bims-mikwok 2023-04-09 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023‒04‒09
eight papers selected by
Avinash N. Mukkala, University of Toronto

Sodium ion influx regulates liquidity of biomolecular condensates in hyperosmotic stress response.
Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA.
Mechanistic correlation between mitochondrial permeability transition pores and mitochondrial ATP dependent potassium channels in ischemia reperfusion.
Deficiency of neutrophil high-mobility group box protein-1, in liver transplant recipients, exacerbates early allograft injury in mice.
Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation.
Fibrinogen Inhibits Metalloproteinase-9 Activation and Syndecan-1 Cleavage to Protect Lung Function in ApoE Null Mice After Hemorrhagic Shock.
Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA.
The mitochondrial ATP synthase as an ATP consumer-a surprising therapeutic target.

Cell Rep. 2023 Mar 29. pii: S2211-1247(23)00326-1. [Epub ahead of print] 112315

Sodium ion influx regulates liquidity of biomolecular condensates in hyperosmotic stress response.

Kazuhiro Morishita, Kengo Watanabe, Isao Naguro, Hidenori Ichijo.

  Biomolecular condensates are membraneless structures formed through phase separation. Recent studies have demonstrated that the material properties of biomolecular condensates are crucial for their biological functions and pathogenicity. However, the phase maintenance of biomolecular condensates in cells remains elusive. Here, we show that sodium ion (Na+) influx regulates the condensate liquidity under hyperosmotic stress. ASK3 condensates have higher fluidity at the high intracellular Na+ concentration derived from extracellular hyperosmotic solution. Moreover, we identified TRPM4 as a cation channel that allows Na+ influx under hyperosmotic stress. TRPM4 inhibition causes the liquid-to-solid phase transition of ASK3 condensates, leading to impairment of the ASK3 osmoresponse. In addition to ASK3 condensates, intracellular Na+ widely regulates the condensate liquidity and aggregate formation of biomolecules, including DCP1A, TAZ, and polyQ-protein, under hyperosmotic stress. Our findings demonstrate that changes in Na+ contribute to the cellular stress response via liquidity maintenance of biomolecular condensates.

Keywords:  CP: Molecular biology; biomolecular condensate; liquidity; osmotic stress; phase separation; polyQ; protein aggregation; sodium ion

DOI:  https://doi.org/10.1016/j.celrep.2023.112315
Free Radic Biol Med. 2023 Apr 01. pii: S0891-5849(23)00368-4. [Epub ahead of print]

Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA.

Mansoor Hussain, Xixia Chu, Burcin Duan Sahbaz, Samuel Gray, Komal Pekhale, Jae-Hyeon Park, Deborah L Croteau, Vilhelm A Bohr.

Aging is accompanied by a decline in DNA repair efficiency, which leads to the accumulation of different types of DNA damage. Age-associated chronic inflammation and generation of reactive oxygen species exacerbate the aging process and age-related chronic disorders. These inflammatory processes establish conditions that favor accumulation of DNA base damage, especially 8-oxo-7,8 di-hydroguanine (8-oxoG), which in turn contributes to various age associated diseases. 8-oxoG is repaired by 8-oxoG glycosylase1 (OGG1) through the base excision repair (BER) pathway. OGG1 is present in both the cell nucleus and in mitochondria. Mitochondrial OGG1 has been implicated in mitochondrial DNA repair and increased mitochondrial function. Using transgenic mouse models and cell lines that have been engineered to have enhanced expression of mitochondria-targeted OGG1 (mtOGG1), we show that elevated levels of mtOGG1 in mitochondria can reverse aging-associated inflammation and improve functions. Old male mtOGG1Tg mice show decreased inflammation response, decreased TNFα levels and multiple pro-inflammatory cytokines. Moreover, we observe that male mtOGG1Tg mice show resistance to STING activation. Interestingly, female mtOGG1Tg mice did not respond to mtOGG1 overexpression. Further, HMC3 cells expressing mtOGG1 display decreased release of mtDNA into the cytoplasm after lipopolysacchride induction and regulate inflammation through the pSTING pathway. Also, increased mtOGG1 expression reduced LPS-induced loss of mitochondrial functions. These results suggest that mtOGG1 regulates age-associated inflammation by controlling release of mtDNA into the cytoplasm.

DOI: https://doi.org/10.1016/j.freeradbiomed.2023.03.262
Biomed Pharmacother. 2023 Mar 31. pii: S0753-3322(23)00387-6. [Epub ahead of print]162 114599

Mechanistic correlation between mitochondrial permeability transition pores and mitochondrial ATP dependent potassium channels in ischemia reperfusion.

Rajalaxmi Behera, Veerta Sharma, Amarjot Kaur Grewal, Amit Kumar, Bhaskar Arora, Agnieszka Najda, Ghadeer M Albadrani, Ahmed E Altyar, Mohamed M Abdel-Daim, Thakur Gurjeet Singh.

  Mitochondrial dysfunction is one of the fundamental causes of ischemia reperfusion (I/R) damage. I/R refers to the paradoxical progression of cellular dysfunction and death that occurs when blood flow is restored to previously ischemic tissues. I/R causes a significant rise in mitochondrial permeability resulting in the opening of mitochondrial permeability transition pores (MPTP). The MPTP are broad, nonspecific channels present in the inner mitochondrial membrane (IMM), and are known to mediate the deadly permeability alterations that trigger mitochondrial driven cell death. Protection from reperfusion injury occurs when long-term ischemia is accompanied by short-term ischemic episodes or inhibition of MPTP from opening via mitochondrial ATP dependent potassium (mitoKATP) channels. These channels located in the IMM, play an essential role in ischemia preconditioning (PC) and protect against cell death by blocking MPTP opening. This review primarily focuses on the interaction between the MPTP and mitoKATP along with their role in the I/R injury. This article also describes the molecular composition of the MPTP and mitoKATP in order to promote future knowledge and treatment of diverse I/R injuries in various organs.

Keywords:  Ischemia reperfusion; Mitochondrial ATP dependent potassium channels; Mitochondrial permeability transition pores; Protein kinase C; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.biopha.2023.114599
Hepatology. 2023 Apr 06.

Deficiency of neutrophil high-mobility group box protein-1, in liver transplant recipients, exacerbates early allograft injury in mice.

Zhuolun Song, Hui Han, Xiaodong Ge, Sukanta Das, Romain Desert, Dipti Athavale, Wei Chen, Sai Santosh Babu Komakula, Daniel Lantvit, Natalia Nieto.

BACKGROUND AIMS: Early allograft dysfunction (EAD) is a severe event, leading to graft failure after liver transplant (LT). Extracellular high-mobility group box-1 (HMGB1) is a damage-associated molecular pattern (DAMP) that contributes to hepatic ischemia-reperfusion injury (IRI). However, the contribution of intracellular HMGB1 to LT graft injury, remains elusive. We hypothesized that intracellular neutrophil-derived HMGB1 from recipients, protects from post-LT EAD.APPROACH RESULTS: We generated mice with conditional ablation or overexpression of Hmgb1 in hepatocytes, myeloid cells, or both. We performed LTs and injected lipopolysaccharide (LPS) to evaluate the effect of intracellular HMGB1 in EAD. Ablation of Hmgb1 in hepatocytes and myeloid cells of donors and recipients, exacerbated early allograft injury after LT. Ablation of Hmgb1 from liver grafts, did not affect graft injury; however, lack of Hmgb1 from recipient myeloid cells, increased reactive oxygen species (ROS) and inflammation in liver grafts, and exacerbated injury. Neutrophils lacking HMGB1 were more activated, showed enhanced pro-oxidant and pro-inflammatory signatures, and reduced biosynthesis and metabolism of inositol polyphosphates (InsPs). Upon LT reperfusion or LPS treatment, there was significant neutrophil mobilization and infiltration into the liver, and enhanced production of ROS and pro-inflammatory cytokines, when intracellular Hmgb1 was absent. Depletion of neutrophils using anti-Ly6G antibody (Ab), attenuated graft injury in recipients with myeloid cell Hmgb1 ablation.
CONCLUSIONS: Neutrophil HMGB1 from recipients is central to regulate their activation, limiting production of ROS and pro-inflammatory cytokines, and protects from early liver allograft injury.

DOI: https://doi.org/10.1097/HEP.0000000000000346
Hepatology. 2023 Apr 05.

Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation.

Suyavaran Arumugam, Binghua Li, Sri Lakshmi Tejaswi Boodapati, Michael Harris Nathanson, Beicheng Sun, Xinshou Ouyang, Wajahat Zafar Mehal.

BACKGROUND AND AIMS: TGF-β induces multiple structural and functional changes in quiescent hepatic stellate cells (HSC) including an increase in proliferation, mitochondrial mass, and matrix deposition. HSC trans-differentiation requires significant bioenergetic capacity and it is not known how TGF-β mediated transcriptional up-regulation is coordinated with the bioenergetic capacity of HSC.APPROACH AND RESULTS: Mitochondria are key bioenergetic organelles and here we report that TGF-β induces release of mitochondrial DNA (mtDNA) from healthy HSC via voltage-dependent anions channels (VDACs), with the formation of a mtDNA-CAP on the external mitochondrial membrane. This stimulates organization of cytosolic cGAS onto the mtDNA-CAP, and subsequent activation of the cGAS-STING-IRF3 pathway. TGF-β is unable to induce conversion of HSC from a quiescent to a trans-differentiated phenotype in the absence of mtDNA, VDAC or STING. Trans-differentiation by TGF-β is blocked by a STING inhibitor which also reduces liver fibrosis prophylactically and therapeutically.
CONCLUSION: We have identified a pathway which requires the presence of functional mitochondria for TGF-β to mediate HSC transcriptional regulation and transdifferentiation, and therefore provides a key link between bioenergetic capacity of HSC and signals for transcriptional up-regulation of genes of anabolic pathways.

DOI: https://doi.org/10.1097/HEP.0000000000000388
J Surg Res. 2023 Apr 04. pii: S0022-4804(23)00095-1. [Epub ahead of print]288 208-214

Fibrinogen Inhibits Metalloproteinase-9 Activation and Syndecan-1 Cleavage to Protect Lung Function in ApoE Null Mice After Hemorrhagic Shock.

Feng Wu, Brooke Dorman, Ahmad Zeineddin, Rosemary Ann Kozar.

  INTRODUCTION: Obesity is associated with higher mortality following trauma, although the pathogenesis is unclear. Both obesity and trauma are associated with syndecan-1 shedding and metalloproteinase-9 (MMP-9) activation, which can adversely affect endothelial cell function. We recently demonstrated that fibrinogen stabilizes endothelial cell surface syndecan-1 to reduce shedding and maintain endothelial barrier integrity. We thus hypothesized that MMP-9 activation and syndecan-1 shedding would be exacerbated by obesity after trauma but attenuated by fibrinogen-based resuscitation.MATERIALS AND METHODS: ApoE null (-/-) mice were fed a Western diet to induce obesity. Mice were subjected to hemorrhage shock and laparotomy then resuscitated with Lactated Ranger's (LR) or LR containing fibrinogen and compared to null and lean sham wild type mice. Mean arterial pressure (MAP) was monitored. Bronchial alveolar lavage protein as an indicator of permeability and lung histopathologic injury were assessed. Syndecan-1 protein and active MMP-9 protein were measured.
RESULTS: MAP was similar between lean sham and ApoE-/- sham mice. However, following hemorrhage, ApoE-/- mice resuscitated with fibrinogen had significantly higher MAP than LR mice. Lung histopathologic injury and permeability were increased in LR compared to fibrinogen resuscitated animals. Compared with lean sham mice, both active MMP-9 and cleaved syndecan-1 level were significantly higher in ApoE-/- sham mice. Resuscitation with fibrinogen but not lactated Ringers largely reduced these changes.
CONCLUSIONS: Fibrinogen as a resuscitative adjunct in ApoE-/- mice after hemorrhage shock augmented MAP and reduced histopathologic injury and lung permeability, suggesting fibrinogen protects the endothelium by inhibiting MMP-9-mediated syndecan-1 cleavage in obese mice.

Keywords:  Fibrinogen; Hemorrhage shock; Lung permeability; MMP-9; Obesity; Syndecan-1

DOI:  https://doi.org/10.1016/j.jss.2023.02.043
Mol Cell. 2023 Apr 06. pii: S1097-2765(23)00167-3. [Epub ahead of print]83(7): 1180-1196.e8

Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA.

Max Paget, Cristhian Cadena, Sadeem Ahmad, Hai-Tao Wang, Tristan X Jordan, Ehyun Kim, Beechui Koo, Shawn M Lyons, Pavel Ivanov, Benjamin tenOever, Xin Mu, Sun Hur.

  Proper defense against microbial infection depends on the controlled activation of the immune system. This is particularly important for the RIG-I-like receptors (RLRs), which recognize viral dsRNA and initiate antiviral innate immune responses with the potential of triggering systemic inflammation and immunopathology. Here, we show that stress granules (SGs), molecular condensates that form in response to various stresses including viral dsRNA, play key roles in the controlled activation of RLR signaling. Without the SG nucleators G3BP1/2 and UBAP2L, dsRNA triggers excessive inflammation and immune-mediated apoptosis. In addition to exogenous dsRNA, host-derived dsRNA generated in response to ADAR1 deficiency is also controlled by SG biology. Intriguingly, SGs can function beyond immune control by suppressing viral replication independently of the RLR pathway. These observations thus highlight the multi-functional nature of SGs as cellular "shock absorbers" that converge on protecting cell homeostasis by dampening both toxic immune response and viral replication.

Keywords:  ADAR1; RIG-I-like receptor; antiviral signaling; dsRNA; immune-mediated apoptosis; immunopathology; innate immunity; integrated stress response; molecular condensate; stress granule

DOI:  https://doi.org/10.1016/j.molcel.2023.03.010
EMBO J. 2023 Apr 06. e114141

The mitochondrial ATP synthase as an ATP consumer-a surprising therapeutic target.

Gabriel E Valdebenito, Anitta R Chacko, Michael R Duchen.

The mitochondrial F1 Fo -ATP synthase uses a rotary mechanism to synthesise ATP. This mechanism can, however, also operate in reverse, pumping protons at the expense of ATP, with significant potential implications for mitochondrial and age-related diseases. In a recent study, Acin-Perez et al (2023) use an elegant assay to screen compounds for the capacity to selectively inhibit ATP hydrolysis without affecting ATP synthesis. They show that (+)-epicatechin is one such compound and has significant benefits for cell and tissue function in disease models. These findings signpost a novel therapeutic approach for mitochondrial disease.

DOI: https://doi.org/10.15252/embj.2023114141