Tumour necrosis factor-α promotes liver ischaemia-reperfusion injury through the PGC-1α/Mfn2 pathway.
Bottom Line: This was associated with hepatic mitochondrial swelling, decreased adenosine triphosphate (ATP) production, and increased levels of reactive oxygen species (ROS) and alanine aminotransferase (ALT) activity as well as cell apoptosis.Treatment by rosiglitazone sustained PGC-1α and Mfn2 expression both in IR livers, and L02 cells treated with TNF-α as indicated by increased hepatic mitochondrial integrity and ATP production, reduced ROS and ALT activity as well as decreased cell apoptosis.Overexpression of Mfn2 by lentiviral-Mfn2 transfection decreased hepatic injury in IR livers and L02 cells treated with TNF-α.
Affiliation: Department of Urology Surgery, Cancer Institute, Chongqing, China.Show MeSH
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Mentions: We further explored the influence of PGC-1α/Mfn2 pathway on hepatocytes injury with TNF-α. Compared with L02 cells treated with TNF-α, both rosiglitazone and transfection of Ltv-Mfn2 decreased mitochondrial swelling and maintained ATP production (12.29 ± 2.27, 13.07 ± 1.62 pmol; Fig. 3A and B). Conversely, ROS production was significantly reduced by rosiglitazone and transfection of Ltv-Mfn2 (43.54 ± 11.76, 45.72 ± 8.74 RLU, respectively; Fig. 3B). As expected, reduction in mitochondrial swelling and ROS resulted in decreased ALT activity in the media of L02 cells treated with TNF-α (165.54 ± 23.22, 194.22 ± 21.93 U/l). Apoptosis of L02 cells as determined by PI and Annexin V labelling was also decreased (2.0%, 1.7%, respectively; Fig. 3B and C), indicating a protective role of rosiglitazone and Ltv-Mfn2 in mitochondria and hepatocytes against TNF-α. Since TNF-α inhibited whereas rosiglitazone and Ltv-Mfn2 increased PGC-1α/Mfn2 expression, we suggest that the PGC-1α/Mfn2 pathway plays a protective role in TNF-α-induced hepatocyte injury with mitochondrial dysfunction. Suppression of the PGC-1α/Mfn2 pathway mediates TNF-α-induced mitochondrial dysfunction and hepatocyte injury.
Affiliation: Department of Urology Surgery, Cancer Institute, Chongqing, China.