is far too important to be left to something that seemed so messy and radically different from other signal transduction cascades. Her investigation of hydrogen peroxide’s action is described online this week in the journal Proceedings of the National Academy of Sciences (PNAS).

Patterson followed up on a few neglected, decades-old studies implicating Syk in hydrogen peroxide signaling in chicken B cells, intuiting that there was something important behind these findings. She determined that hydrogen peroxide signaling has many hallmark features of a traditional signal transduction cascade—with the important distinction that the mitochondrial respiratory chain triggers the signal. She blocked individual components of the pathway to show, step by step, how the signal set in motion by hydrogen peroxide flows downstream from the respiratory chain along the Syk pathway. Other characteristics typical for a signal transduction cascade she determined were: showing that Syk controls an important and distinct response by identifying Syk’s targets; demonstrating that the Syk pathway proteins are co-located between the mitochondrial membranes within physical proximity to their activator, the respiratory chain; and determining that the pathway is similarly important across different species and types of tissues. The one thing she was unable to pinpoint is hydrogen peroxide’s receptor.

“That’s the million dollar question right now,” says Patterson, who is co-author of the PNAS paper. “We need to identify the receptor that hydrogen peroxide interacts with. This paper gets us closer, and we are continuing to work toward that goal.”

This work was supported by National Institutes of Health (NIH grants KO8 GM102718, T32 HL007627, and RO1 DK047618), the Deutsche Forschungsgemeinschaft (fellowship Kn1106/1-1), and a Ludwig Postdoctoral Fellowship.

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Harvey Lodish’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology and a professor of biological engineering at Massachusetts Institute of Technology (MIT).

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Patterson, H. C. et al. “A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates H2O2 signaling." PNAS, online the week of October 5, 2015.