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Defective mitophagy driven by dysregulation of rheb and KIF5B contributes to mitochondrial reactive oxygen species (ROS)-induced nod-like receptor 3 (NLRP3) dependent proinflammatory response and aggravates lipotoxicity.

Authors: Yang, S  Xia, C  Li, S  Du, L  Zhang, L  Zhou, R 
Citation: Yang S, etal., Redox Biol. 2014;3:63-71. doi: 10.1016/j.redox.2014.04.001. Epub 2014 Apr 12.
Pubmed: (View Article at PubMed) PMID:25462067
DOI: Full-text: DOI:10.1016/j.redox.2014.04.001

High-fat diet (HFD) and inflammation are the key contributors to insulin resistance and type 2 diabetes (T2D). Previous study shows fatty acid-induced accumulation of damaged, reactive oxygen species (ROS)-generating mitochondria, and this in turn activates the NLRP3 inflammasome interference with insulin signaling. Our previous research shows NLRP3 inflammasome activation signal originates from defects in autophagy. Yet how the fatty acid related to mitophagy alteration leads to the activation of NLRP3-ASC inflammasome has not been considered. Here we demonstrated that palmitate (PA) induced mitophagy deficiency, leading to damaged mitochondrion as characterized by mito-ROS production and loss of membrane potential. Antioxidant APDC or Ca(2+) signaling inhibitor Nifedipine blocked PA-induced NLRP3 inflammasome activation. Further, we provided evidences that PA reduced the expression of Ras homolog enriched in brain (Rheb) and disrupted Rheb recruitment to the mitochondrial outer membrane. In addition, sustained PA caused disassociation of kinesin family member 5B (KIF5B) from binding with mitochondria via Ca(2+)-dependent effects. Disruption of Rheb and KIF5B interaction with mitochondria blocked mitochondrial degradation along with IL-1beta dependent insulin resistance, which was majorly attenuated by Rheb/KIF5B overexpression. In a consequence, defective mitophagy led to the accumulation of damaged-ROS-generating mitochondria, down pathway of NLRP3-ASC-Caspase 1 activation, and subsequently, insulin resistance. These findings provide insights into the association of inflammation, mitophagy and T2D.

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CRRD Object Information
CRRD ID: 11059539
Created: 2016-04-15
Species: All species
Last Modified: 2016-04-15
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.