MITOCHONDRIA FACILITATE VASCULAR INFLAMMATION: THE ROLE OF CANONICAL INFLAMMATORY SIGNALING IN THE REGULATION OF MITOCHONDRIAL MORPHOLOGY

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.

Grantor dc:publisher

Temple University. Libraries

Year dc:date.issued

2017

Author dc:creator

• Forrester, Steven James

Advisors dc:contributor.advisor

• Eguchi, Satoru
• Rizzo, Victor

Committee members dc:contributor.committeemember

• Eguchi, Satoru
• Rizzo, Victor
• Griendling, Kathy K.
• Scalia, Rosario
• Hudson, Matthew Bryant
• Autieri, Michael V.

• Physiology
• Cellular biology
• Medicine

Statement dc:rights

• IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/20.500.12613/1235

OAI identifier oai:identifier

oai:scholarshare.temple.edu:20.500.12613/1235