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: 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.