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Melatonin attenuates TNF-α-mediated hepatocytes damage via inhibiting mitochondrial stress and activating the Akt-Sirt3 signaling pathway.

Abstract：

:The role of mitochondrial dysfunction and its molecular mechanism in inflammation-induced acute liver failure (ALF) remain unknown. Despite the numerous studies performed to date, very few therapies are available for inflammation-induced ALF. Therefore, our study is aimed to explore the regulatory effects of mitochondrial stress and the Akt-Sirt3 pathway on the development of TNF-α-induced hepatocyte death and assess the therapeutic effects of melatonin on the damaged liver. Our results exhibited that TNF-α treatment induced hepatocyte damage in vitro; the effect of which was dose-dependently inhibited by melatonin. At the molecular level, TNF-α-treated hepatocytes expressed lower levels of Sirt3 and subsequently exhibited mitochondrial stress. Interestingly, melatonin treatment improved mitochondrial bioenergetics, reduced mitochondrial oxidative stress, reversed mitochondrial dynamics, and repressed mitochondrial apoptosis by reversing the decrease in Sirt3 expression after TNF-α challenge. In addition, we found that melatonin-regulated Sirt3 expression in a manner dependent on the Akt pathway. Blockade of the Akt pathway abolished the protective exerted by melatonin on mitochondria and hepatocyte under TNF-α treatment. In conclusion, TNF-α promotes hepatocyte apoptosis by inducing mitochondrial stress. However, melatonin significantly increases the activity of the Akt/Sirt3 axis and consequently maintains mitochondrial homeostasis, restoring hepatocyte viability in an inflammatory environment. Thus, the information compiled here might provide important perspectives for the use of melatonin in the clinic for preventive and therapeutic applications in patients with ALF based on its anti-inflammatory and mitochondria-protective effects.

journal_name

J Cell Physiol

journal_title

Journal of cellular physiology

authors

Song J,Lu C,Zhao W,Shao X

doi

10.1002/jcp.28701

subject

Has Abstract

pub_date

2019-11-01 00:00:00

pages

20969-20979

issue

eissn

0021-9541

issn

1097-4652

journal_volume

234

pub_type

杂志文章

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Melatonin attenuates TNF-α-mediated hepatocytes damage via inhibiting mitochondrial stress and activating the Akt-Sirt3 signaling pathway.