title: 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.
abstract: 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-1β 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.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China. Electronic address: sijuny@vt.edu.
authors.forename: Sijun
authors.initials: S
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Chunxiang
authors.initials: C
authors.lastname: Xia
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Shali
authors.initials: S
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Du
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Ronbin
authors.initials: R
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D016547:Kinesins / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D063306:Mitophagy / Q000187:drug effects / Q000235:genetics; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009479:Neuropeptides / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology / Q000633:toxicity; D021381:Protein Transport; D059748:Proteolysis / Q000187:drug effects; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D007328:Insulin; C521566:KIF5B protein, rat; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009479:Neuropeptides; C573346:Nlrp3 protein, rat; D010168:Palmitates; D000076205:Ras Homolog Enriched in Brain Protein; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; C087693:Rheb protein, rat; D016547:Kinesins; D020559:Monomeric GTP-Binding Proteins; D005947:Glucose; D002118:Calcium
keywords: KIF5B; Mitophagy; Proinflammatory response; Rheb