SIRT6 Relieves Acute Lung Injury by Enhancing PGC-1α Expression and Improving Mitochondrial Function.

INTRODUCTION

Sepsis-induced acute lung injury (ALI) is closely related to the dysfunction of mitochondria. Sirtuin 6 (SIRT6), as a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylase, is involved in several cellular processes. However, research has shown that the interaction of SIRT6 and mitochondrial function plays a role in acute lung injury. The objective of this research study was to explore the effect of SIRT6 on mitochondrial function during septic lung injury.

METHODS

Lipopolysaccharide (LPS) was used to establish ALI models in C57BL/6J, SIRT6fl/fl/CAG-CreERT2 mice and in MLE12 cells. Hematoxylin and eosin staining, cell counting kit-8 (CCK-8), and enzyme-linked immunosorbent assay (ELISA) were used to evaluate lung injury, cell viability, and inflammation. Western blot (WB) was used to measure the protein expression of SIRT6 and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). The function and integrity of mitochondria were detected by transmission electron microscopy (TEM), etc. Results and Discussion: In this study, LPS stimulation reduced the protein expression levels of SIRT6 and PGC-1α. Furthermore, it inhibited mitochondrial DNA (mtDNA), mitochondrial membrane potential, and mitochondrial oxygen consumption rate, while promoting mitochondrial swelling in vivo in a model of acute lung injury. Adenovirus-mediated SIRT6 overexpression alleviated acute lung injury, simultaneously enhancing the protein levels of PGC-1α, mtDNA content, mitochondrial membrane potential, and mitochondrial oxygen consumption rate, and inhibiting mitochondrial swelling in vivo. Conversely, the deletion or knockout of SIRT6 diminished PGC-1α protein expression levels, enhanced mitochondrial dysfunction, and further aggravated acute lung injury.

CONCLUSION

SIRT6 protected against LPS-induced acute lung injury by promoting PGC-1α expression and improving mitochondrial function both in vivo and in vitro.