Abstract
The loss of mitochondrial function impairs intracellular energy production and potentially results in chronic liver disease. Increasing evidence suggests that mitochondrial dysfunction in hepatocytes contributes to the activation of hepatic stellate cells (HSCs), thereby resulting in hepatic fibrogenesis. High-temperature requirement protein A2 (HtrA2/Omi), a mitochondrial serine protease with various functions, is responsible for quality control in mitochondrial homeostasis. However, little information is available regarding its role in mitochondrial damage during the development of liver fibrosis. This study examined whether HtrA2/Omi regulates mitochondrial homeostasis in hepatocyte during the development of hepatic fibrogenesis. In this study, we demonstrated that HtrA2/Omi expression considerably decreased in liver tissues from the CCl4-induced liver fibrotic mice model and from patients with liver cirrhosis. Knockdown of HtrA2/Omi in hepatocytes induced the accumulation of damaged mitochondria and provoked mitochondrial reactive oxygen species (mtROS) stress. We further show that the damaged mtDNA isolated from HtrA2/Omi-deficient hepatocytes as a form of damage-associated molecular patterns can induce HSCs activation. Moreover, we found that motor neuron degeneration 2-mutant mice harboring the missense mutation Ser276Cys in the protease domain of HtrA2/Omi displayed altered mitochondrial morphology and function, which increased oxidative stress and promoted liver fibrosis. Conversely, the overexpression of HtrA2/Omi via hydrodynamics-based gene transfer led to the antifibrotic effects in CCl4-induced liver fibrosis mice model through decreasing collagen accumulation and enhancing anti-oxidative activity by modulating mitochondrial homeostasis in the liver. These results suggest that suppressing HtrA2/Omi expression promotes hepatic fibrogenesis via modulating mtROS generation, and these novel mechanistic insights involving the regulation of mitochondrial homeostasis by HtrA2/Omi may be of importance for developing new therapeutic strategies for hepatic fibrosis.
Highlights
Hepatic fibrosis is a histological consequence of the wound-healing process resulting from chronic liver injuries induced by various causes
As has been reported for liver fibrosis, most forms of chronic liver diseases are associated with the accumulation of damaged mitochondria, which are responsible for abnormal reactive oxygen species (ROS) formation and respiratory complex alterations [23]
We hypothesized that the structural alterations of mitochondria were due to mitochondrial damage and that mitochondrial DNA (mtDNA) damage, such as damage-associated molecular patterns (DAMPs), accumulated in necrotic hepatocytes
Summary
Hepatic fibrosis is a histological consequence of the wound-healing process resulting from chronic liver injuries induced by various causes. During long-standing liver injuries, the activation of hepatic stellate cells (HSCs) following hepatocyte damage and the recruitment. Cells 2019, 8, 1119 of inflammatory mediators lead to the accumulation of extracellular matrix (ECM) [2]. At this time, reactive oxygen species (ROS) are primarily generated in the mitochondria and endoplasmic reticulum of hepatocytes, leading to further hepatocyte damage that results in HSC activation and enhanced. These vicious pathogenic events of involving hepatocyte damage, inflammation, ROS production, and excessive ECM accumulation can accelerate hepatic fibrosis. Mitochondria in hepatocytes serve as the primary source of energy; their dysfunction is commonly associated with increased ROS production. Once mtDNA is damaged by ROS produced in mitochondria, a cascade of events culminating in apoptosis or cell death proceeds
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