The mitochondrial protease HtrA2 restricts the NLRP3 and AIM2 inflammasomes

Rodrigue-Gervais, Ian Gaël; Doiron, Karine; Champagne, Claudia; Mayes, Lindsey; Leiva‐Torres, Gabriel André; Vanié, Paulin; Douglas, Todd; Vidal, Silvia M.; Alnemri, Emad S.; Saleh, Maya

doi:10.1038/s41598-018-26603-1

Cited by 21 publications

(17 citation statements)

References 73 publications

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“…Rodrigue et al reported that ROS levels were similar in macrophages of HtrA2 mnd2(-/-) mice compared to WT [33], which is in agreement with our results. Conversely, three independent studies showed significantly elevated production of ROS in HtrA2/Omi KO mouse embryonic fibroblasts (MEFs) [30,74,75].…”

Section: Discussionsupporting

confidence: 93%

“…However, the upregulation of UPR mt -related genes were not observed in HtrA2 mnd2(-/-) brain [30]. ROS levels were also found to be similar in macrophages of HtrA2 mnd2(-/-) mice compared to wild type (WT) [33]. Taken together, these facts raises the question of whether the cytoprotective effect of HtrA2/Omi might be achieved in a manner of mitonuclear signaling.…”

Section: Introductionmentioning

confidence: 87%

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Loss of HtrA2/Omi protease activity induces mitonuclear imbalance and sarcopenia via differential regulation of mitochondrial biogenesis

Zhou

Yuan

Gao

et al. 2020

Preprint

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Background Cellular homeostasis requires tight coordination between nucleus and mitochondria, organelles that each possess their own genomes. Disrupted mitonuclear communication has been found to be implicated in many aging processes. However little is known about mitonuclear signaling regulator in sarcopenia which is a major contributor to the risk of poor health-related quality of life, disability and premature death in older people. HtrA2/Omi is a mitochondrial protease and play an important role in mitochondrial proteostasis. HtrA2 mnd2(-/-) mice harboring protease-deficient HtrA2/Omi Ser276Cys missense mutants exhibit premature aging phenotype. Additionally, HtrA2/Omi has been established as a signaling regulator in nervous system and tumors. We therefore asked whether HtrA2/Omi participates in mitonuclear signaling regulation in aging muscle.Methods Using motor functional, histological and molecular biological methods, we characterized the muscle phenotype of HtrA2 mnd2(-/-) mice. We employed bioinformatics analysis and identified HtrA2/Omi as a gene differentially associated with nDNA/mtDNA gene expression in sarcopenia. Further, we isolated the gastrocnemius muscle of HtrA2 mnd2(-/-) mice and determined expression of genes in UPR mt , mitohormesis, electron transport chain (ETC), and mitochondrial biogenesis.Results Here, we showed that HtrA2/Omi protease deficiency induced denervation-independent skeletal muscle degeneration. Despite of mitochondrial hypofunction, upregulation of UPR mt and mitohormesis related genes and elevated reactive oxygen species (ROS) production were not observed in HtrA2 mnd2(-/-) mice, contrary to previous assumptions that loss of protease activity of HtrA2/Omi would lead to mitochondrial dysfunction as a result of proteostasis disturbance and ROS burst. Instead, we showed that HtrA2/Omi protease deficiency results in different changes between the expression of nDNA and mtDNA encoded ETC subunits, which is in consistent with their transcription factors NRF-1/2 and coactivator PGC-1α, suggesting that HtrA2/Omi protease activity may differentially regulate mitonuclear signaling via mitochondrial biogenesis in sarcopenia. Besides, Akt1 but not GSK3β showed increased expression level in HtrA2 mnd2(-/-) muscles, indicating an involvement of Akt1 in PGC-1α regulation response to HtrA2/Omi protease deficiency.Conclusions HtrA2/Omi protease deficiency induces mitonuclear imbalance and sarcopenia via differential regulation of mitochondrial biogenesis. The novel mechanistic insights may be of importance in developing new therapeutic strategies for sarcopenia.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 87%

Loss of HtrA2/Omi protease activity induces mitonuclear imbalance and sarcopenia via differential regulation of mitochondrial biogenesis

Zhou

Yuan

Gao

et al. 2020

Preprint

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“…Very recently, Rodrigue‐Gervais et al (2018) showed that HtrA2 can inhibit ASC‐dependent activation of the NLRP3 and AIM2 inflammasomes in BMDMs. The HtrA2 protease can regulate autophagy and the magnitude and duration of the inflammasome pathway by preventing long‐term accumulation of ASC …”

Section: Nlrp3 Inflammasome‐mediated Inflammatory Pathways In Pdmentioning

confidence: 99%

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

et al. 2019

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Excessive activation of microglia and subsequent release of proinflammatory cytokines play a crucial role in neuroinflammation and neurodegeneration in Parkinson's disease (PD). Components of the nucleotide‐binding oligomerization domain and leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome complex, leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3, caspase‐1, and apoptosis‐associated speck‐like protein containing a CARD, are highly expressed in activated microglia in PD patient brains. Findings suggest that neurotoxins, aggregation of α‐synuclein, mitochondrial reactive oxygen species, and disrupted mitophagy are the key regulators of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and release of interleukin‐1β and interleukin‐18 caspase‐1‐mediated pyroptotic cell death in the substantia nigra of the brain. Although this evidence suggests the leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome may be a potential drug target for treatment of PD, the exact mechanism of how the microglia sense these stimuli and initiate leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome signaling is unknown. Here, the molecular mechanism and regulation of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and its role in the pathogenesis of PD are discussed. Moreover, the potential of both endogenous and synthetic leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome modulators, long noncoding RNA, microRNA to develop novel therapeutics to treat PD is presented. Overall, we recommend that the microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome can be a potential target for PD treatment. © 2019 International Parkinson and Movement Disorder Society

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“…Initially, the roles of HtrA2/Omi in apoptosis, mitochondrial protein folding quality control, and cell survival were investigated [9]. A recent study reported that HtrA2/Omi regulates autophagy and inflammasome signaling by preventing prolonged accumulation of the inflammasome adaptor ASC [44]. In addition, Michell et al found that expression of the pro-apoptotic protein Bcl-2 in the liver protected against CCl 4 induced-mitochondrial dysfunction and -oxidative stress in hepatocytes [8].…”

Section: Discussionmentioning

confidence: 99%

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

Hur

Kang

Kim

et al. 2019

Cells

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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.

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The mitochondrial protease HtrA2 restricts the NLRP3 and AIM2 inflammasomes

Cited by 21 publications

References 73 publications

Loss of HtrA2/Omi protease activity induces mitonuclear imbalance and sarcopenia via differential regulation of mitochondrial biogenesis

Loss of HtrA2/Omi protease activity induces mitonuclear imbalance and sarcopenia via differential regulation of mitochondrial biogenesis

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

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

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