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, 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 Gi- and G12/13-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.
| Errataetall: |
CommentIn: Science. 2022 Aug 5;377(6606):579-580. - PMID 35926037 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:377 |
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| Enthalten in: |
Science (New York, N.Y.) - 377(2022), 6606 vom: 05. Aug., Seite 621-629 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wyant, Gregory A [VerfasserIn] |
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| Links: |
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| Themen: |
8L70Q75FXE |
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| Anmerkungen: |
Date Completed 08.08.2022 Date Revised 13.12.2023 published: Print-Electronic CommentIn: Science. 2022 Aug 5;377(6606):579-580. - PMID 35926037 Citation Status MEDLINE |
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| doi: |
10.1126/science.abm1638 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM344455890 |
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| 500 | |a CommentIn: Science. 2022 Aug 5;377(6606):579-580. - PMID 35926037 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 Gi- and G12/13-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 | ||
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