Mitochondrial remodeling and ischemic protection by G protein-coupled receptor 35 agonists

被引：70

作者：

Wyant, Gregory A. ^{[1
,2
]}

Yu, Wenyu ^{[1
]}

Doulamis, IIias P. ^{[3
]}

Nomoto, Rio S. ^{[3
]}

Saeed, Mossab Y. ^{[3
]}

Duignan, Thomas ^{[3
]}

McCully, James D. ^{[3
]}

Kaelin Jr, William G. ^{[1
,2
,4
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[3] Harvard Med Sch, Boston Childrens Hosp, Dept Cardiac Surg, Dept Surg, Boston, MA 02215 USA

[4] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA

来源：

SCIENCE | 2022年 / 377卷 / 6606期

基金：

美国国家卫生研究院;

关键词：

ATPASE INHIBITORY FACTOR-1; KYNURENIC ACID; RESPIRATORY PARAMETERS; MYOCARDIAL-INFARCTION; LIGAND; GPR35; EXPRESSION; BRAIN; IF1; METABOLITES;

D O I：

10.1126/science.abm1638

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Kynurenic acid (KynA) is tissue protective in cardiac, cerebral, renal, and retinal ischemia models, but the mechanism is unknown. KynA can bind to multiple receptors, including the aryl hydrocarbon receptor, the a7 nicotinic acetylcholine receptor (a7nAChR), multiple ionotropic glutamate receptors, and the orphan G protein-coupled receptor GPR35. Here, we show that GPR35 activation was necessary and sufficient for ischemic protection by KynA. When bound by KynA, GPR35 activated G(i)- and G(12/13)-coupled signaling and trafficked to the outer mitochondria membrane, where it bound, apparantly indirectly, to ATP synthase inhibitory factor subunit 1 (ATPIF1). Activated GPR35, in an ATPIF1-dependent and pertussis toxin-sensitive manner, induced ATP synthase dimerization, which prevented ATP loss upon ischemia. These findings provide a rationale for the development of specific GPR35 agonists for the treatment of ischemic diseases.

引用

页码：621 / 629

页数：9

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