bims-unfpre 2023-04-16 papers

Issue of 2023–04–16
seven papers selected by
Susan Logue, University of Manitoba

Nat Commun. 2023 Apr 14. 14(1): 2132

Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death.

Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukaemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.

DOI: https://doi.org/10.1038/s41467-023-37652-0

J Cell Biol. 2023 May 01. pii: e202304013. [Epub ahead of print]222(5):

Disagreement among the three musketeers of the unfolded protein response.

András Jipa, Gábor Juhász.

Jipa and Juhász preview results from the lab of Tao Wang (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202208147) which show a surprising antagonism between two branches of the unfolded protein response that dictates disease progression in a model of autosomal dominant retinitis pigmentosa.

DOI: https://doi.org/10.1083/jcb.202304013

Cancer Lett. 2023 Apr 11. pii: S0304-3835(23)00122-2. [Epub ahead of print] 216171

Single-cell RNA sequencing reveals XBP1-SLC38A2 axis as a metabolic regulator in cytotoxic T lymphocytes in multiple myeloma.

Yike Wan, Mengping Chen, Xin Li, Xiaofeng Han, Lu Zhong, Fei Xiao, Jia Liu, Jing Xiang, Jinxing Jiang, Xiaotong Chen, Junling Liu, Hua Li, Bin Li, Honghui Huang, Jian Hou.

The mechanisms underlying the functional impairment and metabolic reprogramming of T lymphocytes in multiple myeloma (MM) have not been fully elucidated. In this study, single-cell RNA sequencing was used to compare gene expression profiles in T cells in bone marrow and peripheral blood of 10 newly diagnosed MM patients versus 3 healthy donors. Unbiased bioinformatics analysis revealed 9 cytotoxic T cell clusters. All 9 clusters in MM had higher expression of senescence markers (e.g., KLRG1 and CTSW) than the healthy control; some had higher expression of exhaustion-related markers (e.g., LAG3 and TNFRSF14). Pathway enrichment analyses showed downregulated amino acid metabolism and upregulated unfolded protein response (UPR) pathways, along with absent expression of glutamine transporter SLC38A2 and increased expression of UPR hallmark XBP1 in cytotoxic T cells in MM. In vitro studies revealed that XBP1 inhibited SLC38A2 by directly binding to its promoter, and silencing SLC38A2 resulted in decreased glutamine uptake and immune dysfunction of T cells. This study provided a landscape description of the immunosuppressive and metabolic features in T lymphocytes in MM, and suggested an important role of XBP1-SLC38A2 axis in T cell function.

Keywords: Cell exhaustion; Cell senescence; Glutamine metabolism; Immune microenvironment; Unfolded protein response

DOI: https://doi.org/10.1016/j.canlet.2023.216171

Molecules. 2023 Apr 03. pii: 3185. [Epub ahead of print]28(7):

Persistent Lipid Accumulation Leads to Persistent Exacerbation of Endoplasmic Reticulum Stress and Inflammation in Progressive NASH via the IRE1α/TRAF2 Complex.

Na Lei, Hongfei Song, Ling Zeng, Shaoxiu Ji, Xiangbo Meng, Xiuying Zhu, Xiuyan Li, Quansheng Feng, Jibin Liu, Jie Mu.

Non-alcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to other severe liver diseases, yet treatment options are limited. Endoplasmic reticulum (ER) stress is an important pathogenetic mechanism of NASH and plays a key role in tandem steatosis as well as liver inflammation. This study aims to develop a progressive NASH model through sustained lipid accumulation and to elucidate its molecular mechanism through IRE1α/TRAF2 complex. Male SD rats were fed a high-fat diet (HFD) for 4, 8, and 12 weeks to induce progressive NASH. MRNA sequencing and PPI analysis were used to screen core genes. Transmission electron microscopy, immunofluorescence staining, ELISA, qRT-PCR, and Western blotting were used at each time point to compare differences between each index of progressive NASH at 4, 8, and 12 weeks. Sustained lipid accumulation led to structural disruption of the ER, a reduction in ER number, and an increase of lipid droplet aggregation in hepatocytes. Persistent lipid accumulation led to a persistent increase in mRNA and protein expression of the IRE1α/TRAF2 complex, IKK/IκB/NF-κB signaling pathway and ASK1/JNK1 signaling pathway, and TNF-α, IL-1β, and IL-6 also continued to increase. Persistent lipid accumulation led to a persistent exacerbation of ER stress and inflammation in progressive NASH via the IRE1α/TRAF2 complex.

Keywords: ASK1/JNK1 signaling pathway; IKK/IκB/NF-κB signaling pathway; IRE1α/TRAF2 complex; endoplasmic reticulum stress; inflammation; lipid accumulation; non-alcoholic steatohepatitis

DOI: https://doi.org/10.3390/molecules28073185

Antioxid Redox Signal. 2023 Apr 13.

Mitofusin2 ameliorated ER stress and mitochondrial ROS through maintaining mitochondria-associated ER membrane integrity in cisplatin-induced acute kidney injury.

Yu-Ting Liu, Hao Zhang, Shao-Bin Duan, Jianwen Wang, Hong Chen, Ming Zhan, Wei Zhang, Ai-Mei Li, Yan Liu, Yang Yang, Shikun Yang.

AIMS: This study investigated the regulatory effect of Mitofusin2 (Mfn2) on mitochondria-associated endoplasmic reticulum membrane (MAMs) integrity and cellular injury in cisplatin-induced acute kidney injury (CP-AKI).
RESULTS: CP- AKI mice exhibited decreased expression of Mfn2, increased expression of phosphorylated adenosine monophosphate activated protein kinase (P-AMPK), abnormal mitochondrial morphology, and reduced MAMs integrity, accompanied by the activation of mitochondrial ROS and ER stress (IRE1 and PERK pathways). In in vitro studies, CP-induced mitochondrial ROS, ER stress activation, and increased apoptosis were accompanied by the downregulation of Mfn2 and MAMs integrity reduction in Boston University mouse proximal tubular (BUMPT) cells and human proximal tubular epithelial (HK-2) cells. Pretreatment of BUMPT cells with the Mfn2 plasmid partially restored the integrity of MAMs, negatively controled IRE1 and PERK pathways, and inhibited cell apoptosis. In contrast, ER stress and MAMs integrity violations were increased after Mfn2 siRNA treatment in HK-2 cells under CP treatment. Co-immunoprecipitation analysis demonstrated that Mfn2 interacted with PERK and IRE1. Furthermore, the AMPK agonist, AICAR had a similar effect like Mfn2 plasmid in the regulation of ER stress and MAMs. Conversely, the ER stress inhibitor, 4-PBA, had no effect on the expression of Mfn2 and MAMs integrity.
INNOVATION AND CONCLUSION: This is the first study to explore the association between MAMs, ER stress, and Mfn2 in CP-AKI. Downregulation of Mfn2 expression abolished the MAMs integrity and induced ER stress, mitochondrial ROS, and tubular cell apoptosis. This suggests that the Mfn2-MAMs pathway is a potential therapeutic target in CP-AKI.

DOI: https://doi.org/10.1089/ars.2022.0178

Front Cell Dev Biol. 2023 ;11 1146963

Trends in mitochondrial unfolded protein response research from 2004 to 2022: A bibliometric analysis.

Zelin Ye, Ruoning Chai, Yujie Luan, Yihang Du, Wenjing Xue, Shuqing Shi, Huaqin Wu, Yi Wei, Limei Zhang, Yuanhui Hu.

The mitochondrial unfolded protein response (UPRmt) is a stress response pathway that regulates the expression of mitochondrial chaperones, proteases, and other proteins involved in protein folding and degradation, thereby ensuring proper mitochondrial function. In addition to this critical function, the UPRmt also plays a role in other cellular processes such as mitochondrial biogenesis, energy metabolism, and cellular signaling. Moreover, the UPRmt is strongly associated with various diseases. From 2004 to 2022, there has been a lot of interest in UPRmt. The present study aims to utilized bibliometric tools to assess the genesis, current areas of focus, and research trends pertaining to UPRmt, thereby highlighting avenues for future research. There were 442 papers discovered to be related to UPRmt, with the overall number of publications rising yearly. International Journal of Molecular Sciences was the most prominent journal in this field. 2421 authors from 1,402 institutions in 184 nations published studies on UPRmt. The United States was the most productive country (197 documents). The top three authors were Johan Auwerx, Cole M Haynes, and Dongryeol Ryu. The early focus of UPRmt is "protein." And then the UPRmt research shifted from Caenorhabditis elegans back to mammals, and its close link to aging and various diseases. The top emerging research hotspots are neurodegenerative diseases and metabolic diseases. These findings provide the trends and frontiers in the field of UPRmt, and valuable information for clinicians and scientists to identify new perspectives with potential collaborators and cooperative countries.

Keywords: Citespace; UPR mt; VOSviewer; bibliometrics analysis; bibliometrix; mitochondrial unfolded protein response

DOI: https://doi.org/10.3389/fcell.2023.1146963

J Physiol. 2023 Apr 12.

Increased mitochondrial surface area and cristae density in the skeletal muscle of strength athletes.

Javier Botella, Camilla T Schytz, Thomas F Pehrson, Rune Hokken, Simon Laugesen, Per Aagaard, Charlotte Suetta, Britt Christensen, Niels Ørtenblad, Joachim Nielsen.

Mitochondria are the cellular organelles responsible for resynthesising the majority of ATP. In skeletal muscle, there is an increased ATP turnover during resistance exercise to sustain the energetic demands of muscle contraction. Despite this, little is known regarding the mitochondrial characteristics of chronically strength-trained individuals and any potential pathways regulating the strength-specific mitochondrial remodelling. Here, we investigated the mitochondrial structural characteristics in skeletal muscle of strength athletes and age-matched untrained controls. The mitochondrial pool in strength athletes was characterised by increased mitochondrial cristae density, decreased mitochondrial size, and increased surface-to-volume ratio, despite similar mitochondrial volume density. We also provide a fibre-type and compartment specific assessment of mitochondria morphology in human skeletal muscle, which reveals across groups a compartment-specific influence on mitochondrial morphology that is largely independent of fibre-type. Furthermore, we show that resistance exercise leads to signs of mild mitochondrial stress, without an increase in the number of damaged mitochondria. Using publicly available transcriptomic data we show that acute resistance exercise increases the expression of markers of mitochondrial biogenesis, fission, and mitochondrial unfolded protein responses (UPRmt ). Further, we observed an enrichment of the UPRmt in the basal transcriptome of strength-trained individuals. Together, these findings show that strength athletes possess a unique mitochondrial remodelling, which minimises the space required for mitochondria. We propose that the concurrent activation of markers of mitochondrial biogenesis and mitochondrial remodelling pathways (fission and UPRmt ) with resistance exercise may be partially responsible for the observed mitochondrial phenotype of strength athletes. KEY POINTS: Untrained individuals and strength athletes possess comparable skeletal muscle mitochondrial volume density. In contrast, strength athletes'mitochondria are characterised by increased cristae density, decreased size, and increased surface-to-volume ratio. Type I fibres have an increased number of mitochondrial profiles with minor differences in the mitochondrial morphological characteristics compared to type II fibres. The mitochondrial morphology is distinct across the subcellular compartments in both groups, with subsarcolemmal mitochondria being bigger in size when compared to intermyofibrillar. Acute resistance exercise leads to signs of mild morphological mitochondrial stress accompanied by increased gene expression of markers of mitochondrial biogenesis, fission, and mitochondrial unfolded protein response (UPRmt). Abstract figure legend: Mitochondria are the cellular organelles responsible for resynthesising the majority of ATP. The present study aimed to investigate the mitochondrial structural characteristics of strength athletes when compared to age-matched untrained individuals. Here we show that the mitochondria of strength athletes have an increased mitochondrial cristae density, increased number of profiles, and an increased surface-to-volume ratio; despite similar mitochondrial volumetric density. Furthermore, we show that human type I fibres, when compared to type II fibres, are characterised by an increased number of mitochondrial profiles without differences in their morphological characteristics. Finally, we show that acute resistance exercise leads to mild signs of mitochondrial morphological stress and an increased expression of markers of mitochondrial biogenesis, fission, and mitochondrial unfolded protein response (UPRmt ). This article is protected by copyright. All rights reserved.

Keywords: Mitochondria; Olympic weightlifting; cristae density; resistance exercise; skeletal muscle; strength

DOI: https://doi.org/10.1113/JP284394