Serine Protease HtrA2/Omi Deficiency Impairs Mitochondrial Homeostasis and Promotes Hepatic Fibrogenesis via Activation of Hepatic Stellate Cells
| Autor: | Hyangshuk Rhim, Wonhee Hur, Gil Won Lee, Seung Kew Yoon, Jung-Hee Kim, Min-Kyung Nam, Sung Min Kim, Byung Yoon Kang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Liver Cirrhosis Mitochondrial DNA Cirrhosis Mice Transgenic HtrA2/Omi Mitochondrion medicine.disease_cause Chronic liver disease Article 03 medical and health sciences Mice 0302 clinical medicine mitochondrial function medicine Hepatic Stellate Cells Animals Homeostasis Humans lcsh:QH301-705.5 Cells Cultured Mice Inbred BALB C Chemistry General Medicine High-Temperature Requirement A Serine Peptidase 2 medicine.disease Cell biology Mitochondria Mice Inbred C57BL reactive oxygen species stress Oxidative Stress 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) 030220 oncology & carcinogenesis Hepatocyte Hepatic stellate cell Disease Progression Hepatic fibrosis Reactive Oxygen Species hepatic fibrogenesis Oxidative stress mitochondrial homeostasis |
| Zdroj: | Cells, Vol 8, Iss 10, p 1119 (2019) Cells Volume 8 Issue 10 |
| ISSN: | 2073-4409 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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