bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2021‒08‒08
forty-seven papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit


  1. Cell Rep. 2021 Aug 03. pii: S2211-1247(21)00905-0. [Epub ahead of print]36(5): 109478
      Oxidative stress is a ubiquitous cellular challenge implicated in aging, neurodegeneration, and cancer. By studying pathogenic mutations in the tumor suppressor BRCA2, we identify a general mechanism by which oxidative stress restricts mitochondrial (mt)DNA replication. BRCA2 inactivation induces R-loop accumulation in the mtDNA regulatory region and diminishes mtDNA replication initiation. In BRCA2-deficient cells, intracellular reactive oxygen species (ROS) are elevated, and ROS scavengers suppress the mtDNA defects. Conversely, wild-type cells exposed to oxidative stress by pharmacologic or genetic manipulation phenocopy these defects. Mechanistically, we find that 8-oxoguanine accumulation in mtDNA caused by oxidative stress suffices to impair recruitment of the mitochondrial enzyme RNaseH1 to sites of R-loop accrual, restricting mtDNA replication initiation. Thus, oxidative stress impairs RNaseH1 function to cripple mtDNA maintenance. Our findings highlight a molecular mechanism that links oxidative stress to mitochondrial dysfunction and is elicited by the inactivation of genes implicated in neurodegeneration and cancer.
    Keywords:  BRCA2; PRPF8; R-loops; RNaseH1; SETX; cancer; mitochondrial DNA replication; neurodegeneration; oxidative stress
    DOI:  https://doi.org/10.1016/j.celrep.2021.109478
  2. Mol Cell. 2021 Jul 27. pii: S1097-2765(21)00583-9. [Epub ahead of print]
      The emerging role of mitochondria as signaling organelles raises the question of whether individual mitochondria can initiate heterotypic communication with neighboring organelles. Using fluorescent probes targeted to the endoplasmic-reticulum-mitochondrial interface, we demonstrate that single mitochondria generate oxidative bursts, rapid redox oscillations, confined to the nanoscale environment of the interorganellar contact sites. Using probes fused to inositol 1,4,5-trisphosphate receptors (IP3Rs), we show that Ca2+ channels directly sense oxidative bursts and respond with Ca2+ transients adjacent to active mitochondria. Application of specific mitochondrial stressors or apoptotic stimuli dramatically increases the frequency and amplitude of the oxidative bursts by enhancing transient permeability transition pore openings. Conversely, blocking interface Ca2+ transport via elimination of IP3Rs or mitochondrial calcium uniporter channels suppresses ER-mitochondrial Ca2+ feedback and cell death. Thus, single mitochondria initiate local retrograde signaling by miniature oxidative bursts and, upon metabolic or apoptotic stress, may also amplify signals to the rest of the cell.
    Keywords:  Ca2+ microdomain; Inositol-1,4,5-trisphosphate receptor; Mitochondrial retrograde signaling; Organelle contacts; Redox nanodomain
    DOI:  https://doi.org/10.1016/j.molcel.2021.07.014
  3. Int J Mol Sci. 2021 Aug 02. pii: 8306. [Epub ahead of print]22(15):
      Mitochondria are energetic and dynamic organelles with a crucial role in bioenergetics, metabolism, and signaling. Mitochondrial proteins, encoded by both nuclear and mitochondrial DNA, must be properly regulated to ensure proteostasis. Mitochondrial protein quality control (MPQC) serves as a critical surveillance system, employing different pathways and regulators as cellular guardians to ensure mitochondrial protein quality and quantity. In this review, we describe key pathways and players in MPQC, such as mitochondrial protein translocation-associated degradation, mitochondrial stress responses, chaperones, and proteases, and how they work together to safeguard mitochondrial health and integrity. Deregulated MPQC leads to proteotoxicity and dysfunctional mitochondria, which contributes to numerous human diseases, including cancer. We discuss how alterations in MPQC components are linked to tumorigenesis, whether they act as drivers, suppressors, or both. Finally, we summarize recent advances that seek to target these alterations for the development of anti-cancer drugs.
    Keywords:  MPQC; cancer; chaperone; mitochondria; oncogene; protease; proteostasis; therapeutic targeting; tumor suppressor; tumorigenesis
    DOI:  https://doi.org/10.3390/ijms22158306
  4. EMBO Rep. 2021 Aug 05. e51991
      Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs-Zellweger spectrum disorder (ZSD)-is caused by mutations in peroxin genes that result in both non-functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter-organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.
    Keywords:  mitochondria; mitochondrial quality control; peroxisomal biogenesis disorder; peroxisomal import; peroxisomes
    DOI:  https://doi.org/10.15252/embr.202051991
  5. Proc Natl Acad Sci U S A. 2021 Aug 10. pii: e2101675118. [Epub ahead of print]118(32):
      Viruses modulate mitochondrial processes during infection to increase biosynthetic precursors and energy output, fueling virus replication. In a surprising fashion, although it triggers mitochondrial fragmentation, the prevalent pathogen human cytomegalovirus (HCMV) increases mitochondrial metabolism through a yet-unknown mechanism. Here, we integrate molecular virology, metabolic assays, quantitative proteomics, and superresolution confocal microscopy to define this mechanism. We establish that the previously uncharacterized viral protein pUL13 is required for productive HCMV replication, targets the mitochondria, and functions to increase oxidative phosphorylation during infection. We demonstrate that pUL13 forms temporally tuned interactions with the mitochondrial contact site and cristae organizing system (MICOS) complex, a critical regulator of cristae architecture and electron transport chain (ETC) function. Stimulated emission depletion superresolution microscopy shows that expression of pUL13 alters cristae architecture. Indeed, using live-cell Seahorse assays, we establish that pUL13 alone is sufficient to increase cellular respiration, not requiring the presence of other viral proteins. Our findings address the outstanding question of how HCMV targets mitochondria to increase bioenergetic output and expands the knowledge of the intricate connection between mitochondrial architecture and ETC function.
    Keywords:  HCMV; metabolism; mitochondria; pUL13; proteomics
    DOI:  https://doi.org/10.1073/pnas.2101675118
  6. Cell Metab. 2021 Aug 03. pii: S1550-4131(21)00328-4. [Epub ahead of print]33(8): 1505-1506
      In a new study, Zhang et al. (2021) show that reducing iron levels in adipose tissue improves metabolic function. This occurs through an interorgan communication system where signals from the adipocyte reduce intestinal lipid absorption.
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.012
  7. Development. 2021 Aug 06. pii: dev.199686. [Epub ahead of print]
      Male germline development involves choreographed changes to mitochondrial number, morphology, and organization. Mitochondrial reorganization during spermatogenesis was recently shown to require mitochondrial fusion and fission. Mitophagy, the autophagic degradation of mitochondria, is another mechanism for controlling mitochondrial number and physiology, but its role during spermatogenesis is largely unknown. During post-meiotic spermatid development, restructuring of the mitochondrial network results in packing of mitochondria into a tight array in the sperm midpiece to fuel motility. Here, we show that disruption of mouse Fis1 in the male germline results in early spermatid arrest that is associated with increased mitochondrial content. Mutant spermatids coalesce into multinucleated giant cells (GCs) that accumulate mitochondria of aberrant ultrastructure and numerous mitophagic and autophagic intermediates, suggesting a defect in mitophagy. We conclude that Fis1 regulates mitochondrial morphology and turnover to promote spermatid maturation.
    Keywords:  Autophagy; Mitochondrial dynamics; Mitophagy; Spermatid; Spermatogenesis
    DOI:  https://doi.org/10.1242/dev.199686
  8. Nat Protoc. 2021 Aug 04.
      T cells are integral players in the adaptive immune system that readily adapt their metabolism to meet their energetic and biosynthetic needs. A major hurdle to understand physiologic T-cell metabolism has been the differences between in vitro cell culture conditions and the complex in vivo milieu. To address this, we have developed a protocol that merges traditional immunology infection models with whole-body metabolite infusion and mass-spectrometry-based metabolomic profiling to assess T-cell metabolism in vivo. In this protocol, pathogen-infected mice are infused via the tail vein with an isotopically labeled metabolite (2-6 h), followed by rapid magnetic bead isolation to purify T-cell populations (<1 h) and then stable isotope labeling analysis conducted by mass spectrometry (~1-2 d). This procedure enables researchers to evaluate metabolic substrate utilization into central carbon metabolic pathways (i.e., glycolysis and the tricarboxylic acid cycle) by specific T-cell subpopulations in the context of physiological immune responses in vivo.
    DOI:  https://doi.org/10.1038/s41596-021-00586-2
  9. Biol Chem. 2021 Jul 30.
      Hepatic encephalopathy (HE) is a well-studied, neurological syndrome caused by liver dysfunctions. Ammonia, the major toxin during HE pathogenesis, impairs many cellular processes within astrocytes. Yet, the molecular mechanisms causing HE are not fully understood. Here we will recapitulate possible underlying mechanisms with a clear focus on studies revealing a link between altered energy metabolism and HE in cellular models and in vivo. The role of the mitochondrial glutamate dehydrogenase and its role in metabolic rewiring of the TCA cycle will be discussed. We propose an updated model of ammonia-induced toxicity that may also be exploited for therapeutic strategies in the future.
    Keywords:  TCA cycle; autophagy; glutamine metabolism; hepatic encephalopathy; hyperammonemia; mitochondrial dysfunction
    DOI:  https://doi.org/10.1515/hsz-2021-0172
  10. Int J Mol Sci. 2021 Aug 02. pii: 8312. [Epub ahead of print]22(15):
      Mitochondria are complex intracellular organelles traditionally identified as the powerhouses of eukaryotic cells due to their central role in bioenergetic metabolism. In recent decades, the growing interest in mitochondria research has revealed that these multifunctional organelles are more than just the cell powerhouses, playing many other key roles as signaling platforms that regulate cell metabolism, proliferation, death and immunological response. As key regulators, mitochondria, when dysfunctional, are involved in the pathogenesis of a wide range of metabolic, neurodegenerative, immune and neoplastic disorders. Far more recently, mitochondria attracted renewed attention from the scientific community for their ability of intercellular translocation that can involve whole mitochondria, mitochondrial genome or other mitochondrial components. The intercellular transport of mitochondria, defined as horizontal mitochondrial transfer, can occur in mammalian cells both in vitro and in vivo, and in physiological and pathological conditions. Mitochondrial transfer can provide an exogenous mitochondrial source, replenishing dysfunctional mitochondria, thereby improving mitochondrial faults or, as in in the case of tumor cells, changing their functional skills and response to chemotherapy. In this review, we will provide an overview of the state of the art of the up-to-date knowledge on intercellular trafficking of mitochondria by discussing its biological relevance, mode and mechanisms underlying the process and its involvement in different pathophysiological contexts, highlighting its therapeutic potential for diseases with mitochondrial dysfunction primarily involved in their pathogenesis.
    Keywords:  bioenergetics; cancer; ccf-mtDNA; extracellular mitochondria; extracellular mitovesicles; immune-metabolic regulation; intercellular mitochondria trafficking; mitochondria; mitochondrial transplantation; neurodegenerative diseases; neurodevelopmental disorders; oxidative phosphorylation; tunneling nanotubes
    DOI:  https://doi.org/10.3390/ijms22158312
  11. Cell Metab. 2021 Aug 03. pii: S1550-4131(21)00327-2. [Epub ahead of print]33(8): 1507-1509
      Lipid metabolism is altered in the acidic tumor microenvironment. Here, the authors show that polyunsaturated fatty acid supplementation, together with concomitant inhibition of lipid droplet biogenesis, induces ferroptosis in acidic cancer cells. These findings highlight the potential to exploit cancer dependence on exogenous lipids as a therapeutic vulnerability.
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.011
  12. Cell Metab. 2021 Jul 27. pii: S1550-4131(21)00324-7. [Epub ahead of print]
      Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance.
    Keywords:  OPA-1; POMC neurons; cristae; hypothalamus; lipolysis; mitochondria; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.008
  13. Cell. 2021 Aug 05. pii: S0092-8674(21)00857-6. [Epub ahead of print]184(16): 4348-4371.e40
      Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.
    Keywords:  CPTAC; acetylation; genomics; lung cancer; phosphorylation; protein; proteogenomics; proteomics; squamous; ubiquitylation
    DOI:  https://doi.org/10.1016/j.cell.2021.07.016
  14. J Biol Chem. 2021 Jul 30. pii: S0021-9258(21)00834-6. [Epub ahead of print] 101032
      The progression of cancer involves not only the gradual evolution of cells by mutations in DNA but also alterations in the gene expression induced by those mutations and input from the surrounding microenvironment. Such alterations contribute to cancer cells' abilities to reprogram metabolic pathways and to undergo epithelial-to-mesenchymal transition (EMT), which facilitate the survival of cancer cells and their metastasis to other organs. Recently, BACH1 (BTB and CNC homology 1), a heme-regulated transcription factor that represses genes involved in iron- and heme-metabolism in normal cells, was shown to shape the metabolism and metastatic potential of cancer cells. The growing list of BACH1 target genes in cancer cells reveals that BACH1 promotes metastasis by regulating various sets of genes beyond iron metabolism. BACH1 represses the expression of genes that mediate cell-cell adhesion and oxidative phosphorylation, but activates the expression of genes required for glycolysis, cell motility, and matrix protein degradation. Furthermore, BACH1 represses FOXA1 gene encoding an activator of epithelial genes and activates SNAI2 encoding a repressor of epithelial genes, forming a feed-forward loop of EMT. By synthesizing these observations, we propose a "two-faced BACH1 model", which accounts for the dynamic switching between metastasis and stress-resistance along with cancer progression. We discuss here the possibility that BACH1-mediated promotion of cancer also brings increased sensitivity to iron-dependent cell death (ferroptosis) through crosstalk of BACH1 target genes, imposing programmed vulnerability upon cancer cells. We also discuss the future directions of this field, including the dynamics and plasticity of EMT.
    Keywords:  BACH1; NRF2; cancer; epithelial-mesenchymal transition; ferroptosis; glycolysis; heme; iron; metastasis; transcription factor
    DOI:  https://doi.org/10.1016/j.jbc.2021.101032
  15. Cell Metab. 2021 Jul 30. pii: S1550-4131(21)00331-4. [Epub ahead of print]
      Exercise is a powerful driver of physiological angiogenesis during adulthood, but the mechanisms of exercise-induced vascular expansion are poorly understood. We explored endothelial heterogeneity in skeletal muscle and identified two capillary muscle endothelial cell (mEC) populations that are characterized by differential expression of ATF3/4. Spatial mapping showed that ATF3/4+ mECs are enriched in red oxidative muscle areas while ATF3/4low ECs lie adjacent to white glycolytic fibers. In vitro and in vivo experiments revealed that red ATF3/4+ mECs are more angiogenic when compared with white ATF3/4low mECs. Mechanistically, ATF3/4 in mECs control genes involved in amino acid uptake and metabolism and metabolically prime red (ATF3/4+) mECs for angiogenesis. As a consequence, supplementation of non-essential amino acids and overexpression of ATF4 increased proliferation of white mECs. Finally, deleting Atf4 in ECs impaired exercise-induced angiogenesis. Our findings illustrate that spatial metabolic angiodiversity determines the angiogenic potential of muscle ECs.
    Keywords:  amino acid metabolism; endothelial heterogeneity; endothelial metabolism; exercise; muscle angiogenesis; single-cell RNA-seq
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.015
  16. Nat Cell Biol. 2021 Aug 02.
      Metastasis is the leading cause of cancer-related deaths and enables cancer cells to compromise organ function by expanding in secondary sites. Since primary tumours and metastases often share the same constellation of driver mutations, the mechanisms that drive their distinct phenotypes are unclear. Here we show that inactivation of the frequently mutated tumour suppressor gene LKB1 (encoding liver kinase B1) has evolving effects throughout the progression of lung cancer, which leads to the differential epigenetic re-programming of early-stage primary tumours compared with late-stage metastases. By integrating genome-scale CRISPR-Cas9 screening with bulk and single-cell multi-omic analyses, we unexpectedly identify LKB1 as a master regulator of chromatin accessibility in lung adenocarcinoma primary tumours. Using an in vivo model of metastatic progression, we further show that loss of LKB1 activates the early endoderm transcription factor SOX17 in metastases and a metastatic-like sub-population of cancer cells within primary tumours. The expression of SOX17 is necessary and sufficient to drive a second wave of epigenetic changes in LKB1-deficient cells that enhances metastatic ability. Overall, our study demonstrates how the downstream effects of an individual driver mutation can change throughout cancer development, with implications for stage-specific therapeutic resistance mechanisms and the gene regulatory underpinnings of metastatic evolution.
    DOI:  https://doi.org/10.1038/s41556-021-00728-4
  17. Biochim Biophys Acta Biomembr. 2021 Jul 31. pii: S0005-2736(21)00164-4. [Epub ahead of print] 183716
      Mitochondrial outer membrane permeabilization (MOMP) is a key checkpoint in apoptosis that activates the caspase cascade and irreversibly causes the majority of cells to die. The proteins of the Bcl-2 family are master regulators of apoptosis that form a complex interaction network within the mitochondrial membrane that determines the induction of MOMP. This culminates in the activation of the effector members Bax and Bak, which permeabilize the mitochondrial outer membrane to mediate MOMP. Although the key role of Bax and Bak has been established, many questions remain unresolved regarding molecular mechanisms that control the apoptotic pore. In this review, we discuss the recent progress in our understanding of the regulation of Bax/Bak activity within the mitochondrial membrane.
    Keywords:  Apoptosis; BCL-2 proteins; Lipids; MOMP; Membrane dynamics; Protein-protein interaction
    DOI:  https://doi.org/10.1016/j.bbamem.2021.183716
  18. Redox Biol. 2021 Jul 26. pii: S2213-2317(21)00241-X. [Epub ahead of print]46 102082
      Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to chronically compromising lung function and death. However, very little is known about the metabolic alterations of fibroblasts in IPF, and there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Here we show a glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts from fibrotic lung, and perturbation of glycolysis and FAO affects fibroblasts transdifferentiation. In addition, there is a significant accumulation of succinate both in fibrotic lung tissues and myofibroblasts, where succinate dehydrogenase (SDH) operates in reverse by reducing fumarate to succinate. Then succinate contributes to glycolysis upregulation and FAO downregulation by stabilizing HIF-1α, which promotes the development of lung fibrosis. In addition, we identify a near-infrared small molecule dye, IR-780, as a targeting agent which stimulates mild inhibition of succinate dehydrogenase subunit A (SDHA) in fibroblasts, and which inhibits TGF-β1 induced SDH and succinate elevation, then to prevent fibrosis formation and respiratory dysfunction. Further, enhanced cell retention of IR-780 is shown to promote severe inhibition of SDHA in myofibroblasts, which may contribute to excessive ROS generation and selectively induces myofibroblasts to apoptosis, and then therapeutically improves established lung fibrosis in vivo. These findings indicate that targeting metabolic dysregulation has significant implications for therapies aimed at lung fibrosis and succinate dehydrogenase is an exciting new therapeutic target to treat IPF.
    Keywords:  IR-780; Idiopathic pulmonary fibrosis; Metabolic dysregulation; Succinate; Succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.redox.2021.102082
  19. Cell Calcium. 2021 Jul 27. pii: S0143-4160(21)00105-6. [Epub ahead of print]98 102451
      Nakamura et al. recently discovered that the mitochondrial calcium uniporter gatekeeper, MICU1, is required for cold-induced ferroptotic cell death by modulating mitochondrial membrane potential. This function appears to be independent of its Ca2+-sensing ability. Here, we discuss their findings and suggest next steps to define MICU1's role in ferroptotic cell death.
    DOI:  https://doi.org/10.1016/j.ceca.2021.102451
  20. Cell Rep. 2021 Aug 03. pii: S2211-1247(21)00914-1. [Epub ahead of print]36(5): 109487
      Ketone bodies are bioactive metabolites that function as energy substrates, signaling molecules, and regulators of histone modifications. β-hydroxybutyrate (β-OHB) is utilized in lysine β-hydroxybutyrylation (Kbhb) of histones, and associates with starvation-responsive genes, effectively coupling ketogenic metabolism with gene expression. The emerging diversity of the lysine acylation landscape prompted us to investigate the full proteomic impact of Kbhb. Global protein Kbhb is induced in a tissue-specific manner by a variety of interventions that evoke β-OHB. Mass spectrometry analysis of the β-hydroxybutyrylome in mouse liver revealed 891 sites of Kbhb within 267 proteins enriched for fatty acid, amino acid, detoxification, and one-carbon metabolic pathways. Kbhb inhibits S-adenosyl-L-homocysteine hydrolase (AHCY), a rate-limiting enzyme of the methionine cycle, in parallel with altered metabolite levels. Our results illuminate the role of Kbhb in hepatic metabolism under ketogenic conditions and demonstrate a functional consequence of this modification on a central metabolic enzyme.
    Keywords:  AHCY; S-adenosyl-L-homocysteine hydrolase; ketogenesis; ketogenic diet; liver metabolism; lysine acylation; methionine cycle; β-hydroxybutyrate; β-hydroxybutyrylation
    DOI:  https://doi.org/10.1016/j.celrep.2021.109487
  21. Cell Metab. 2021 Aug 03. pii: S1550-4131(21)00322-3. [Epub ahead of print]33(8): 1546-1564
      The brain has almost no energy reserve, but its activity coordinates organismal function, a burden that requires precise coupling between neurotransmission and energy metabolism. Deciphering how the brain accomplishes this complex task is crucial to understand central facets of human physiology and disease mechanisms. Each type of neural cell displays a peculiar metabolic signature, forcing the intercellular exchange of metabolites that serve as both energy precursors and paracrine signals. The paradigm of this biological feature is the astrocyte-neuron couple, in which the glycolytic metabolism of astrocytes contrasts with the mitochondrial oxidative activity of neurons. Astrocytes generate abundant mitochondrial reactive oxygen species and shuttle to neurons glycolytically derived metabolites, such as L-lactate and L-serine, which sustain energy needs, conserve redox status, and modulate neurotransmitter-receptor activity. Conversely, early disruption of this metabolic cooperation may contribute to the initiation or progression of several neurological diseases, thus requiring innovative therapies to preserve brain energetics.
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.006
  22. Cell Metab. 2021 Aug 03. pii: S1550-4131(21)00320-X. [Epub ahead of print]33(8): 1509-1511
      The tumor microenvironment is immunosuppressive. Here we preview two recent studies from Ma et al. (2021) in Cell Metabolism and Xu et al. (2021) in Immunity that describe a key role of T cell-expressed CD36 in enhancing lipid uptake and mediating lipid peroxidation that ultimately leads to CD8+ T cell dysfunction, ferroptosis, and reduced anti-tumor function.
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.004
  23. Biomedicines. 2021 Jul 10. pii: 799. [Epub ahead of print]9(7):
      Discovery of point mutations in the genes encoding isocitrate dehydrogenases (IDH) in gliomas about a decade ago has challenged our view of the role of metabolism in tumor progression and provided a new stratification strategy for malignant gliomas. IDH enzymes catalyze the conversion of isocitrate to alpha-ketoglutarate (α-KG), an intermediate in the citric acid cycle. Specific mutations in the genes encoding IDHs cause neomorphic enzymatic activity that produces D-2-hydroxyglutarate (2-HG) and result in the inhibition of α-KG-dependent enzymes such as histone and DNA demethylases. Thus, chromatin structure and gene expression profiles in IDH-mutant gliomas appear to be different from those in IDH-wildtype gliomas. IDH mutations are highly common in lower grade gliomas (LGG) and secondary glioblastomas, and they are among the earliest genetic events driving tumorigenesis. Therefore, inhibition of mutant IDH enzymes in LGGs is widely accepted as an attractive therapeutic strategy. On the other hand, the metabolic consequences derived from IDH mutations lead to selective vulnerabilities within tumor cells, making them more sensitive to several therapeutic interventions. Therefore, instead of shutting down mutant IDH enzymes, exploiting the selective vulnerabilities caused by them might be another attractive and promising strategy. Here, we review therapeutic options and summarize current preclinical and clinical studies on IDH-mutant gliomas.
    Keywords:  clinical trials; glioblastoma; glioma; isocitrate dehydrogenase (IDH); mutations; therapeutics
    DOI:  https://doi.org/10.3390/biomedicines9070799
  24. Front Physiol. 2021 ;12 715485
      The mitochondria of the proximal tubule are essential for providing energy in this nephron segment, whose ATP generation is almost exclusively oxygen dependent. In addition, mitochondria are involved in a variety of metabolic processes and complex signaling networks. Proximal tubular mitochondrial dysfunction can therefore affect renal function in very different ways. Two autosomal dominantly inherited forms of renal Fanconi syndrome illustrate how multifaceted mitochondrial pathology can be: Mutation of EHHADH, an enzyme in fatty acid metabolism, results in decreased ATP synthesis and a consecutive transport defect. In contrast, mutations of GATM, an enzyme in the creatine biosynthetic pathway, leave ATP synthesis unaffected but do lead to mitochondrial protein aggregates, inflammasome activation, and renal fibrosis with progressive renal failure. In this review article, the distinct pathophysiological mechanisms of these two diseases are presented, which are examples of the spectrum of proximal tubular mitochondrial diseases.
    Keywords:  autosomal dominant mutation; inflammasome; mitochondrial damage associated molecular patterns; peroxisome; protein aggregates; renal fibrosis
    DOI:  https://doi.org/10.3389/fphys.2021.715485
  25. Proc Natl Acad Sci U S A. 2021 Aug 10. pii: e2110344118. [Epub ahead of print]118(32):
      The increasing complexity of different cell types revealed by single-cell analysis of tissues presents challenges in efficiently elucidating their functions. Here we show, using prostate as a model tissue, that primary organoids and freshly isolated epithelial cells can be CRISPR edited ex vivo using Cas9-sgRNA (guide RNA) ribotnucleoprotein complex technology, then orthotopically transferred in vivo into immunocompetent or immunodeficient mice to generate cancer models with phenotypes resembling those seen in traditional genetically engineered mouse models. Large intrachromosomal (∼2 Mb) or multigenic deletions can be engineered efficiently without the need for selection, including in isolated subpopulations to address cell-of-origin questions.
    Keywords:  CRISPR; cancer modeling; editing; organoids
    DOI:  https://doi.org/10.1073/pnas.2110344118
  26. EMBO Rep. 2021 Aug 02. e53086
      Mitochondria are dynamic organelles whose architecture changes depending on the cell's energy requirements and other signalling events. These structural changes are collectively known as mitochondrial dynamics. Mitochondrial dynamics are crucial for cellular functions such as differentiation, energy production and cell death. Importantly, it has become clear in recent years that mitochondrial dynamics are a critical control point for immune cell function. Mitochondrial remodelling allows quiescent immune cells to rapidly change their metabolism and become activated, producing mediators, such as cytokines, chemokines and even metabolites to execute an effective immune response. The importance of mitochondrial dynamics in immunity is evident, as numerous pathogens have evolved mechanisms to manipulate host cell mitochondrial remodelling in order to promote their own survival. In this review, we comprehensively address the roles of mitochondrial dynamics in immune cell function, along with modulation of host cell mitochondrial morphology during viral and bacterial infections to facilitate either pathogen survival or host immunity. We also speculate on what the future may hold in terms of therapies targeting mitochondrial morphology for bacterial and viral control.
    Keywords:  bacteria; immune response; mitochondrial dynamics; therapy; virus
    DOI:  https://doi.org/10.15252/embr.202153086
  27. Cell. 2021 Aug 05. pii: S0092-8674(21)00838-2. [Epub ahead of print]184(16): 4109-4112
      Interplay between metabolic and epigenetic remodeling may be key to cell fate control. In this issue of Cell, Puleston et al. and Wagner et al. use metabolomic, computational, and genetic approaches to uncover that polyamine metabolism directs T helper cell lineage choices, epigenetic state, and pathogenic potential in inflammation.
    DOI:  https://doi.org/10.1016/j.cell.2021.07.012
  28. J Clin Pathol. 2021 Aug 05. pii: jclinpath-2021-207830. [Epub ahead of print]
      Fumarate hydratase (FH), encoded by the FH gene, is an enzyme which catalyses the conversion of fumarate to L-malate as part of the tricarboxylic acid cycle. Biallelic germline mutations in FH result in fumaric aciduria, a metabolic disorder resulting in severe neurological and developmental abnormalities. Heterozygous germline mutations in FH result in hereditary leiomyomatosis and renal cell carcinoma, a cancer predisposition syndrome. FH deficiency has multiple oncogenic mechanisms including through promotion of aerobic glycolysis, induction of pseudohypoxia, post-translational protein modification and impairment of DNA damage repair by homologous recombination. FH-deficient neoplasms can present with characteristic morphological features that raise suspicion for FH alterations and also frequently demonstrate loss of FH immunoreactivity and intracellular accumulation of 2-succinocysteine, also detected by immunohistochemistry.
    Keywords:  genetics; hereditary; neoplastic syndromes; oncogenes
    DOI:  https://doi.org/10.1136/jclinpath-2021-207830
  29. Cancers (Basel). 2021 Jul 27. pii: 3769. [Epub ahead of print]13(15):
      Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors derived from neural crest cells. Germline variants in approximately 20 PHEO/PGL susceptibility genes are found in about 40% of patients, half of which are found in the genes that encode succinate dehydrogenase (SDH). Patients with SDH subunit B (SDHB)-mutated PHEO/PGL exhibit a higher likelihood of developing metastatic disease, which can be partially explained by the metabolic cell reprogramming and redox imbalance caused by the mutation. Reactive oxygen species (ROS) are highly reactive molecules involved in a multitude of important signaling pathways. A moderate level of ROS production can help regulate cellular physiology; however, an excessive level of oxidative stress can lead to tumorigenic processes including stimulation of growth factor-dependent pathways and the induction of genetic instability. Tumor cells effectively exploit antioxidant enzymes in order to protect themselves against harmful intracellular ROS accumulation, which highlights the essential balance between ROS production and scavenging. Exploiting ROS accumulation can be used as a possible therapeutic strategy in ROS-scavenging tumor cells. Here, we focus on the role of ROS production in PHEO and PGL, predominantly in SDHB-mutated cases. We discuss potential strategies and approaches to anticancer therapies by enhancing ROS production in these difficult-to-treat tumors.
    Keywords:  metastatic pheochromocytoma; paraganglioma; reactive oxygen species; succinate dehydrogenase
    DOI:  https://doi.org/10.3390/cancers13153769
  30. J Clin Invest. 2021 Aug 02. pii: 148276. [Epub ahead of print]131(15):
      Circadian rhythm evolved to allow organisms to coordinate intrinsic physiological functions in anticipation of recurring environmental changes. The importance of this coordination is exemplified by the tight temporal control of cardiac metabolism. Levels of metabolites, metabolic flux, and response to nutrients all oscillate in a time-of-day-dependent fashion. While these rhythms are affected by oscillatory behavior (feeding/fasting, wake/sleep) and neurohormonal changes, recent data have unequivocally demonstrated an intrinsic circadian regulation at the tissue and cellular level. The circadian clock - through a network of a core clock, slave clock, and effectors - exerts intricate temporal control of cardiac metabolism, which is also integrated with environmental cues. The combined anticipation and adaptability that the circadian clock enables provide maximum advantage to cardiac function. Disruption of the circadian rhythm, or dyssynchrony, leads to cardiometabolic disorders seen not only in shift workers but in most individuals in modern society. In this Review, we describe current findings on rhythmic cardiac metabolism and discuss the intricate regulation of circadian rhythm and the consequences of rhythm disruption. An in-depth understanding of the circadian biology in cardiac metabolism is critical in translating preclinical findings from nocturnal-animal models as well as in developing novel chronotherapeutic strategies.
    DOI:  https://doi.org/10.1172/JCI148276
  31. Dis Model Mech. 2021 Aug 01. pii: dmm048993. [Epub ahead of print]14(8):
      An uninterrupted energy supply is critical for the optimal functioning of all our organs, and in this regard the human brain is particularly energy dependent. The study of energy metabolic pathways is a major focus within neuroscience research, which is supported by genetic defects in the oxidative phosphorylation mechanism often contributing towards neurodevelopmental disorders and changes in glucose metabolism presenting as a hallmark feature in age-dependent neurodegenerative disorders. However, as recent studies have illuminated roles of cellular metabolism that span far beyond mere energetics, it would be valuable to first comprehend the physiological involvement of metabolic pathways in neural cell fate and function, and to subsequently reconstruct their impact on diseases of the brain. In this Review, we first discuss recent evidence that implies metabolism as a master regulator of cell identity during neural development. Additionally, we examine the cell type-dependent metabolic states present in the adult brain. As metabolic states have been studied extensively as crucial regulators of malignant transformation in cancer, we reveal how knowledge gained from the field of cancer has aided our understanding in how metabolism likewise controls neural fate determination and stability by directly wiring into the cellular epigenetic landscape. We further summarize research pertaining to the interplay between metabolic alterations and neurodevelopmental and psychiatric disorders, and expose how an improved understanding of metabolic cell fate control might assist in the development of new concepts to combat age-dependent neurodegenerative diseases, particularly Alzheimer's disease.
    Keywords:  Brain aging; Epigenetics; Metabolic state; Neural development; Psychiatric disorder
    DOI:  https://doi.org/10.1242/dmm.048993
  32. Proc Natl Acad Sci U S A. 2021 Aug 10. pii: e2101498118. [Epub ahead of print]118(32):
      Trimethylamine (TMA) is an important gut microbial metabolite strongly associated with human disease. There are prominent gaps in our understanding of how TMA is produced from the essential dietary nutrient l-carnitine, particularly in the anoxic environment of the human gut where oxygen-dependent l-carnitine-metabolizing enzymes are likely inactive. Here, we elucidate the chemical and genetic basis for anaerobic TMA generation from the l-carnitine-derived metabolite γ-butyrobetaine (γbb) by the human gut bacterium Emergencia timonensis We identify a set of genes up-regulated by γbb and demonstrate that the enzymes encoded by the induced γbb utilization (bbu) gene cluster convert γbb to TMA. The key TMA-generating step is catalyzed by a previously unknown type of TMA-lyase enzyme that utilizes a putative flavin cofactor to catalyze a redox-neutral transformation. We identify additional cultured and uncultured host-associated bacteria that possess the bbu gene cluster, providing insights into the distribution of anaerobic γbb metabolism. Lastly, we present genetic, transcriptional, and metabolomic evidence that confirms the relevance of this metabolic pathway in the human gut microbiota. These analyses indicate that the anaerobic pathway is a more substantial contributor to TMA generation from l-carnitine in the human gut than the previously proposed aerobic pathway. The discovery and characterization of the bbu pathway provides the critical missing link in anaerobic metabolism of l-carnitine to TMA, enabling investigation into the connection between this microbial function and human disease.
    Keywords:  l-carnitine; microbiota; trimethylamine
    DOI:  https://doi.org/10.1073/pnas.2101498118
  33. Nat Cell Biol. 2021 Aug 02.
      The memory of stresses experienced by parents can be passed on to descendants as a forecast of the challenges to come. Here, we discovered that the neuronal mitochondrial perturbation-induced systemic mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans can be transmitted to offspring over multiple generations. The transgenerational activation of UPRmt is mediated by maternal inheritance of elevated levels of mitochondrial DNA (mtDNA), which causes the proteostasis stress within mitochondria. Furthermore, results from intercrossing studies using wild C. elegans strains further support that maternal inheritance of higher levels of mtDNA can induce the UPRmt in descendants. The mitokine Wnt signalling pathway is required for the transmission of elevated mtDNA levels across generations, thereby conferring lifespan extension and stress resistance to offspring. Collectively, our results reveal that the nervous system can transmit stress signals across generations by increasing mtDNA in the germline, enabling descendants to better cope with anticipated challenges.
    DOI:  https://doi.org/10.1038/s41556-021-00724-8
  34. Int J Mol Sci. 2021 Aug 03. pii: 8325. [Epub ahead of print]22(15):
      Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding details to the mitochondrial proteome and defining novel metabolic cellular interrelations, especially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition such as 'mitoexome', 'mitoproteome' and 'mitointeractome' have entered the field of 'mitochondrial medicine'. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism, mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic origin of the OxPhos complexes is one of the reasons for the complexity of the genotype-phenotype correlation when facing human diseases associated with mitochondrial defects. Such complexity clinically manifests with extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the future directions of the multi-omics study of human brain disorders.
    Keywords:  OxPhos complexes; bioenergetics; genomics; mitochondria; mitochondrial DNA; mitochondrial diseases; nervous tissue; proteomics
    DOI:  https://doi.org/10.3390/ijms22158325
  35. Elife. 2021 Aug 03. pii: e59828. [Epub ahead of print]10
      Poly(ADP-ribose) polymerase (PARP) enzymes initiate (mt)DNA repair mechanisms and use nicotinamide adenine dinucleotide (NAD+) as energy source. Prolonged PARP activity can drain cellular NAD+ reserves, leading to de-regulation of important molecular processes. Here, we provide evidence of a pathophysiological mechanism that connects mtDNA damage to cardiac dysfunction via reduced NAD+ levels and loss of mitochondrial function and communication. Using a transgenic model, we demonstrate that high levels of mice cardiomyocyte mtDNA damage cause a reduction in NAD+ levels due to extreme DNA repair activity, causing impaired activation of NAD+-dependent SIRT3. In addition, we show that myocardial mtDNA damage in combination with high dosages of nicotinamideriboside (NR) causes an inhibition of sirtuin activity due to accumulation of nicotinamide (NAM), in addition to irregular cardiac mitochondrial morphology. Consequently, high doses of NR should be used with caution, especially when cardiomyopathic symptoms are caused by mitochondrial dysfunction and instability of mtDNA.
    Keywords:  DNA repair; NAD+; SIRT3; biochemistry; cardiovascular disease; chemical biology; human; mitochondrial dna; mouse; nicotinamide riboside
    DOI:  https://doi.org/10.7554/eLife.59828
  36. Cancer Res. 2021 Aug 04. pii: canres.0753.2021. [Epub ahead of print]
      Hypoxia is known to be commonly present in breast tumor microenvironments. Stem-like cells that repopulate breast tumors, termed tumor-repopulating cells (TRC), thrive under hypoxic conditions, but the underlying mechanism remains unclear. Here we show that hypoxia promotes the growth of breast TRCs through metabolic reprogramming. Hypoxia mobilized transcription factors HIF-1α and FoxO1 and induced epigenetic reprogramming to upregulate cytosolic phosphoenolpyruvate carboxykinase (PCK1), a key enzyme that initiates gluconeogenesis. PCK1 subsequently triggered retrograde carbon flow from gluconeogenesis to glycogenesis, glycogenolysis, and the pentose phosphate pathway. The resultant NADPH facilitated reduced glutathione production, leading to a moderate increase of reactive oxygen species that stimulated hypoxic breast TRC growth. Notably, this metabolic mechanism was absent in differentiated breast tumor cells. Targeting PCK1 synergized with paclitaxel to reduce the growth of triple-negative breast cancer (TNBC). These findings uncover an altered glycogen metabolic program in breast cancer, providing potential metabolic strategies to target hypoxic breast TRCs and TNBC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0753
  37. EXCLI J. 2021 ;20 1170-1183
      Thyroid cancers (TCs) are the most prevalent malignancy of the endocrine system and the seventh most common cancer in women. According to estimates from the Global Cancer Observatory (GCO) in 2020, the incidence of thyroid cancer globally was 586,000 cases. As thyroid cancer incidences have dramatically increased, identifying the most important metabolic pathways and biochemical markers involved in thyroid tumorigenesis can be critical strategies for controlling the prevalence and ultimately treatment of this disease. Cancer cells undergo cellular metabolism and energy alteration in order to promote cell proliferation and invasion. Glutamine is one of the most abundant free amino acids in the human body that contributes to cancer metabolic remodeling as a carbon and nitrogen source to sustain cell growth and proliferation. In the present review, glutamine metabolism and its regulation in cancer cells are highlighted. Thereafter, emphasis is given to the perturbation of glutamine metabolism in thyroid cancer, focusing on metabolomics studies.
    Keywords:  amino acids; glutamine; metabolism; metabolomics; thyroid cancers
    DOI:  https://doi.org/10.17179/excli2021-3826
  38. Oncogene. 2021 Aug 04.
      Although the role of isocitrate dehydrogenase (IDH) mutation in promoting cancer development has been well-characterized, the impact of wild-type IDH on cancer cells remains unclear. Here we show that the wild-type isocitrate dehydrogenase 2 (IDH2) is highly expressed in colorectal cancer (CRC) cells, and plays an unexpected role in protecting the cancer cells from oxidative damage. Genetic abrogation of IDH2 in CRC cells leads to reactive oxygen species (ROS)-mediated DNA damage and an accumulation of 8-oxoguanine with DNA strand breaks, which activates DNA damage response (DDR) with elevated γH2AX and phosphorylation of ataxia telangiectasia-mutated (ATM) protein, leading to a partial cell cycle arrest and eventually cell senescence. Mechanistically, the suppression of IDH2 results in a reduction of the tricarboxylic acid (TCA) cycle activity due to a decrease in the conversion of isocitrate to α-ketoglutarate (α-KG) with a concurrent decrease in NADPH production, leading to ROS accumulation and oxidative DNA damage. Importantly, abrogation of IDH2 inhibits CRC cell growth in vitro and in vivo, and renders CRC cells more vulnerable to DNA-damaging drugs. Screening of an FDA-approved drug library has identified oxaliplatin as a compound highly effective against CRC cells when IDH2 was suppressed. Our study has uncovered an important role of the wild-type IDH2 in protecting DNA from oxidative damage, and provides a novel biochemical basis for developing metabolic intervention strategy for cancer treatment.
    DOI:  https://doi.org/10.1038/s41388-021-01968-2
  39. PLoS Biol. 2021 Aug;19(8): e3001357
      Plant mitochondrial genomes undergo frequent homologous recombination (HR). Ectopic HR activity is inhibited by the HR surveillance pathway, but the underlying regulatory mechanism is unclear. Here, we show that the mitochondrial RNase H1 AtRNH1B impairs the formation of RNA:DNA hybrids (R-loops) and participates in the HR surveillance pathway in Arabidopsis thaliana. AtRNH1B suppresses ectopic HR at intermediate-sized repeats (IRs) and thus maintains mitochondrial DNA (mtDNA) replication. The RNase H1 AtRNH1C is restricted to the chloroplast; however, when cells lack AtRNH1B, transport of chloroplast AtRNH1C into the mitochondria secures HR surveillance, thus ensuring the integrity of the mitochondrial genome and allowing embryogenesis to proceed. HR surveillance is further regulated by the single-stranded DNA-binding protein ORGANELLAR SINGLE-STRANDED DNA BINDING PROTEIN1 (OSB1), which decreases the formation of R-loops. This study uncovers a facultative dual targeting mechanism between organelles and sheds light on the roles of RNase H1 in organellar genome maintenance and embryogenesis.
    DOI:  https://doi.org/10.1371/journal.pbio.3001357
  40. J Clin Invest. 2021 Aug 02. pii: 148278. [Epub ahead of print]131(15):
      Circadian rhythms evolved through adaptation to daily light/dark changes in the environment; they are believed to be regulated by the core circadian clock interlocking feedback loop. Recent studies indicate that each core component executes general and specific functions in metabolism. Here, we review the current understanding of the role of these core circadian clock genes in the regulation of metabolism using various genetically modified animal models. Additionally, emerging evidence shows that exposure to environmental stimuli, such as artificial light, unbalanced diet, mistimed eating, and exercise, remodels the circadian physiological processes and causes metabolic disorders. This Review summarizes the reciprocal regulation between the circadian clock and metabolism, highlights remaining gaps in knowledge about the regulation of circadian rhythms and metabolism, and examines potential applications to human health and disease.
    DOI:  https://doi.org/10.1172/JCI148278
  41. J Exp Bot. 2021 Jul 31. pii: erab361. [Epub ahead of print]
      The amino acid proline has been known for many years to be a component of proteins as well as an osmolyte. Many recent studies have demonstrated that proline has other roles such as regulating redox balance and energy status. In animals and plants, the well-described proline cycle is concomitantly responsible for the preferential accumulation of proline and shuttling of redox equivalents from the cytosol to mitochondria. The impact of the proline cycle goes beyond regulating proline levels. In this review, we focus on recent evidence of how the proline cycle regulates redox status in relation to other redox shuttles. We discuss how the interconversion of proline to glutamate shuttles reducing power between cellular compartments. Spatial aspects of the proline cycle in the entire plant are considered in terms of proline transport between organs with different metabolic regimes (photosynthesis versus respiration). Furthermore, we highlight the importance of this shuttle in the regulation of energy and redox power in plants, through a particularly intricate coordination notably between mitochondria and cytosol.
    Keywords:  Mitochondria; Proline cycle; Proline metabolism; Proline transport; Redox shuttle; Redox status; Redox valve
    DOI:  https://doi.org/10.1093/jxb/erab361
  42. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00049-X. [Epub ahead of print]152 103-177
      Metabolism is an important part of tumorigenesis as well as progression. The various cancer metabolism pathways, such as glucose metabolism and glutamine metabolism, directly regulate the development and progression of cancer. The pathways by which the cancer cells rewire their metabolism according to their needs, surrounding environment and host tissue conditions are an important area of study. The regulation of these metabolic pathways is determined by various oncogenes, tumor suppressor genes, as well as various constituent cells of the tumor microenvironment. Expanded studies on metabolism will help identify efficient biomarkers for diagnosis and strategies for therapeutic interventions and countering ways by which cancers may acquire resistance to therapy.
    Keywords:  Cancer; Hypoxia; Metabolism; Therapy; Warburg effect
    DOI:  https://doi.org/10.1016/bs.acr.2021.06.002
  43. Nature. 2021 Aug 04.
      
    Keywords:  Epigenetics; Genetics; Genomics; Medical research
    DOI:  https://doi.org/10.1038/d41586-021-02005-8
  44. J Mol Cell Cardiol. 2021 Jul 28. pii: S0022-2828(21)00149-8. [Epub ahead of print]
      A serious consequence of myocardial ischemia-reperfusion injury (I/R) is oxidative damage, which causes mitochondrial dysfunction. The cascading ROS can propagate and potentially induce heme bleaching and protein cysteine sulfonation (PrSO3H) of the mitochondrial electron transport chain. Herein we studied the mechanism of I/R-mediated irreversible oxidative injury of complex III in mitochondria from rat hearts subjected to 30-min of ischemia and 24-h of reperfusion in vivo. In the I/R region, the catalytic activity of complex III was significantly impaired. Spectroscopic analysis indicated that I/R mediated the destruction of hemes b and c + c1 in the mitochondria, supporting I/R-mediated complex III impairment. However, no significant impairment of complex III activity and heme damage were observed in mitochondria from the risk region of rat hearts subjected only to 30-min ischemia, despite a decreased state 3 respiration. In the I/R mitochondria, carbamidomethylated C122/C125 of cytochrome c1 via alkylating complex III with a down regulation of HCCS was exclusively detected, supporting I/R-mediated thioether defect of heme c1. LC-MS/MS analysis showed that I/R mitochondria had intensely increased complex III PrSO3H levels at the C236 ligand of the [2Fe2S] cluster of the Rieske iron‑sulfur protein (uqcrfs1), thus impairing the electron transport activity. MS analysis also indicated increased PrSO3H of the hinge protein at C65 and of cytochrome c1 at C140 and C220, which are confined in the intermembrane space. MS analysis also showed that I/R extensively enhanced the PrSO3H of the core 1 (uqcrc1) and core 2 (uqcrc2) subunits in the matrix compartment, thus supporting the conclusion that complex III releases ROS to both sides of the inner membrane during reperfusion. Analysis of ischemic mitochondria indicated a modest reduction from the basal level of complex III PrSO3H detected in the mitochondria of sham control hearts, suggesting that the physiologic hyperoxygenation and ROS overproduction during reperfusion mediated the enhancement of complex III PrSO3H. In conclusion, reperfusion-mediated heme damage with increased PrSO3H controls oxidative injury to complex III and aggravates mitochondrial dysfunction in the post-ischemic heart.
    Keywords:  Complex III; Cysteine sulfonation; Heme damage; Myocardial ischemia and reperfusion; Oxidative stress; Protein structure
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.07.008