Cardioprotective Trafficking of Caveolin to Mitochondria Is Gi-protein Dependent

Background: Caveolae are a nexus for protective signaling. Trafficking of caveolin to mitochondria is essential for adaptation to cellular stress though the trafficking mechanisms remain unknown. The authors hypothesized that G protein-coupled receptor/inhibitory G protein (G(i)) activation leads to caveolin trafficking to mitochondria. Methods: Mice were exposed to isoflurane or oxygen vehicle (30 min, +/- 36 h pertussis toxin pretreatment, an irreversible G(i) inhibitor). Caveolin trafficking, cardioprotective survival kinase signaling, mitochondrial function, and ultrastructure were assessed. Results: Isoflurane increased cardiac caveolae (n = 8 per group; data presented as mean +/- SD for Ctrl versus isoflurane; [caveolin-1: 1.78 +/- 0.12 vs. 3.53 +/- 0.77; P < 0.05]; [caveolin-3: 1.68 +/- 0.29 vs. 2.67 +/- 0.46; P < 0.05]) and mitochondrial caveolin levels (n = 16 per group; [caveolin-1: 0.87 +/- 0.18 vs. 1.89 +/- .19; P < 0.05]; [caveolin-3: 1.10 +/- 0.29 vs. 2.26 +/- 0.28; P < 0.05]), and caveolin-enriched mitochondria exhibited improved respiratory function (n = 4 per group; [state 3/complex I: 10.67 +/- 1.54 vs. 37.6 +/- 7.34; P < 0.05]; [state 3/complex II: 37.19 +/- 4.61 vs. 71.48 +/- 15.28; P < 0.05]). Isoflurane increased phosphorylation of survival kinases (n = 8 per group; [protein kinase B: 0.63 +/- 0.20 vs. 1.47 +/- 0.18; P < 0.05]; [glycogen synthase kinase 3 beta: 1.23 +/- 0.20 vs. 2.35 +/- 0.20; P < 0.05]). The beneficial effects were blocked by pertussis toxin. Conclusions: G(i) proteins are involved in trafficking caveolin to mitochondria to enhance stress resistance. Agents that target G(i) activation and caveolin trafficking may be viable cardioprotective agents.