Onion-Mitochondria Inhibit Lipopolysaccharide-Induced Acute Lung Injury by Shaping Lung Macrophage Mitochondrial Function

Abstract

Mitochondrial dysfunction contributes to various inflammatory-related diseases by triggering the release of inflammatory molecules. Targeting mitochondrial dysfunction is emerging as a promising avenue for treating inflammatory diseases. Here, it is demonstrated that dietary plant-derived mitochondria (P-Mit) are capable of rescuing the lung macrophage mitochondrial (M-Mit) dysfunction in lipopolysaccharide (LPS)-induced mouse acute lung injury (ALI). Specifically, oral administration of dietary onion-derived mitochondria (O-Mit) can travel from the gut to the lungs in ALI mice, where preferentially uptake by lung macrophage mediated by the interaction between O-Mit phosphatic acid (PA) and macrophage complement C3b/C4b receptor 1 Like (CR1L), followed by fusing with murine M-Mit and by reprograming the M-Mit energy metabolism in the lungs of ALI mice. Further evidence suggests that O-Mit enriches methyl 3,4-dihydroxybenzoate (MDHB) inhibits M-Mit NADH dehydrogenase subunit 1 (ND1) gene expression in the epigenetic process, which represses LPS-induced complex I-related oxidative stress activation and excessive mitochondrial fission via modulating dynamin-related protein 1 (DRP1) phosphorylation and cardiolipin peroxidation in M-Mit, eventually rescues the LPS-induced ALI. Given LPS-induced mouse model of ALI is widely used to study human ALI and acute respiratory distress syndrome, this finding provides a clinical potential for the treatment of human ALI via edible P-Mit.

Keywords: Cardiolipin peroxidation; Complex I subunits NADH dehydrogenase 1 (ND1); Dynamin‐related protein 1 (DRP1) phosphorylation; Mitochondrial dysfunction; Plant mitochondria‐animal mitochondria cross‐kingdom fusion.