Lipotoxicity‑polarised macrophage‑derived exosomes regulate mitochondrial fitness through Miro1‑mediated mitophagy inhibition and contribute to type 2 diabetes development in mice – published online 24/08/2023

Jian‑Ming Li, Xianyu Li, Lawrence W. C. Chan, Ruinian Hu, Tian Zheng, Haojie Li, Sijun Yang

Insulin resistance plays a key role in the development of type 2 diabetes and experimental and clinical studies have shown that insulin resistance can be exacerbated by sustained lipotoxicity-induced mitophagy deficiency. Emerging evidence suggests that exosomes (Exos) from macrophages play an essential role in regulating metabolic homeostasis. In this issue, Li et al (https://doi.org/10.1007/s00125-023-05992-7) show that lipopolysaccharide and palmitic acid-induced macrophages produce M1 Exos, which couple to the mitochondrial transport and fusion machinery and lead to abnormal mitophagy that can promote insulin resistance. The authors report that miR-27-3p is responsible for the effects of lipotoxicity-polarized macrophage-derived M1 Exos both in vitro and in vivo. They show that M1 Exos modulate mitochondrial fitness through upregulation of dynamin-related protein 1 and mitochondrial fission factor and downregulation of mitofusin 2 and optic atrophy protein 1, affecting mitochondrial transport and leading to mitochondrial fission rather than fusion. The authors identify the miR-27-3p–mitochondrial rho GTPase 1 (Miro1) axis as a key insulin-supressing pathway leading to the accumulation of fragmented dysfunctional mitochondria, resulting in a decrease in insulin sensitivity and triggering NOD-like receptor 3-dependent proinflammatory responses. The authors conclude that the miR-27-3p–Miro1 axis could be a new therapeutic target for drug development in type 2 diabetes.

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