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MITOCHONDRIA FACILITATE VASCULAR INFLAMMATION: THE ROLE OF CANONICAL INFLAMMATORY SIGNALING IN THE REGULATION OF MITOCHONDRIAL MORPHOLOGY
Forrester, Steven James
Forrester, Steven James
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2017
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Kinesiology
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http://dx.doi.org/10.34944/dspace/1217
Abstract
Vascular inflammation is an underlying cause to numerous diseases and is characterized by classical NF-κB activation and downstream physiological responses including inflammatory gene induction and immune cell recruitment. Although inflammatory based diseases are associated with mitochondrial dysfunction and morphological alterations, the direct mechanisms tying the mitochondria to canonical NF-κB signaling remain elusive. Using pharmacological and genetic approaches, we show inflammatory-mediated mitochondrial fission, through DRP1 and MFF, is required for NF-κB activation, VCAM-1 induction and vascular inflammation in vitro and in vivo. In addition, inflammatory signaling in the endothelium mediates mitochondrial fission through an IKKβ/IκBα-dependent pathway. IκBα is found to localize on the mitochondrial outer membrane where it inhibits DRP1 recruitment to the mitochondria. Inhibition of this cascade promotes elongated mitochondria that are unable to go through fission. Cumulatively, these results highlight the requirement of mitochondrial fission in the inflammatory response. Our results point to a shift in how classical NF-κB induction and downstream inflammatory signaling is viewed, as well as highlights a new inflammatory-dependent mechanism in mitochondrial dynamics. This work also suggests a link between inflammatory-based diseases of different etiologies and a conserved mitochondrial fission pathway.
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