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

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,...

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Published in:Science (American Association for the Advancement of Science) 2022-08, Vol.377 (6606), p.621-629
Main Authors: Wyant, Gregory A, Yu, Wenyu, Doulamis, IIias P, Nomoto, Rio S, Saeed, Mossab Y, Duignan, Thomas, McCully, James D, Kaelin, Jr, William G
Format: Article
Language:English
Subjects:
Adenosine triphosphate
Adenosine Triphosphate - metabolism
Agonists
Amino acids
Animal models
Animals
ATP
ATP synthase
ATPase Inhibitory Protein
Cardiomyocytes
G protein-coupled receptors
Guanine
Humans
Ischemia
Kynurenic acid
Kynurenic Acid - metabolism
Kynurenic Acid - pharmacology
Kynurenic Acid - therapeutic use
Metabolism
Mice
Mitochondria
Mitochondria, Heart - drug effects
Mitochondria, Heart - metabolism
Myocardial infarction
Myocardial Ischemia - metabolism
Myocardial Ischemia - prevention & control
Neonates
Nucleotides
Proteins
Proteins - metabolism
Rabbits
Receptors
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - metabolism
Tryptophan
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Summary: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 - and G -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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.abm1638