Harnessing mitohormesis: A thiazole-based mitochondrial respiration inhibitor restores metabolic homeostasis in type 2 diabetes.

Mitohormesis, an adaptive cellular response to moderate mitochondrial stress, represents a promising therapeutic paradigm. To pharmacologically harness this phenomenon, we developed mitochondrial respiration inhibitors by conjugating a thiazole-based pharmacophore to a triphenylphosphonium (TPP) cation. Here, we report three TPP-thiazole conjugates which are distinguished by their hydrolytically labile linkers, comprising an ester (Compound 1), a more labile thioester (Compound 2), and a more stable amide (Compound 3). In vitro evaluation demonstrated that the hydrolytic stability of the linkers correlated inversely with inhibitory potency, where Compound 2 exhibited the strongest inhibition, followed by Compound 1. In contrast, Compound 3 showed negligible activity, lacking a clear dose-response relationship. As therapeutic mitohormesis requires a mild stress induction within a beneficial hormetic window, Compound 1 was selected for further investigation based on its intermediate inhibition and pronounced biphasic effects. Compound 1 activated the mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans (C. elegans) and stimulated transcription of mitokines in both C. elegans and mice. In a murine model of diet-induced type 2 diabetes, Compound 1 significantly improved systemic metabolism, ameliorating glucose intolerance, insulin resistance, and hepatic steatosis. Furthermore, it outperformed metformin at an equivalent dose without observed toxicity. Collectively, these findings establish the rationally tuned inhibition of mitochondria as a viable small-molecule strategy for the treatment of metabolic disorders through mitohormesis.