Neutralization of mitochondrial superoxide by superoxide dismutase 2 promotes bacterial clearance and regulates phagocyte numbers in zebrafish.
Mitochondria are known primarily as the location of the electron transport chain and energy production in cells. More recently, mitochondria have been shown to be signaling centers for apoptosis and inflammation. Reactive oxygen species (ROS) generated as by-products of the electron transport chain within mitochondria significantly impact cellular signaling pathways. Because of the toxic nature of ROS, mitochondria possess an antioxidant enzyme, superoxide dismutase 2 (SOD2), to neutralize ROS. If mitochondrial antioxidant enzymes are overwhelmed during severe infections, mitochondrial dysfunction can occur and lead to multiorgan failure or death. Pseudomonas aeruginosa is an opportunistic pathogen that can infect immunocompromised patients. Infochemicals and exotoxins associated with P. aeruginosa are capable of causing mitochondrial dysfunction. In this work, we describe the roles of SOD2 and mitochondrial ROS regulation in the zebrafish innate immune response to P. aeruginosa infection. sod2 is upregulated in mammalian macrophages and neutrophils in response to lipopolysaccharide in vitro, and sod2 knockdown in zebrafish results in an increased bacterial burden. Further investigation revealed that phagocyte numbers are compromised in Sod2-deficient zebrafish. Addition of the mitochondrion-targeted ROS-scavenging chemical MitoTEMPO rescues neutrophil numbers and reduces the bacterial burden in Sod2-deficient zebrafish. Our work highlights the importance of mitochondrial ROS regulation by SOD2 in the context of innate immunity and supports the use of mitochondrion-targeted ROS scavengers as potential adjuvant therapies during severe infections.
Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, USA.
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Peterman
Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, USA Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA.
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Sullivan
Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, USA.
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Goody
Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.
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Rodriguez-Nunez
Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.
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Yoder
Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, USA Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA carolkim@maine.edu.
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Kim
D000818:Animals; D007113:Immunity, Innate; D007958:Leukocyte Count; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D015027:Zebrafish; D000099156:Superoxide Dismutase 2
D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2