Serine Protease HtrA2/Omi Deficiency Impairs Mitochondrial Homeostasis and Promotes Hepatic Fibrogenesis via Activation of Hepatic Stellate Cells

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.

A novel model for predicting prognosis in patients with idiopathic pulmonary fibrosis based on endoplasmic reticulum stress‐related genes

“…HTRA2 is an integral member of the HTRA family of serine proteases, which plays an essential role in mitochondrial homeostasis and cell apoptosis (Toyama et al, 2021; Wang & Nie, 2021; Zheng et al, 2021). Hur et al (2019) found that HTRA2 deficiency impaired mitochondrial homeostasis and promoted hepatic fibrogenesis. However, no direct evidence has shown that HTRA2 serves as a regulator in the progression of pulmonary fibrosis.…”

Perilipin 5 regulates hepatic stellate cell activation and high‐fat diet‐induced non‐alcoholic fatty liver disease

“…Accumulating evidence indicates that mitochondrial dysfunction plays a key role in activated HSCs, although the mechanisms underlying this dysfunction are still unclear. 36 , 37 , 38 The main function of mitochondria is to carry out oxidative phosphorylation (OXPHOS) to synthesize ATP, and mitochondria are the site of the final oxidation of sugars, fats and amino acids to release energy. 39 Therefore, we first analyzed mitochondrial function by changing PLIN 5 expression in in vitro‐cultured rHSC‐primary cells.…”

Inhibition of High-Temperature Requirement Protein A2 Protease Activity Represses Myogenic Differentiation via UPRmt

“…Mitochondrial copy numbers were measured using absolute RT-qPCR, as previously described [ 59 ]. Briefly, genomic DNA from C2C12 myoblasts was isolated using the DNeasy Blood and Tissue Kit (QIAGEN, Hilden, Germany) according to the manufacturer’s instructions.…”