bims-mikwok 2022-10-02 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2022–10–02
thirteen papers selected by
Avinash N. Mukkala, University of Toronto

Eisosome protein Pil1 regulates mitochondrial morphology, mitophagy, and cell death in Saccharomyces cerevisiae.
Mitochondria-ER cooperation: NLRX1 detects mitochondrial protein import stress and promotes mitophagy through the ER protein RRBP1.
ANGEL2 phosphatase activity is required for non-canonical mitochondrial RNA processing.
MICU1 and MICU2 potentiation of Ca2+ uptake by the mitochondrial Ca2+ uniporter of Trypanosoma cruzi and its inhibition by Mg2.
Differential requirements for mitochondrial electron transport chain components in the adult murine liver.
USP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion.
Mitochondrial ferritin alleviates apoptosis by enhancing mitochondrial bioenergetics and stimulating glucose metabolism in cerebral ischemia reperfusion.
PGC-1β maintains mitochondrial metabolism and restrains inflammatory gene expression.
Nrf1 is an indispensable redox-determining factor for mitochondrial homeostasis by integrating multi-hierarchical regulatory networks.
Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins.
Dichloroacetate as a metabolic modulator of heart mitochondrial proteome under conditions of reduced oxygen utilization.
TFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis.
Resveratrol promotes liver cell survival in mice liver-induced ischemia-reperfusion through unfolded protein response: a possible approach in liver transplantation.

J Biol Chem. 2022 Sep 23. pii: S0021-9258(22)00976-0. [Epub ahead of print] 102533

Eisosome protein Pil1 regulates mitochondrial morphology, mitophagy, and cell death in Saccharomyces cerevisiae.

Amita Pal, Arunkumar Paripati, Pallavi Deolal, Arpan Chatterjee, Pushpa Rani Prasad, Priyanka Adla, Naresh Babu V Sepuri.

  Mitochondrial morphology and dynamics maintain mitochondrial integrity by regulating its size, shape, distribution, and connectivity, thereby modulating various cellular processes. Several studies have established a functional link between mitochondrial dynamics, mitophagy, and cell death, but further investigation is needed to identify specific proteins involved in mitochondrial dynamics. Any alteration in the integrity of the mitochondria has severe ramifications that include disorders like cancer and neurodegeneration. In this study, we used budding yeast as a model organism and found that Pil1, the major component of the eisosome complex, also localizes to the periphery of mitochondria. Interestingly, the absence of Pil1 causes the branched tubular morphology of mitochondria to be abnormally fused or aggregated, whereas its overexpression leads to mitochondrial fragmentation. Most importantly, pil1Δ cells are defective in mitophagy and bulk autophagy, resulting in elevated levels of ROS and protein aggregates. In addition, we show that pil1Δ cells are more prone to cell death. Yeast two-hybrid analysis and co-immunoprecipitations show the interaction of Pil1 with two major proteins in mitochondrial fission, Fis1 and Dnm1. Additionally, our data suggest that the role of Pil1 in maintaining mitochondrial shape is dependent on Fis1 and Dnm1, but it functions independently in mitophagy and cell death pathways. Together, our data suggest that Pil1, an eisosome protein, is a novel regulator of mitochondrial morphology, mitophagy, and cell death.

Keywords:  Saccharomyces cerevisiae; autophagy; cell death; mitochondria; mitophagy; protein aggregation; reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.jbc.2022.102533
Autophagy. 2022 Sep 28.

Mitochondria-ER cooperation: NLRX1 detects mitochondrial protein import stress and promotes mitophagy through the ER protein RRBP1.

Samuel A Killackey, Yuntian Bi, Dana J Philpott, Damien Arnoult, Stephen E Girardin.

  Mitochondria rely on efficient protein import across their membranes for optimal function. We have shown that numerous mitochondrial stressors all converge on a common pathway disrupting this import efficiency. We identified a novel pathway involving NLRX1 and RRBP1 that responds to this import stress, resulting in LC3 lipidation, mitochondrial targeting and ultimate degradation. Furthermore, we demonstrated the relevance of this mitophagy axis in murine skeletal muscle following acute exercise. We propose that mitochondrial protein import stress is an underlying, common trigger for mitophagy, offering a novel avenue for therapeutic exploration and mechanistic insight.

Keywords:  Autophagy; NLR; exercise; import; mitochondria; mitophagy; proteostasis

DOI:  https://doi.org/10.1080/15548627.2022.2129763
Nat Commun. 2022 Sep 30. 13(1): 5750

ANGEL2 phosphatase activity is required for non-canonical mitochondrial RNA processing.

Paula Clemente, Javier Calvo-Garrido, Sarah F Pearce, Florian A Schober, Megumi Shigematsu, Stefan J Siira, Isabelle Laine, Henrik Spåhr, Christian Steinmetzger, Katja Petzold, Yohei Kirino, Rolf Wibom, Oliver Rackham, Aleksandra Filipovska, Joanna Rorbach, Christoph Freyer, Anna Wredenberg.

Canonical RNA processing in mammalian mitochondria is defined by tRNAs acting as recognition sites for nucleases to release flanking transcripts. The relevant factors, their structures, and mechanism are well described, but not all mitochondrial transcripts are punctuated by tRNAs, and their mode of processing has remained unsolved. Using Drosophila and mouse models, we demonstrate that non-canonical processing results in the formation of 3' phosphates, and that phosphatase activity by the carbon catabolite repressor 4 domain-containing family member ANGEL2 is required for their hydrolysis. Furthermore, our data suggest that members of the FAST kinase domain-containing protein family are responsible for these 3' phosphates. Our results therefore propose a mechanism for non-canonical RNA processing in metazoan mitochondria, by identifying the role of ANGEL2.

DOI: https://doi.org/10.1038/s41467-022-33368-9
Cell Calcium. 2022 Sep 21. pii: S0143-4160(22)00127-0. [Epub ahead of print]107 102654

MICU1 and MICU2 potentiation of Ca2+ uptake by the mitochondrial Ca2+ uniporter of Trypanosoma cruzi and its inhibition by Mg2.

Mayara S Bertolini, Roberto Docampo.

  The mitochondrial Ca2+ uptake, which is important to regulate bioenergetics, cell death and cytoplasmic Ca2+ signaling, is mediated via the calcium uniporter complex (MCUC). In animal cells the MCUC is regulated by the mitochondrial calcium uptake 1 and 2 dimer (MICU1/MICU2), which has been proposed to act as gatekeeper preventing mitochondrial Ca2+ overload at low cytosolic Ca2+ levels. In contrast to animal cells, knockout of either MICU1 or MICU2 in Trypanosoma cruzi, the etiologic agent of Chagas disease, did not allow Ca2+ uptake at low extramitochondrial Ca2+ concentrations ([Ca2+]ext) and it was though that in the absence of one MICU the other would replace its role. However, previous attempts to knockout both genes were unsuccessful. Here, we designed a strategy to generate TcMICU1/TcMICU2 double knockout cell lines using CRISPR/Cas9 genome editing. Ablation of both genes was confirmed by PCR and Southern blot analyses. The absence of both proteins did not allow Ca2+ uptake at low [Ca2+]ext, significantly decreased the mitochondrial Ca2+ uptake at different [Ca2+]ext, without dissipation of the mitochondrial membrane potential, and increased the [Ca2+]ext set point needed for Ca2+ uptake, as we have seen with TcMICU1-KO and TcMICU2-KO cells. Mg2+ was found to be a negative regulator of MCUC-mediated mitochondrial Ca2+ uptake at different [Ca2+]ext. Occlusion of the MCUC pore by Mg2+ could partially explain the lack of mitochondrial Ca2+ uptake at low [Ca2+]ext in TcMICU1/TcMICU2-KO cells. In addition, TcMICU1/TcMICU2-KO epimastigotes had a lower growth rate, while infective trypomastigotes have a reduced capacity to invade host cells and to replicate within them as amastigotes.

Keywords:  CRISPR/Cas9; Gatekeeping; MICU; Magnesium; Mitochondrial calcium uniporter; Trypanosoma cruzi

DOI:  https://doi.org/10.1016/j.ceca.2022.102654
Elife. 2022 Sep 26. pii: e80919. [Epub ahead of print]11

Differential requirements for mitochondrial electron transport chain components in the adult murine liver.

Nicholas P Lesner, Xun Wang, Zhenkang Chen, Anderson Frank, Cameron Menezes, Sara House, Spencer D Shelton, Andrew Lemoff, David G McFadden, Janaka Wanaspura, Ralph J DeBerardinis, Prashant Mishra.

  Mitochondrial electron transport chain (ETC) dysfunction due to mutations in the nuclear or mitochondrial genome is a common cause of metabolic disease in humans and displays striking tissue specificity depending on the affected gene. The mechanisms underlying tissue specific phenotypes are not understood. Complex I (cI) is classically considered the entry point for electrons into the ETC, and in vitro experiments indicate that cI is required for basal respiration and maintenance of the NAD+/NADH ratio, an indicator of cellular redox status. This finding has largely not been tested in vivo. Here, we report that mitochondrial complex I is dispensable for homeostasis of the adult mouse liver; animals with hepatocyte-specific loss of cI function display no overt phenotypes or signs of liver damage, and maintain liver function, redox and oxygen status. Further analysis of cI-deficient livers did not reveal significant proteomic or metabolic changes, indicating little to no compensation is required in the setting of complex I loss. In contrast, complex IV (cIV) dysfunction in adult hepatocytes results in decreased liver function, impaired oxygen handling, steatosis, and liver damage, accompanied by significant metabolomic and proteomic perturbations. Our results support a model whereby complex I loss is tolerated in the mouse liver because hepatocytes use alternative electron donors to fuel the mitochondrial ETC.

Keywords:  cell biology; genetics; genomics; mouse

DOI:  https://doi.org/10.7554/eLife.80919
Cell Death Dis. 2022 Sep 26. 13(9): 823

USP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion.

Xinyao Tian, Yan Zhao, Zhe Yang, Qianrang Lu, Lin Zhou, Shusen Zheng.

Liver ischemia/reperfusion (I/R) injury is a major clinical concern of liver transplantation, which accounts for organ rejection and liver dysfunction. The adaptor protein p66Shc acts as a crucial redox enzyme and is implicated in liver I/R. Elevated p66Shc expression is associated with hepatocellular apoptosis in liver I/R, but the molecular mechanisms of p66Shc responsible for its aberrant expression and function remain unknown. In the present study, hepatocyte-specific p66Shc-knockdown mice exhibited clear inhibition in hepatocellular apoptosis and oxidative stress under liver I/R, while hepatocyte-specific p66Shc overexpression mice displayed the deteriorative impairment. Mechanistically, p66Shc-triggered mitochondrial fission and apoptosis in liver I/R by mediating ROS-driven Drp1 activation. Furthermore, a screening for p66Shc-interacting proteins identified ubiquitin-specific protease 15 (USP15) as a mediator critical for abnormal p66Shc expression. Specifically, USP15 interacted with the SH2 domain of p66Shc and maintained its stabilization by removing ubiquitin. In vivo, p66Shc knockdown abrogated USP15-driven hepatocellular apoptosis, whereas p66Shc overexpression counteracted the antiapoptotic effect of USP15 silencing in response to liver I/R. There was clinical evidence for the positive association between p66Shc and USP15 in patients undergoing liver transplantation. In summary, p66Shc contributes to mitochondrial fission and apoptosis associated with Drp1 activation, and abnormal p66Shc expression relies on the activity of USP15 deubiquitination under liver I/R. The current study sheds new light on the molecular mechanism of p66Shc, and identifies USP15 as a novel mediator of p66Shc to facilitate better therapeutics against liver I/R.

DOI: https://doi.org/10.1038/s41419-022-05277-8
Redox Biol. 2022 Sep 24. pii: S2213-2317(22)00247-6. [Epub ahead of print]57 102475

Mitochondrial ferritin alleviates apoptosis by enhancing mitochondrial bioenergetics and stimulating glucose metabolism in cerebral ischemia reperfusion.

Peina Wang, Yanmei Cui, Yuanyuan Liu, Zhongda Li, Huiyuan Bai, Yashuo Zhao, Yan-Zhong Chang.

  Oxidative stress and deficient bioenergetics are key players in the pathological process of cerebral ischemia reperfusion injury (I/R). As a mitochondrial iron storage protein, mitochondrial ferritin (FtMt) plays a pivotal role in protecting neuronal cells from oxidative damage under stress conditions. However, the effects of FtMt in mitochondrial function and activation of apoptosis under cerebral I/R are barely understood. In the present study, we found that FtMt deficiency exacerbates neuronal apoptosis via classical mitochondria-depedent pathway and the endoplasmic reticulum (ER) stress pathway in brains exposed to I/R. Conversely, FtMt overexpression significantly inhibited oxygen and glucose deprivation and reperfusion (OGD/R)-induced apoptosis and the activation of ER stress response. Meanwhile, FtMt overexpression rescued OGD/R-induced mitochondrial iron overload, mitochondrial dysfunction, the generation of reactive oxygen species (ROS) and increased neuronal GSH content. Using the Seahorse and O2K cellular respiration analyser, we demonstrated that FtMt remarkably improved the ATP content and the spare respiratory capacity under I/R conditions. Importantly, we found that glucose consumption was augmented in FtMt overexpressing cells after OGD/R insult; overexpression of FtMt facilitated the activation of glucose 6-phosphate dehydrogenase and the production of NADPH in cells after OGD/R, indicating that the pentose-phosphate pathway is enhanced in FtMt overexpressing cells, thus strengthening the antioxidant capacity of neuronal cells. In summary, our results reveal that FtMt protects against I/R-induced apoptosis through enhancing mitochondrial bioenergetics and regulating glucose metabolism via the pentose-phosphate pathway, thus preventing ROS overproduction, and preserving energy metabolism.

Keywords:  G6PDH; Glucose metabolism; Ischemic stroke; Mitochondrial bioenergetics; Mitochondrial ferritin

DOI:  https://doi.org/10.1016/j.redox.2022.102475
Sci Rep. 2022 Sep 26. 12(1): 16028

PGC-1β maintains mitochondrial metabolism and restrains inflammatory gene expression.

Hannah Guak, Ryan D Sheldon, Ian Beddows, Alexandra Vander Ark, Matthew J Weiland, Hui Shen, Russell G Jones, Julie St-Pierre, Eric H Ma, Connie M Krawczyk.

Metabolic programming of the innate immune cells known as dendritic cells (DCs) changes in response to different stimuli, influencing their function. While the mechanisms behind increased glycolytic metabolism in response to inflammatory stimuli are well-studied, less is known about the programming of mitochondrial metabolism in DCs. We used lipopolysaccharide (LPS) and interferon-β (IFN-β), which differentially stimulate the use of glycolysis and oxidative phosphorylation (OXPHOS), respectively, to identify factors important for mitochondrial metabolism. We found that the expression of peroxisome proliferator-activated receptor gamma co-activator 1β (PGC-1β), a transcriptional co-activator and known regulator of mitochondrial metabolism, decreases when DCs are activated with LPS, when OXPHOS is diminished, but not with IFN-β, when OXPHOS is maintained. We examined the role of PGC-1β in bioenergetic metabolism of DCs and found that PGC-1β deficiency indeed impairs their mitochondrial respiration. PGC-1β-deficient DCs are more glycolytic compared to controls, likely to compensate for reduced OXPHOS. PGC-1β deficiency also causes decreased capacity for ATP production at steady state and in response to IFN-β treatment. Loss of PGC-1β in DCs leads to increased expression of genes in inflammatory pathways, and reduced expression of genes encoding proteins important for mitochondrial metabolism and function. Collectively, these results demonstrate that PGC-1β is a key regulator of mitochondrial metabolism and negative regulator of inflammatory gene expression in DCs.

DOI: https://doi.org/10.1038/s41598-022-20215-6
Redox Biol. 2022 Sep 13. pii: S2213-2317(22)00242-7. [Epub ahead of print]57 102470

Nrf1 is an indispensable redox-determining factor for mitochondrial homeostasis by integrating multi-hierarchical regulatory networks.

Shaofan Hu, Jing Feng, Meng Wang, Reziyamu Wufuer, Keli Liu, Zhengwen Zhang, Yiguo Zhang.

  To defend against a vast variety of challenges in oxygenated environments, all life forms have evolutionally established a set of antioxidants, detoxification, and cytoprotective systems during natural selection and adaptive survival, to maintain cell redox homeostasis and organ integrity in the healthy development and growth. Such antioxidant defense systems are predominantly regulated by two key transcription factors Nrf1 and Nrf2, but the underlying mechanism(s) for their coordinated redox control remains elusive. Here, we found that loss of full-length Nrf1 led to a dramatic increase in reactive oxygen species (ROS) and oxidative damages in Nrf1α-∕- cells, and this increase was not eliminated by drastic elevation of Nrf2, even though the antioxidant systems were also substantially enhanced by hyperactive Nrf2. Further studies revealed that the increased ROS production in Nrf1α-∕- resulted from a striking impairment in the mitochondrial oxidative respiratory chain and its gene expression regulated by nuclear respiratory factors, called αPalNRF1 and GABPNRF2. In addition to the antioxidant capacity of cells, glycolysis was greatly augmented by aberrantly-elevated Nrf2, so to partially relieve the cellular energy demands, but aggravate its mitochondrial stress. The generation of ROS was also differentially regulated by Nrf1 and Nrf2 through miR-195 and/or mIR-497-mediated UCP2 pathway. Consequently, the epithelial-mesenchymal transformation (EMT) of Nrf1α-∕- cells was activated by putative ROS-stimulated signaling via MAPK, HIF1α, NF-ƙB, PI3K and AKT, all players involved in cancer development and progression. Taken together, it is inferable that Nrf1 acts as a potent integrator of redox regulation by multi-hierarchical networks.

Keywords:  Antioxidant response; GABP(NRF2); Metabolism; Mitochondrion; Nrf1; Nrf2; ROS; Redox regulation; UCP2; UPR(mt); miR-195; miR-497; αPal(NRF1)

DOI:  https://doi.org/10.1016/j.redox.2022.102470
Cell Death Differ. 2022 Sep 28.

Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins.

Allan Shuai Huang, Hui San Chin, Boris Reljic, Tirta M Djajawi, Iris K L Tan, Jia-Nan Gong, David A Stroud, David C S Huang, Mark F van Delft, Grant Dewson.

Intrinsic apoptosis is principally governed by the BCL-2 family of proteins, but some non-BCL-2 proteins are also critical to control this process. To identify novel apoptosis regulators, we performed a genome-wide CRISPR-Cas9 library screen, and it identified the mitochondrial E3 ubiquitin ligase MARCHF5/MITOL/RNF153 as an important regulator of BAK apoptotic function. Deleting MARCHF5 in diverse cell lines dependent on BAK conferred profound resistance to BH3-mimetic drugs. The loss of MARCHF5 or its E3 ubiquitin ligase activity surprisingly drove BAK to adopt an activated conformation, with resistance to BH3-mimetics afforded by the formation of inhibitory complexes with pro-survival proteins MCL-1 and BCL-XL. Importantly, these changes to BAK conformation and pro-survival association occurred independently of BH3-only proteins and influence on pro-survival proteins. This study identifies a new mechanism by which MARCHF5 regulates apoptotic cell death by restraining BAK activating conformation change and provides new insight into how cancer cells respond to BH3-mimetic drugs. These data also highlight the emerging role of ubiquitin signalling in apoptosis that may be exploited therapeutically.

DOI: https://doi.org/10.1038/s41418-022-01067-z
Sci Rep. 2022 Sep 29. 12(1): 16348

Dichloroacetate as a metabolic modulator of heart mitochondrial proteome under conditions of reduced oxygen utilization.

Natalia Andelova, Iveta Waczulikova, Lukas Kunstek, Ivan Talian, Tanya Ravingerova, Magdalena Jasova, Simon Suty, Miroslav Ferko.

Myocardial compensatory mechanisms stimulated by reduced oxygen utilization caused by streptozotocin-induced diabetes mellitus (DM) and treated with dichloroacetate (DCA) are presumably associated with the regulation of mitochondria. We aimed to promote the understanding of key signaling pathways and identify effectors involved in signal transduction. Proteomic analysis and fluorescence spectroscopy measurements revealed significantly decreased membrane potential and upregulated protein amine oxidase [flavin-containing] A (AOFA) in DM mitochondria, indicative of oxidative damage. DCA in diabetic animals (DM + DCA) downregulated AOFA, increased membrane potential, and stimulated thioredoxin-dependent peroxide reductase, a protein with antioxidant function. Furthermore, the DM condition was associated with mitochondrial resistance to calcium overload through mitochondrial permeability transition pores (mPTPs) regulation, despite an increased protein level of voltage-dependent anion-selective protein (VDAC1). In contrast, DM + DCA influenced ROS levels and downregulated VDAC1 and VDAC3 when compared to DM alone. The diabetic myocardium showed an identical pattern of mPTP protein interactions as in the control group, but the interactions were attenuated. Characterization of the combined effect of DM + DCA is a novel finding showing that DCA acted as an effector of VDAC protein interactions, calcium uptake regulation, and ROS production. Overall, DM and DCA did not exhibit an additive effect, but an individual cardioprotective pathway.

DOI: https://doi.org/10.1038/s41598-022-20696-5
Nat Commun. 2022 Sep 28. 13(1): 5696

TFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis.

David Matye, Sumedha Gunewardena, Jianglei Chen, Huaiwen Wang, Yifeng Wang, Mohammad Nazmul Hasan, Lijie Gu, Yung Dai Clayton, Yanhong Du, Cheng Chen, Jacob E Friedman, Shelly C Lu, Wen-Xing Ding, Tiangang Li.

Fatty liver is a highly heterogenous condition driven by various pathogenic factors in addition to the severity of steatosis. Protein insufficiency has been causally linked to fatty liver with incompletely defined mechanisms. Here we report that fatty liver is a sulfur amino acid insufficient state that promotes metabolic inflexibility via limiting coenzyme A availability. We demonstrate that the nutrient-sensing transcriptional factor EB synergistically stimulates lysosome proteolysis and methionine adenosyltransferase to increase cysteine pool that drives the production of coenzyme A and glutathione, which support metabolic adaptation and antioxidant defense during increased lipid influx. Intriguingly, mice consuming an isocaloric protein-deficient Western diet exhibit selective hepatic cysteine, coenzyme A and glutathione deficiency and acylcarnitine accumulation, which are reversed by cystine supplementation without normalizing dietary protein intake. These findings support a pathogenic link of dysregulated sulfur amino acid metabolism to metabolic inflexibility that underlies both overnutrition and protein malnutrition-associated fatty liver development.

DOI: https://doi.org/10.1038/s41467-022-33465-9
BMC Pharmacol Toxicol. 2022 Sep 29. 23(1): 74

Resveratrol promotes liver cell survival in mice liver-induced ischemia-reperfusion through unfolded protein response: a possible approach in liver transplantation.

Hamidreza Totonchi, Pooneh Mokarram, Saeed Karima, Ramazan Rezaei, Sanaz Dastghaib, Farhad Koohpeyma, Shokoofe Noori, Negar Azarpira.

   BACKGROUND: Ischemia-reperfusion (I/R) of the liver is a multifactorial condition that happens during transplantation and surgery. The deleterious effects of I/R result from the acute production of reactive oxygen species (ROS), which can trigger immediate tissue damage and induce a series of destructive cellular responses, including apoptosis organ failure and inflammation. The production of ROS in the I/R process can damage the antioxidant system and cause liver damage. Resveratrol has been shown to have antioxidant properties in several investigations. Here, we address the therapeutic effect of resveratrol on I/R-induced liver injury by focusing on unfolded protein response (UPR) signaling pathway.
METHODS: Five minutes before reperfusion, resveratrol was injected into the tail vein of mice. They were ischemic for 1 h and then re-perfused for 3 h before being slaughtered (I/R). The activity of liver enzymes and the expression levels of genes involved in the unfolded protein response pathway were used to measure the hepatic damage.
RESULTS: Our results revealed that the low dose of resveratrol (0.02 and 0.2 mg/kg) post-ischemic treatment significantly reduced the ALT and AST levels. In addition, compared with the control group, the expression of UPR pathway genes GRP78, PERK, IRE1α, CHOP, and XBP1 was significantly reduced in the resveratrol group. In the mice that received lower doses of resveratrol (0.02 and 0.2 mg/kg), the histopathological changes induced by I/R were significantly improved; however, the highest dose (2 mg/kg) of resveratrol could not significantly protect and solve the I/R damage.
CONCLUSION: The findings of this study suggest that hepatic ischemia occurs after liver transplantation and that receiving low-dose resveratrol treatment before reperfusion may promote graft survival through inhibition of UPR arms, especially PERK and IRE1α.

Keywords:  I/R; Ischemia-reperfusion; Resveratrol; UPR; Unfolded protein response

DOI:  https://doi.org/10.1186/s40360-022-00611-4