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

Abstract

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 space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.

Mitochondrial ROS control of cancer

“…H 2 O 2 -mediated cysteine oxidation is the primary mode by which mROS participate in regulating proliferative and survival signals 29–32 . Cellular proliferation can also be regulated by H 2 O 2 through different mechanisms such as: phosphatase with sequence homology to tensin (PTEN) inactivation 33,34 , activation of cyclin dependent kinase 1 (Cdk1) 35 (Lim 2015), inhibition of the protein tyrosine phosphatase (PTP1b) and mitogen-activated protein kinase (MAPK) phosphatases 36,37 , propagation of growth factor cascades by activation of Lyn and Syk kinases 38 , and positive regulation of the transcription factor activator protein 1 (AP-1) through c-Jun binding at the collagen production regulator CCN1 promoter site 39 .…”

The Roles of Mitochondrial Reactive Oxygen Species in Cellular Signaling and Stress Response in Plants

“…Recently, mtETC-derived H 2 O 2 were shown to be perceived in the intermembrane space (IMS) triggering a phosphorylation cascade in animals (Patterson et al, 2015). As the interface between the mitochondrion and the rest of the cell, the IMS hosts its own redox machinery, which may make it well suited as the integration site to prepare mtETC-derived ROS signals for transduction across the cell before they get quenched by the strong antioxidant defenses of the cytosol.…”

Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

“…Under conditions such as shear stress, a physical distortion of the relationship between the two mitochondrial membranes in the endothelium leads to augmented ROS production and release by mitochondria resulting in coronary artery dilation via a hydrogen peroxidebased mechanism (146,149). Recent evidence indicates that protein kinases in the intermembrane space are targets of mitochondrial-generated ROS and thus may initiate signaling cascades within mitochondria as well as within the cytosol (122).…”

“…Several reports have provided evidence that the renal outer medullary potassium channel is a component of the K + channel of the cardiac mitoK ATP channel (59,129). SDH might also be involved in either the assembly or function of the mitoK ATP channel (122). The pharmacology of the mitoK ATP channel function is well validated; however, additional studies are needed to elucidate the complete structure of the mitoK ATP channels.…”