bims-camemi 2023-01-22 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2023‒01‒22
thirty papers selected by
Christian Frezza, Universität zu Köln

Acetyl-CoA metabolism in cancer.
Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.
GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation.
BAP1 loss is associated with higher ASS1 expression in epithelioid mesothelioma: implications for therapeutic stratification.
CoQ Regulates Brown Adipose Tissue Respiration and Uncoupling Protein 1 Expression.
HDAC1 disrupts the tricarboxylic acid (TCA) cycle through the deacetylation of Nur77 and promotes inflammation in ischemia-reperfusion mice.
Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.
TFEB-mediated lysosomal exocytosis alleviates high fat diet-induced lipotoxicity in the kidney.
Goldilocks calcium concentrations and the regulation of oxidative phosphorylation: too much, too little, or just right.
Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma.
Nucleus-exported CLOCK acetylates PRPS to promote de novo nucleotide synthesis and liver tumour growth.
Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction.
SIRT6 is a key regulator of mitochondrial function in the brain.
Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis.
The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans.
A bittersweet symphony: Metabolic signals in the circadian system.
Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells.
Neddylation is required for perinatal cardiac development through stimulation of metabolic maturation.
Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth.
Hypoxia enhances IPF mesenchymal progenitor cell fibrogenicity via the lactate/GPR81/HIF1α pathway.
RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer.
Gasdermin D pore-forming activity is redox-sensitive.
Coordinated cancer chaos.
Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.
When should I eat: A circadian view on food intake and metabolic regulation.
START smuggling CoQ to fight ferroptosis.
Fructose-1,6-bisphosphatase 1 dephosphorylates IκBα and suppresses colorectal tumorigenesis.
Sex-specificity of the C. elegans metabolome.
Time to hit pause on mitochondria-targeting cancer therapies.
Multi-Omics Approach Reveals Redox Homeostasis Reprogramming in Early-Stage Clear Cell Renal Cell Carcinoma.

Nat Rev Cancer. 2023 Jan 19.

Acetyl-CoA metabolism in cancer.

David A Guertin, Kathryn E Wellen.

Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle and is the essential building block for fatty acid and isoprenoid biosynthesis. It also functions as a signalling metabolite as the substrate for lysine acetylation reactions, enabling the modulation of protein functions in response to acetyl-CoA availability. Recent years have seen exciting advances in our understanding of acetyl-CoA metabolism in normal physiology and in cancer, buoyed by new mouse models, in vivo stable-isotope tracing approaches and improved methods for measuring acetyl-CoA, including in specific subcellular compartments. Efforts to target acetyl-CoA metabolic enzymes are also advancing, with one therapeutic agent targeting acetyl-CoA synthesis receiving approval from the US Food and Drug Administration. In this Review, we give an overview of the regulation and cancer relevance of major metabolic pathways in which acetyl-CoA participates. We further discuss recent advances in understanding acetyl-CoA metabolism in normal tissues and tumours and the potential for targeting these pathways therapeutically. We conclude with a commentary on emerging nodes of acetyl-CoA metabolism that may impact cancer biology.

DOI: https://doi.org/10.1038/s41568-022-00543-5
Nat Cell Biol. 2023 Jan 19.

Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.

Soni Deshwal, Mashun Onishi, Takashi Tatsuta, Tim Bartsch, Eileen Cors, Katharina Ried, Kathrin Lemke, Hendrik Nolte, Patrick Giavalisco, Thomas Langer.

Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis.

DOI: https://doi.org/10.1038/s41556-022-01071-y
Cell Rep. 2023 Jan 18. pii: S2211-1247(23)00008-6. [Epub ahead of print]42(1): 111997

GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation.

Salvatore Rizza, Luca Di Leo, Chiara Pecorari, Paola Giglio, Fiorella Faienza, Costanza Montagna, Emiliano Maiani, Michele Puglia, Francesca M Bosisio, Trine Skov Petersen, Lin Lin, Vendela Rissler, Juan Salamanca Viloria, Yonglun Luo, Elena Papaleo, Daniela De Zio, Blagoy Blagoev, Giuseppe Filomeni.

  Nitric oxide (NO) production in the tumor microenvironment is a common element in cancer. S-nitrosylation, the post-translational modification of cysteines by NO, is emerging as a key transduction mechanism sustaining tumorigenesis. However, most oncoproteins that are regulated by S-nitrosylation are still unknown. Here we show that S-nitrosoglutathione reductase (GSNOR), the enzyme that deactivates S-nitrosylation, is hypo-expressed in several human malignancies. Using multiple tumor models, we demonstrate that GSNOR deficiency induces S-nitrosylation of focal adhesion kinase 1 (FAK1) at C658. This event enhances FAK1 autophosphorylation and sustains tumorigenicity by providing cancer cells with the ability to survive in suspension (evade anoikis). In line with these results, GSNOR-deficient tumor models are highly susceptible to treatment with FAK1 inhibitors. Altogether, our findings advance our understanding of the oncogenic role of S-nitrosylation, define GSNOR as a tumor suppressor, and point to GSNOR hypo-expression as a therapeutically exploitable vulnerability in cancer.

Keywords:  CP: Cancer; CP: Molecular biology; FAK inhibitors; S-nitrosylation; SRC; anoikis; cancer; focal adhesion; nitric oxide; spheroids

DOI:  https://doi.org/10.1016/j.celrep.2023.111997
Mol Cancer Res. 2023 Jan 20. pii: MCR-22-0635. [Epub ahead of print]

BAP1 loss is associated with higher ASS1 expression in epithelioid mesothelioma: implications for therapeutic stratification.

Sarah E Barnett, Jenna Kenyani, Martina Tripari, Zohra Butt, Rudi Grosman, Francesca Querques, Liam Shaw, Luisa C Silva, Zoe Goate, Stefan J Marciniak, Doris M Rassl, Richard Jackson, Lu-Yun Lian, Peter W Szlosarek, Joseph J Sacco, Judy M Coulson.

The nuclear deubiquitylase BRCA1 associated protein 1 (BAP1) is frequently inactivated in malignant pleural mesothelioma (MPM) and germline BAP1 mutation predisposes to cancers including MPM. To explore the influence on cell physiology and drug sensitivity, we sequentially edited a predisposition mutation (w-) and a promoter trap (KO) into human mesothelial cells. BAP1w-/KO MeT5A cells express less BAP1 protein and phenocopy key aspects of BAP1 loss in MPM. SILAC-mass spectrometry revealed evidence of metabolic adaptation, with concomitant alteration of cellular metabolites. In MeT5A, BAP1-deficiency reduces glycolytic enzyme levels but increases enzymes involved in the tricarboxylic acid (TCA) cycle and anaplerotic pathways. Notably both argininosuccinate synthase 1 (ASS1), essential for cellular synthesis of arginine, and its substrate aspartate, are elevated in BAP1w-/KO MeT5A cells. Likewise, ASS1 expression is higher in BAP1-altered MPM cell lines, and inversely correlates with BAP1 in the cancer genome atlas (TCGA) MESO dataset. Elevated ASS1 is also evident by immunohistochemical staining in epithelioid MPM lacking nuclear BAP1 expression, with improved survival amongst patients with BAP1-negative/ASS1-expressing tumours. Alterations in arginine metabolism may sensitise cells to metabolic drugs and we find that BAP1-negative/ASS1-expressing MPM cell lines are more sensitive to ASS1 inhibition, although not to inhibition of purine synthesis by mizoribine. Importantly, BAP1w-/KO MeT5A become desensitised to arginine-deprivation by pegylated arginine deiminase (ADI-PEG20), phenocopying BAP1-negative/ASS1-expressing MPM cell lines. Implications: Our data reveal an inter-relationship between BAP1 and arginine metabolism, providing a potential means of identifying epithelioid MPM patients likely to benefit from ADI-PEG20.

DOI: https://doi.org/10.1158/1541-7786.MCR-22-0635
Antioxidants (Basel). 2022 Dec 22. pii: 14. [Epub ahead of print]12(1):

CoQ Regulates Brown Adipose Tissue Respiration and Uncoupling Protein 1 Expression.

Ching-Fang Chang, Amanda L Gunawan, Irene Liparulo, Peter-James H Zushin, Ambre M Bertholet, Yuriy Kirichok, Andreas Stahl.

  Coenzyme Q (CoQ, aka ubiquinone) is a key component of the mitochondrial electron transport chain (ETC) and membrane-incorporated antioxidant. CoQ10 deficiencies encompass a heterogeneous spectrum of clinical phenotypes and can be caused by hereditary mutations in the biosynthesis pathway or result from pharmacological interventions such as HMG-CoA Reductase inhibitors, and statins, which are widely used to treat hypercholesterolemia and prevent cardiovascular disease. How CoQ deficiency affects individual tissues and cell types, particularly mitochondrial-rich ones such as brown adipose tissue (BAT), has remained poorly understood. Here we show that pharmacological and genetic models of BAT CoQ deficiency show altered respiration that can only in part be explained by classical roles of CoQ in the respiration chain. Instead, we found that CoQ strongly impacts brown and beige adipocyte respiration via the regulation of uncoupling protein 1 (UCP1) expression. CoQ deficiency in BAT robustly decreases UCP1 protein levels and uncoupled respiration unexpectedly, resulting in increased inner mitochondrial membrane potential and decreased ADP/ATP ratios. Suppressed UCP1 expression was also observed in a BAT-specific in vivo model of CoQ deficiency and resulted in enhanced cold sensitivity. These findings demonstrate an as yet unappreciated role of CoQ in the transcriptional regulation of key thermogenic genes and functions.

Keywords:  Coenzyme Q; brown adipose tissue; mitochondrial function; thermogenesis

DOI:  https://doi.org/10.3390/antiox12010014
Cell Death Discov. 2023 Jan 18. 9(1): 10

HDAC1 disrupts the tricarboxylic acid (TCA) cycle through the deacetylation of Nur77 and promotes inflammation in ischemia-reperfusion mice.

Zhenhua Wu, Yunpeng Bai, Yujuan Qi, Chao Chang, Yan Jiao, Yaobang Bai, Zhigang Guo.

Histone deacetylase enzymes (HDACs) regulate protein acetylation. HDAC1 is known to enhance ischemia/reperfusion (I/R) injury, but its underlying mechanism(s) of action have not been defined. Here, in vivo mouse models of myocardial I/R were used to investigate the role of HDAC1 during I/R myocardial injury. We show that HDAC1 enhances the inflammatory responses of I/R mice. Using a constructed macrophage H/R (hypoxia/ regeneration) injury model (Raw264.7 cells), we identified Nur77 as a HDAC1 target in macrophages. Nur77 deficient macrophages failed to downregulate IDH1 (isocitrate dehydrogenase 1) and accumulated succinic acid and other tricarboxylic acid (TCA) cycle-derived metabolites in a glutamine-independent manner. These data show that the inhibition of HDAC1 ameliorates H/R-inflammation in macrophages through the regulation of Nur77 and the TCA cycle.

DOI: https://doi.org/10.1038/s41420-023-01308-1
Sci Transl Med. 2023 Jan 18. 15(679): eabq6288

Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.

Katharina M Eyme, Alessandro Sammarco, Roshani Jha, Hayk Mnatsakanyan, Caline Pechdimaljian, Litia Carvalho, Rudolph Neustadt, Charlotte Moses, Ahmad Alnasser, Daniel F Tardiff, Baolong Su, Kevin J Williams, Steven J Bensinger, Chee Yeun Chung, Christian E Badr.

Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or in combination with temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis complemented with shotgun lipidomics, we show that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drive therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs resistant to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Together, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for the rational integration of DNLS-targeted GBM therapies.

DOI: https://doi.org/10.1126/scitranslmed.abq6288
JCI Insight. 2023 Jan 17. pii: e162498. [Epub ahead of print]

TFEB-mediated lysosomal exocytosis alleviates high fat diet-induced lipotoxicity in the kidney.

Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Satoshi Minami, Atsushi Takahashi, Jun Matsuda, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Isao Matsui, Takayuki Hamano, Masatomo Takahashi, Maiko Goto, Yoshihiro Izumi, Takeshi Bamba, Miwa Sasai, Masahiro Yamamoto, Taiji Matsusaka, Fumio Niimura, Motoko Yanagita, Shuhei Nakamura, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka.

  Obesity is a major risk factor for end-stage kidney disease. We previously found that lysosomal dysfunction and impaired autophagic flux contributed to lipotoxicity in obesity-related kidney disease, both in humans and experimental animal models. However, the regulatory factors involved in countering renal lipotoxicity are largely unknown. Here we found that palmitic acid (PA) strongly promoted dephosphorylation and nuclear translocation of transcription factor EB (TFEB) by inhibiting the mechanistic target of rapamycin kinase complex 1 (MTORC1) pathway in a Rag GTPase-dependent manner, although these effects gradually diminished after extended treatment. We then investigated the role of TFEB in the pathogenesis of obesity-related kidney disease. Proximal tubular epithelial cell (PTEC)-specific Tfeb-deficient mice fed a high-fat diet (HFD) exhibited greater phospholipid accumulation in enlarged lysosomes, which manifested as multilamellar bodies (MLBs). Activated TFEB mediated lysosomal exocytosis of phospholipids, which help reduce MLB accumulation in PTECs. Furthermore, HFD-fed PTEC-specific Tfeb-deficient mice showed autophagic stagnation and exacerbated injury upon renal ischemia-reperfusion. Finally, higher body mass index was associated with increased vacuolation and decreased nuclear TFEB in the proximal tubules of chronic kidney disease patients. These results indicate a critical role of TFEB-mediated lysosomal exocytosis in counteracting renal lipotoxicity.

Keywords:  Chronic kidney disease; Lysosomes; Metabolism; Nephrology; Obesity

DOI:  https://doi.org/10.1172/jci.insight.162498
J Biol Chem. 2023 Jan 12. pii: S0021-9258(23)00036-4. [Epub ahead of print] 102904

Goldilocks calcium concentrations and the regulation of oxidative phosphorylation: too much, too little, or just right.

Eloisa A Vilas-Boas, João Victor Cabral-Costa, Vitor M Ramos, Camille C Caldeira da Silva, Alicia J Kowaltowski.

  Calcium (Ca2+) is a key regulator in diverse intracellular signaling pathways, and has long been implicated in metabolic control and mitochondrial function. Mitochondria can actively take up large amounts of Ca2+, thereby acting as important intracellular Ca2+ buffers and affecting cytosolic Ca2+ transients. Excessive mitochondrial matrix Ca2+ is known to be deleterious due to opening of the mitochondrial permeability transition pore (mPTP) and consequent membrane potential dissipation, leading to mitochondrial swelling, rupture, and cell death. Moderate Ca2+ within the organelle, on the other hand, can directly or indirectly activate mitochondrial matrix enzymes, possibly impacting on ATP production. Here, we aimed to determine in a quantitative manner if extra or intramitochondrial Ca2+ modulate oxidative phosphorylation in mouse liver mitochondria and intact hepatocyte cell lines. To do so, we monitored the effects of more modest versus supra-physiological increases in cytosolic and mitochondrial Ca2+ on oxygen consumption rates. Isolated mitochondria present increased respiratory control ratios (a measure of oxidative phosphorylation efficiency) when incubated with low (2.4 ± 0.6 μM) and medium (22.0 ± 2.4 μM) Ca2+ concentrations in the presence of complex I-linked substrates pyruvate plus malate and α-ketoglutarate, respectively, but not complex II-linked succinate. In intact cells, both low and high cytosolic Ca2+ led to decreased respiratory rates, while ideal rates were present under physiological conditions. High Ca2+ decreased mitochondrial respiration in a substrate-dependent manner, mediated by mPTP. Overall, our results uncover a Goldilocks effect of Ca2+ on liver mitochondria, with specific "just right" concentrations that activate oxidative phosphorylation.

Keywords:  calcium transport; electron transfer chain; metabolic flux; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.jbc.2023.102904
Nat Commun. 2023 Jan 18. 14(1): 292

Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma.

L Paige Ferguson, Jovylyn Gatchalian, Matthew L McDermott, Mari Nakamura, Kendall Chambers, Nirakar Rajbhandari, Nikki K Lytle, Sara Brin Rosenthal, Michael Hamilton, Sonia Albini, Martin Wartenberg, Inti Zlobec, José A Galván, Eva Karamitopoulou, Vera Vavinskaya, Alexis Wascher, Andrew M Lowy, Christian M Schürch, Pier Lorenzo Puri, Benoit G Bruneau, Diana C Hargreaves, Tannishtha Reya.

Pancreatic cancer is characterized by extensive resistance to conventional therapies, making clinical management a challenge. Here we map the epigenetic dependencies of cancer stem cells, cells that preferentially evade therapy and drive progression, and identify SWI/SNF complex member SMARCD3 as a regulator of pancreatic cancer cells. Although SWI/SNF subunits often act as tumor suppressors, we show that SMARCD3 is amplified in cancer, enriched in pancreatic cancer stem cells and upregulated in the human disease. Diverse genetic mouse models of pancreatic cancer and stage-specific Smarcd3 deletion reveal that Smarcd3 loss preferentially impacts established tumors, improving survival especially in context of chemotherapy. Mechanistically, SMARCD3 acts with FOXA1 to control lipid and fatty acid metabolism, programs associated with therapy resistance and poor prognosis in cancer. These data identify SMARCD3 as an epigenetic modulator responsible for establishing the metabolic landscape in aggressive pancreatic cancer cells and a potential target for new therapies.

DOI: https://doi.org/10.1038/s41467-023-35796-7
Nat Cell Biol. 2023 Jan 16.

Nucleus-exported CLOCK acetylates PRPS to promote de novo nucleotide synthesis and liver tumour growth.

Tong Liu, Zheng Wang, Leiguang Ye, Yuran Duan, Hongfei Jiang, Haiyan He, Liwei Xiao, Qingang Wu, Yan Xia, Mengke Yang, Ke Wu, Meisi Yan, Guimei Ji, Yuli Shen, Lei Wang, Lin Li, Peixiang Zheng, Bofei Dong, Fei Shao, Xu Qian, Rilei Yu, Zhiren Zhang, Zhimin Lu, Daqian Xu.

Impairment of the circadian clock is linked to cancer development. However, whether the circadian clock is modulated by oncogenic receptor tyrosine kinases remains unclear. Here we demonstrated that receptor tyrosine kinase activation promotes CK2-mediated CLOCK S106 phosphorylation and subsequent disassembly of the CLOCK-BMAL1 dimer and suppression of the downstream gene expression in hepatocellular carcinoma (HCC) cells. In addition, CLOCK S106 phosphorylation exposes its nuclear export signal to bind Exportin1 for nuclear exportation. Cytosolic CLOCK acetylates PRPS1/2 K29 and blocks HSC70-mediated and lysosome-dependent PRPS1/2 degradation. Stabilized PRPS1/2 promote de novo nucleotide synthesis and HCC cell proliferation and liver tumour growth. Furthermore, CLOCK S106 phosphorylation and PRPS1/2 K29 acetylation are positively correlated in human HCC specimens and with HCC poor prognosis. These findings delineate a critical mechanism by which oncogenic signalling inhibits canonical CLOCK transcriptional activity and simultaneously confers CLOCK with instrumental moonlighting functions to promote nucleotide synthesis and tumour growth.

DOI: https://doi.org/10.1038/s41556-022-01061-0
Nat Cancer. 2023 Jan 16.

Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction.

Jingya Qiu, Bihui Xu, Darwin Ye, Diqiu Ren, Shangshang Wang, Joseph L Benci, Yuanming Xu, Hemant Ishwaran, Jean-Christophe Beltra, E John Wherry, Junwei Shi, Andy J Minn.

Prolonged interferon (IFN) signaling in cancer cells can promote resistance to immune checkpoint blockade (ICB). How cancer cells retain effects of prolonged IFN stimulation to coordinate resistance is unclear. We show that, across human and/or mouse tumors, immune dysfunction is associated with cancer cells acquiring epigenetic features of inflammatory memory. Here, inflammatory memory domains, many of which are initiated by chronic IFN-γ, are maintained by signal transducer and activator of transcription (STAT)1 and IFN regulatory factor (IRF)3 and link histone 3 lysine 4 monomethylation (H3K4me1)-marked chromatin accessibility to increased expression of a subset of IFN-stimulated genes (ISGs). These ISGs include the RNA sensor OAS1 that amplifies type I IFN (IFN-I) and immune inhibitory genes. Abrogating cancer cell IFN-I signaling restores anti-programmed cell death protein 1 (PD1) response by increasing IFN-γ in immune cells, promoting dendritic cell and CD8+ T cell interactions, and expanding T cells toward effector-like states rather than exhausted states. Thus, cancer cells acquire inflammatory memory to augment a subset of ISGs that promote and predict IFN-driven immune dysfunction.

DOI: https://doi.org/10.1038/s43018-022-00490-y
Cell Death Dis. 2023 Jan 18. 14(1): 35

SIRT6 is a key regulator of mitochondrial function in the brain.

Dmitrii Smirnov, Ekaterina Eremenko, Daniel Stein, Shai Kaluski, Weronika Jasinska, Claudia Cosentino, Barbara Martinez-Pastor, Yariv Brotman, Raul Mostoslavsky, Ekaterina Khrameeva, Debra Toiber.

The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it has critical roles in the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics and metabolomics approaches to characterize the functions of SIRT6 in mouse brains. Our analysis reveals that SIRT6 is a central regulator of mitochondrial activity in the brain. SIRT6 deficiency in the brain leads to mitochondrial deficiency with a global downregulation of mitochondria-related genes and pronounced changes in metabolite content. We suggest that SIRT6 affects mitochondrial functions through its interaction with the transcription factor YY1 that, together, regulate mitochondrial gene expression. Moreover, SIRT6 target genes include SIRT3 and SIRT4, which are significantly downregulated in SIRT6-deficient brains. Our results demonstrate that the lack of SIRT6 leads to decreased mitochondrial gene expression and metabolomic changes of TCA cycle byproducts, including increased ROS production, reduced mitochondrial number, and impaired membrane potential that can be partially rescued by restoring SIRT3 and SIRT4 levels. Importantly, the changes we observed in SIRT6-deficient brains are also occurring in aging human brains and particularly in patients with Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis disease. Overall, our results suggest that the reduced levels of SIRT6 in the aging brain and neurodegeneration initiate mitochondrial dysfunction by altering gene expression, ROS production, and mitochondrial decay.

DOI: https://doi.org/10.1038/s41419-022-05542-w
Nat Metab. 2023 Jan 16.

Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis.

Xu Xiao, John Paul Kennelly, Alessandra Ferrari, Bethan L Clifford, Emily Whang, Yajing Gao, Kevin Qian, Jaspreet Sandhu, Kelsey E Jarrett, Madelaine C Brearley-Sholto, Alexander Nguyen, Rohith T Nagari, Min Sub Lee, Sicheng Zhang, Thomas A Weston, Stephen G Young, Steven J Bensinger, Claudio J Villanueva, Thomas Q de Aguiar Vallim, Peter Tontonoz.

In cell models, changes in the 'accessible' pool of plasma membrane (PM) cholesterol are linked with the regulation of endoplasmic reticulum sterol synthesis and metabolism by the Aster family of nonvesicular transporters; however, the relevance of such nonvesicular transport mechanisms for lipid homeostasis in vivo has not been defined. Here we reveal two physiological contexts that generate accessible PM cholesterol and engage the Aster pathway in the liver: fasting and reverse cholesterol transport. During fasting, adipose-tissue-derived fatty acids activate hepatocyte sphingomyelinase to liberate sequestered PM cholesterol. Aster-dependent cholesterol transport during fasting facilitates cholesteryl ester formation, cholesterol movement into bile and very low-density lipoprotein production. During reverse cholesterol transport, high-density lipoprotein delivers excess cholesterol to the hepatocyte PM through scavenger receptor class B member 1. Loss of hepatic Asters impairs cholesterol movement into feces, raises plasma cholesterol levels and causes cholesterol accumulation in peripheral tissues. These results reveal fundamental mechanisms by which Aster cholesterol flux contributes to hepatic and systemic lipid homeostasis.

DOI: https://doi.org/10.1038/s42255-022-00722-6
Nat Commun. 2023 Jan 16. 14(1): 240

The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans.

Nan Wu, Yi-Cheng Ma, Xin-Qian Gong, Pei-Ji Zhao, Yong-Jian Jia, Qiu Zhao, Jia-Hong Duan, Cheng-Gang Zou.

Metabolism is intimately linked to aging. There is a growing number of studies showing that endogenous metabolites may delay aging and improve healthspan. Through the analysis of existing transcriptome data, we discover a link between activation of the transsulfuration pathway and a transcriptional program involved in peroxisome function and biogenesis in long-lived glp-1(e2141ts) mutant Caenorhabditis elegans worms. Subsequently, we show that supplementation with α-ketobutyrate, an intermediate of the transsulfuration pathway, extends lifespan in wild-type worms. Alpha-ketobutyrate augments the production of NAD+ via the lactate dehydrogenase LDH-1, leading to SIR-2.1/SIRT1-mediated enhanced peroxisome function and biogenesis, along with a concomitant increase in the expression of acox-1.2/ACOX1 in the peroxisomal fatty acid β-oxidation pathway. ACOX-1.2/ACOX1 promotes H2O2 formation, thereby resulting in activation of SKN-1/NRF2. This transcription factor in turn extends the lifespan of worms by driving expression of autophagic and lysosomal genes. Finally, we show that α-ketobutyrate also delays the cellular senescence in fibroblast cells through the SIRT1-ACOX1-H2O2-NRF2 pathway. This finding uncovers a previously unknown role for α-ketobutyrate in organismal lifespan and healthspan by coordinating the NAD+-SIRT1 signaling and peroxisomal function.

DOI: https://doi.org/10.1038/s41467-023-35899-1
Curr Opin Plant Biol. 2023 Jan 12. pii: S1369-5266(22)00162-5. [Epub ahead of print]73 102333

A bittersweet symphony: Metabolic signals in the circadian system.

Christopher R Buckley, Xiang Li, María Carmen Martí, Michael J Haydon.

  Plants must match their metabolism to daily and seasonal fluctuations in their environment to maximise performance in natural conditions. Circadian clocks enable organisms to anticipate and adapt to these predictable and unpredictable environmental challenges. Metabolism is increasingly recognised as an integrated feature of the plant circadian system. Metabolism is an important circadian-regulated output but also provides input to this dynamic timekeeping mechanism. The spatial organisation of metabolism within cells and between tissues, and the temporal features of metabolism across days, seasons and development, raise interesting questions about how metabolism influences circadian timekeeping. The various mechanisms by which metabolic signals influence the transcription-translation feedback loops of the circadian oscillator are emerging. These include roles for major metabolic signalling pathways, various retrograde signals, and direct metabolic modifications of clock genes or proteins. Such metabolic feedback loops enable intra- and intercellular coordination of rhythmic metabolism, and recent discoveries indicate these contribute to diverse aspects of daily, developmental and seasonal timekeeping.

Keywords:  Circadian; Development; Environment; Metabolism; Plants; Signalling

DOI:  https://doi.org/10.1016/j.pbi.2022.102333
Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2208176120

Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells.

Jerome Fortin, Ming-Feng Chiang, Cem Meydan, Jonathan Foox, Parameswaran Ramachandran, Julie Leca, François Lemonnier, Wanda Y Li, Miki S Gams, Takashi Sakamoto, Mandy Chu, Chantal Tobin, Eric Laugesen, Troy M Robinson, Annick You-Ten, Daniel J Butler, Thorsten Berger, Mark D Minden, Ross L Levine, Cynthia J Guidos, Ari M Melnick, Christopher E Mason, Tak W Mak.

  Mutations in IDH1, IDH2, and TET2 are recurrently observed in myeloid neoplasms. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1, IDH2, and TET2 mutations may converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have distinct, and even opposite, effects on hematopoietic stem and progenitor cells in genetically engineered mice. Epigenetic and single-cell transcriptomic analyses revealed that Idh2R172K and Tet2 loss-of-function have divergent consequences on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregulation in Idh2R172K cells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects of IDH1/2 and TET2 mutations, providing support for the optimization of genotype-specific therapies.

Keywords:  IDH; TET2; epigenetics; myeloid neoplasm

DOI:  https://doi.org/10.1073/pnas.2208176120
Cell Rep. 2023 Jan 19. pii: S2211-1247(23)00029-3. [Epub ahead of print]42(1): 112018

Neddylation is required for perinatal cardiac development through stimulation of metabolic maturation.

Jianqiu Zou, Wenjuan Wang, Yi Lu, Juan Ayala, Kunzhe Dong, Hongyi Zhou, Jinxi Wang, Weiqin Chen, Neal L Weintraub, Jiliang Zhou, Jie Li, Huabo Su.

  Cardiac maturation is crucial for postnatal cardiac development and is increasingly known to be regulated by a series of transcription factors. However, post-translational mechanisms regulating this process remain unclear. Here we report the indispensable role of neddylation in cardiac maturation. Mosaic deletion of NAE1, an essential enzyme for neddylation, in neonatal hearts results in the rapid development of cardiomyopathy and heart failure. NAE1 deficiency disrupts transverse tubule formation, inhibits physiological hypertrophy, and represses fetal-to-adult isoform switching, thus culminating in cardiomyocyte immaturation. Mechanistically, we find that neddylation is needed for the perinatal metabolic transition from glycolytic to oxidative metabolism in cardiomyocytes. Further, we show that HIF1α is a putative neddylation target and that inhibition of neddylation accumulates HIF1α and impairs fatty acid utilization and bioenergetics in cardiomyocytes. Together, our data show neddylation is required for cardiomyocyte maturation through promoting oxidative metabolism in the developing heart.

Keywords:  CP: Developmental biology; HIF1α; NAE1; cardiac maturation; metabolic transition; neddylation

DOI:  https://doi.org/10.1016/j.celrep.2023.112018
Nat Genet. 2023 Jan 19.

Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth.

Emilie Abby, Stefan C Dentro, Michael W J Hall, Joanna C Fowler, Swee Hoe Ong, Roshan Sood, Albert Herms, Gabriel Piedrafita, Irina Abnizova, Christian W Siebel, Moritz Gerstung, Benjamin A Hall, Philip H Jones.

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.

DOI: https://doi.org/10.1038/s41588-022-01280-z
JCI Insight. 2023 Jan 19. pii: e163820. [Epub ahead of print]

Hypoxia enhances IPF mesenchymal progenitor cell fibrogenicity via the lactate/GPR81/HIF1α pathway.

Libang Yang, Adam Gilbertsen, Hong Xia, Alexey Benyumov, Karen A Smith, Jeremy A Herrera, Emilian Racila, Peter B Bitterman, Craig A Henke.

  Hypoxia is a sentinel feature of IPF. The IPF microenvironment contains high lactate levels and hypoxia enhances cellular lactate production. Lactate, acting through the GPR81 lactate receptor, serves as a signal molecule regulating cellular processes. We previously identified intrinsically fibrogenic mesenchymal progenitor cells (MPCs) in the lungs of IPF patients that drive fibrosis. However, whether hypoxia enhances IPF MPC fibrogenicity is unclear. We hypothesized that hypoxia increases IPF MPC fibrogenicity via lactate and its cognate receptor GPR81. Here we show that hypoxia promotes IPF MPC self-renewal. The mechanism involves hypoxia-mediated enhancement of LDHA function and lactate production and release. Hypoxia also increases HIF1α levels, which in turn augments the expression of GPR81. Exogenous lactate operating through GPR81 promotes IPF MPC self-renewal. IHC analysis of IPF lung tissue demonstrate IPF MPCs expressing GPR81 and hypoxic markers on the periphery of the fibroblastic focus. We show that hypoxia enhances IPF MPC fibrogenicity in vivo. We demonstrate that knock-down of GPR81 inhibits hypoxia-induced IPF MPC self-renewal in vitro and attenuates hypoxia-induced IPF MPC fibrogenicity in vivo. Our data demonstrate that hypoxia creates a feed-forward loop that augments IPF MPC fibrogenicity via the lactate/GPR81/HIF1α pathway.

Keywords:  Adult stem cells; Hypoxia; Pulmonology; Stem cells

DOI:  https://doi.org/10.1172/jci.insight.163820
Cell Rep. 2023 Jan 19. pii: S2211-1247(23)00027-X. [Epub ahead of print]42(1): 112016

RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer.

Hong-Tao Li, H Josh Jang, Krizia Rohena-Rivera, Minmin Liu, Hemant Gujar, Justin Kulchycki, Shuqing Zhao, Sandrin Billet, Xinyi Zhou, Daniel J Weisenberger, Inderbir Gill, Peter A Jones, Neil A Bhowmick, Gangning Liang.

  Tumors with mutations in chromatin regulators present attractive targets for DNA hypomethylating agent 5-aza-2'-deoxycytidine (DAC) therapy, which further disrupts cancer cells' epigenomic fidelity and reactivates transposable element (TE) expression to drive viral mimicry responses. SETD2 encodes a histone methyltransferase (H3K36me3) and is prevalently mutated in advanced kidney cancers. Here, we show that SETD2-mutant kidney cancer cells are especially sensitive in vitro and in vivo to DAC treatment. We find that the viral mimicry response are direct consequences of mis-splicing events, such as exon inclusions or extensions, triggered by DAC treatment in an SETD2-loss context. Comprehensive epigenomic analysis reveals H3K9me3 deposition, rather than DNA methylation dynamics, across intronic TEs might contribute to elevated mis-splicing rates. Through epigenomic and transcriptomic analyses, we show that SETD2-deficient kidney cancers are prone to mis-splicing, which can be therapeutically exacerbated with DAC treatment to increase viral mimicry activation and provide synergy with combinatorial immunotherapy approaches.

Keywords:  CP: Cancer; DNMT inhibitors; RNA mis-splicing; SETD2; ccRCC; viral mimicry

DOI:  https://doi.org/10.1016/j.celrep.2023.112016
Cell Rep. 2023 Jan 19. pii: S2211-1247(23)00019-0. [Epub ahead of print]42(1): 112008

Gasdermin D pore-forming activity is redox-sensitive.

Pascal Devant, Elvira Boršić, Elsy M Ngwa, Haopeng Xiao, Edward T Chouchani, Jay R Thiagarajah, Iva Hafner-Bratkovič, Charles L Evavold, Jonathan C Kagan.

  Reactive oxygen species (ROS) regulate the activities of inflammasomes, which are innate immune signaling organelles that induce pyroptosis. The mechanisms by which ROS control inflammasome activities are unclear and may be multifaceted. Herein, we report that the protein gasdermin D (GSDMD), which forms membrane pores upon cleavage by inflammasome-associated caspases, is a direct target of ROS. Exogenous and endogenous sources of ROS, and ROS-inducing stimuli that prime cells for pyroptosis induction, promote oligomerization of cleaved GSDMD, leading to membrane rupture and cell death. We find that ROS enhance GSDMD activities through oxidative modification of cysteine 192 (C192). Within macrophages, GSDMD mutants lacking C192 show impaired ability to form membrane pores and induce pyroptosis. Reciprocal mutagenesis studies reveal that C192 is the only cysteine within GSDMD that mediates ROS responsiveness. Cellular redox state is therefore a key determinant of GSDMD activities.

Keywords:  CP: Immunology; Ragulator-Rag; cysteine oxidation; gasdermin D; pyroptosis; reactive oxygen species

DOI:  https://doi.org/10.1016/j.celrep.2023.112008
Cell. 2023 Jan 19. pii: S0092-8674(22)01528-8. [Epub ahead of print]186(2): 235-237

Coordinated cancer chaos.

Hendrik A Messal, Jacco van Rheenen.

Stochastic processes, such as genetic instability and microenvironment evolution, drive tumor heterogeneity, thereby creating the chaotic appearance of tumors in histopathology. In this issue of Cell, Lin et al. reveal that tumors are surprisingly spatially organized from a molecular to tissue scale, indicating that cancers evolve as autonomously patterned systems.

DOI: https://doi.org/10.1016/j.cell.2022.12.015
Nat Metab. 2023 Jan 19.

Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.

Z Oaks, A Patel, N Huang, G Choudhary, T Winans, T Faludi, D Krakko, M Duarte, J Lewis, M Beckford, S Blair, R Kelly, S K Landas, F A Middleton, J M Asara, S K Chung, Fernandez, K Banki, A Perl.

Oxidative stress modulates carcinogenesis in the liver; however, direct evidence for metabolic control of oxidative stress during pathogenesis, particularly, of progression from cirrhosis to hepatocellular carcinoma (HCC), has been lacking. Deficiency of transaldolase (TAL), a rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP), restricts growth and predisposes to cirrhosis and HCC in mice and humans. Here, we show that mitochondrial oxidative stress and progression from cirrhosis to HCC and acetaminophen-induced liver necrosis are critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Both TAL and AR are confined to the cytosol; however, their inactivation distorts mitochondrial redox homeostasis in opposite directions. The results suggest that AR acts as a rheostat of carbon recycling and NADPH output of the PPP with broad implications for disease progression from cirrhosis to HCC.

DOI: https://doi.org/10.1038/s42255-022-00711-9
Acta Physiol (Oxf). 2023 Jan 16. e13936

When should I eat: A circadian view on food intake and metabolic regulation.

Rodrigo Chamorro, Céline Jouffe, Henrik Oster, N Henriette Uhlenhaut, Sebastian M Meyhöfer.

  The circadian clock is a hierarchical timing system regulating most physiological and behavioral functions with a period of approximately 24 hours in humans and other mammalian species. The circadian clock drives daily eating rhythms that, in turn, reinforce the circadian clock network itself to anticipate and orchestrate metabolic responses to food intake. Eating is tightly interconnected with the circadian clock and recent evidence shows that the timing of meals is crucial for the control of appetite and metabolic regulation. Obesity results from combined long-term dysregulation in food intake (homeostatic and hedonic circuits), energy expenditure, and energy storage. Increasing evidence supports that the loss of synchrony of daily rhythms significantly impairs metabolic homeostasis and is associated with obesity. This review presents an overview of mechanisms regulating food intake (homeostatic/hedonic) and focuses on the crucial role of the circadian clock on the metabolic response to eating, thus providing a fundamental research axis to maintain a healthy eating behavior.

Keywords:  circadian misalignment; homeostatic/hedonic food intake; mammalian circadian clock; metabolism; obesity

DOI:  https://doi.org/10.1111/apha.13936
Nat Cell Biol. 2023 Jan 19.

START smuggling CoQ to fight ferroptosis.

Deguang Liang, Xuejun Jiang.

DOI: https://doi.org/10.1038/s41556-022-01044-1
Cell Res. 2023 Jan 16.

Fructose-1,6-bisphosphatase 1 dephosphorylates IκBα and suppresses colorectal tumorigenesis.

Wencheng Zhu, Huiying Chu, Yajuan Zhang, Tianhang Luo, Hua Yu, Hongwen Zhu, Ye Liu, Hong Gao, Yun Zhao, Quanlin Li, Xiongjun Wang, Guohui Li, Weiwei Yang.

Emerging evidence demonstrates that some metabolic enzymes that phosphorylate soluble metabolites can also phosphorylate a variety of protein substrates as protein kinases to regulate cell cycle, apoptosis and many other fundamental cellular processes. However, whether a metabolic enzyme dephosphorylates protein as a protein phosphatase remains unknown. Here we reveal the gluconeogenic enzyme fructose 1,6-biphosphatase 1 (FBP1) that catalyzes the hydrolysis of fructose 1,6-bisphosphate (F-1,6-BP) to fructose 6-phosphate (F-6-P) as a protein phosphatase by performing a high-throughput screening of metabolic phosphatases with molecular docking followed by molecular dynamics (MD) simulations. Moreover, we identify IκBα as the substrate of FBP1-mediated dephosphorylation by performing phosphoproteomic analysis. Mechanistically, FBP1 directly interacts with and dephosphorylates the serine (S) 32/36 of IκBα upon TNFα stimulation, thereby inhibiting NF-κB activation. MD simulations indicate that the catalytic mechanism of FBP1-mediated IκBα dephosphorylation is similar to F-1,6-BP dephosphorylation, except for higher energetic barriers for IκBα dephosphorylation. Functionally, FBP1-dependent NF-κB inactivation suppresses colorectal tumorigenesis by sensitizing tumor cells to inflammatory stresses and preventing the mobilization of myeloid-derived suppressor cells. Our finding reveals a previously unrecognized role of FBP1 as a protein phosphatase and establishes the critical role of FBP1-mediated IκBα dephosphorylation in colorectal tumorigenesis.

DOI: https://doi.org/10.1038/s41422-022-00773-0
Nat Commun. 2023 Jan 19. 14(1): 320

Sex-specificity of the C. elegans metabolome.

Russell N Burkhardt, Alexander B Artyukhin, Erin Z Aprison, Brian J Curtis, Bennett W Fox, Andreas H Ludewig, Diana Fajardo Palomino, Jintao Luo, Amaresh Chaturbedi, Oishika Panda, Chester J J Wrobel, Victor Baumann, Douglas S Portman, Siu Sylvia Lee, Ilya Ruvinsky, Frank C Schroeder.

Recent studies of animal metabolism have revealed large numbers of novel metabolites that are involved in all aspects of organismal biology, but it is unclear to what extent metabolomes differ between sexes. Here, using untargeted comparative metabolomics for the analysis of wildtype animals and sex determination mutants, we show that C. elegans hermaphrodites and males exhibit pervasive metabolomic differences. Several hundred small molecules are produced exclusively or in much larger amounts in one sex, including a host of previously unreported metabolites that incorporate building blocks from nucleoside, carbohydrate, lipid, and amino acid metabolism. A subset of male-enriched metabolites is specifically associated with the presence of a male germline, whereas enrichment of other compounds requires a male soma. Further, we show that one of the male germline-dependent metabolites, an unusual dipeptide incorporating N,N-dimethyltryptophan, increases food consumption, reduces lifespan, and accelerates the last stage of larval development in hermaphrodites. Our results serve as a foundation for mechanistic studies of how the genetic sex of soma and germline shape the C. elegans metabolome and provide a blueprint for the discovery of sex-dependent metabolites in other animals.

DOI: https://doi.org/10.1038/s41467-023-36040-y
Nat Med. 2023 Jan 19.

Time to hit pause on mitochondria-targeting cancer therapies.

Xue Zhang, Chi V Dang.

DOI: https://doi.org/10.1038/s41591-022-02129-y
Antioxidants (Basel). 2022 Dec 29. pii: 81. [Epub ahead of print]12(1):

Multi-Omics Approach Reveals Redox Homeostasis Reprogramming in Early-Stage Clear Cell Renal Cell Carcinoma.

Wei Zhang, Xinhua Qiao, Ting Xie, Wenbin Cai, Xu Zhang, Chang Chen, Yaoguang Zhang.

  Clear cell renal cell carcinoma (ccRCC) is a malignant tumor originating from proximal tubular epithelial cells, and despite extensive research efforts, its redox homeostasis characteristics and protein S-nitrosylation (or S-nitrosation) (SNO) modification remain largely undefined. This serves as a reminder that the aforementioned features demand a comprehensive inspection. We collected tumor samples and paracancerous normal samples from five patients with early-stage ccRCC (T1N0M0) for proteomic, SNO-proteome, and redox-targeted metabolic analyses. The localization and functional properties of SNO proteins in ccRCC tumors and paracancerous normal tissues were elucidated for the first time. Several highly useful ccRCC-associated SNO proteins were further identified. Metabolic reprogramming, redox homeostasis reprogramming, and tumorigenic alterations are the three major characteristics of early-stage ccRCC. Peroxidative damage caused by rapid proliferation coupled with an increased redox buffering capacity and the antioxidant pool is a major mode of redox homeostasis reprogramming. NADPH and NADP+, which were identified from redox species, are both effective biomarkers and promising therapeutic targets. According to our findings, SNO protein signatures and redox homeostasis reprogramming are valuable for understanding the pathogenesis of ccRCC and identifying novel topics that should be seriously considered for the diagnosis and precise therapy of ccRCC.

Keywords:  S-nitrosation; S-nitrosylation; clear cell renal cell carcinoma; metabolic reprogramming; multi-omics; proteomics; redox homeostasis

DOI:  https://doi.org/10.3390/antiox12010081