SIRT5 regulates fatty acid oxidation and mitochondrial oxidative stress to exacerbate airway inflammation in experimental asthma

Background

Mitochondrial dysfunction is a critical factor in the pathogenesis of asthma. SIRT5(sirtuin 5), a key regulator of metabolic homeostasis, modulates various pathways, including fatty acid oxidation (FAO), through the desuccinylation of essential enzymes. However, the precise role of SIRT5 and FAO in mitochondrial dysfunction and their contribution to asthma progression remain unclear.

Methods

Male C57BL/6J mice were sensitized and challenged with toluene-2, 4-diisocyanate (TDI) to generate a steroid-insensitive asthma model, and mice were treated by SIRT5 inhibitor MC3482. In vitro, human bronchial epithelial cells (16HBE) were pretreated by MC3482 before TDI-human serum albumin (HSA) stimulation.

Results

We observed an upregulation of SIRT5 in TDI-exposed mice and 16HBE cells. Inhibiting SIRT5 with MC3482 dramatically attenuated airway hyperresponsiveness (AHR), airway inflammation, airway goblet cell metaplasia and collagen deposition in TDI-induced asthmatic mice. In addition, MC3482 effectively decreased mitochondrial ROS production, alleviated mitochondrial morphology disruption, mitochondrial membrane potential deficiency and superoxide dismutase(SOD)activity, as well as reduced the expression of IL-6 and IL-1β in 16HBE cells treated by TDI-HSA. Mechanistically, succinylation of CPT2, VLCAD and HADHA was significantly increased by SIRT5 inhibition, leading to the inactivation of its enzymatic activity and the subsequent decrease of FAO in asthma.

Conclusions

We identify SIRT5 as a novel regulator of FAO and mitochondrial oxidative stress in TDI-induced asthma. Targeting SIRT5 by MC3482 may provide promising therapeutic approach for asthma.