Editors' ChoiceWound Healing

ROS to the Rescue!

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Sci. Signal.  21 Oct 2014:
Vol. 7, Issue 348, pp. ec290
DOI: 10.1126/scisignal.aaa1023

In vertebrates and invertebrates, epidermal wounding rapidly induces local calcium (Ca2+) waves and the production of reactive oxygen species (ROS) by cytoplasmic and plasma membrane–localized oxidases. Extracellular ROS recruits immune cells to the wound site to guard against infection and promote healing. Xu et al. report that the Ca2+ waves triggered by wounding the nematode Caenorhabditis elegans also induce the production of mitochondrial ROS (mtROS) that promote healing. Laser wounding of the C. elegans epidermis induced transient increases in the abundance of a fluorescent mitochondrial superoxide reporter near the wound. Treating wounds with various oxidants enhanced these mtROS bursts, increased the accumulation of F-actin in the contractile ring that closes the wound, and accelerated wound closure. Conversely, treating wounds with antioxidants reduced mtROS production and F-actin accumulation and delayed wound closure. Worms with various mutations affecting superoxide dismutase or components of the electron transport chain have abnormally high mtROS. Wound closure was accelerated in these mutants, and treatment with an antioxidant following wounding suppressed the accelerated closure phenotype. Wounding-induced mtROS bursts, wound-site F-actin accumulation, and proper wound closure required MCU-1, a component of the mitochondrial Ca2+ uniporter. Experiments with a pharmacological inhibitor of the mitochondrial permeability transition pore (mPTP) suggested that mitochondrial accumulation of Ca2+ triggered opening of the mPTP, which causes the production and release of mtROS. The small guanosine triphosphatase RHO-1, which controls actin dynamics and inhibits wound closure in C. elegans, rapidly accumulated at wound sites. RHO-1 has a redox-sensitive motif that contains cysteine residues that can be oxidized to inhibit activity of the protein. Overexpressing a version of RHO-1 in which alanine was substituted for one of these cysteine residues (Cys16→Ala16) reduced wound-site F-actin accumulation and inhibited wound closure, suggesting that this cysteine residue is a physiologically relevant ROS target. Thus, wounding triggers waves of Ca2+ that is transported into mitochondria, where it triggers the production and release of mtROS that, in turn, inhibits RHO-1 to promote wound closure. Commentary by Niethammer explores the idea of mitochondria as sensors of tissue homeostasis and considers how these findings may highlight differences between wound healing across species.

S. Xu, A. D. Chisholm, Celegans epidermal wounding induces a mitochondrial ROS burst that promotes wound repair. Dev. Cell 31, 48–60 (2014). [PubMed]

P. Niethammer, Stress heals. Dev. Cell 31, 5–6 (2014). [PubMed]