bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2021‒07‒25
forty-five papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit


  1. Cell Death Dis. 2021 Jul 22. 12(8): 727
      All organisms exposed to metabolic and environmental stresses have developed various stress adaptive strategies to maintain homeostasis. The main bacterial stress survival mechanism is the stringent response triggered by the accumulation "alarmone" (p)ppGpp, whose level is regulated by RelA and SpoT. While metazoan genomes encode MESH1 (Metazoan SpoT Homolog 1) with ppGpp hydrolase activity, neither ppGpp nor the stringent response is found in metazoa. The deletion of Mesh1 in Drosophila triggers a transcriptional response reminiscent of the bacterial stringent response. However, the function of MESH1 remains unknown until our recent discovery of MESH1 as the first cytosolic NADPH phosphatase that regulates ferroptosis. To further understand whether MESH1 knockdown triggers a similar transcriptional response in mammalian cells, here, we employed RNA-Seq to analyze the transcriptome response to MESH1 knockdown in human cancer cells. We find that MESH1 knockdown induced different genes involving endoplasmic reticulum (ER) stress, especially ATF3, one of the ATF4-regulated genes in the integrative stress responses (ISR). Furthermore, MESH1 knockdown increased ATF4 protein, eIF2a phosphorylation, and induction of ATF3, XBPs, and CHOP mRNA. ATF4 induction contributes to ~30% of the transcriptome induced by MESH1 knockdown. Concurrent ATF4 knockdown re-sensitizes MESH1-depleted RCC4 cells to ferroptosis, suggesting its role in the ferroptosis protection mediated by MESH1 knockdown. ATF3 induction is abolished by the concurrent knockdown of NADK, implicating a role of NADPH accumulation in the integrative stress response. Collectively, these results suggest that MESH1 depletion triggers ER stress and ISR as a part of its overall transcriptome changes to enable stress survival of cancer cells. Therefore, the phenotypic similarity of stress tolerance caused by MESH1 removal and NADPH accumulation is in part achieved by ISR to regulate ferroptosis.
    DOI:  https://doi.org/10.1038/s41419-021-04018-7
  2. Redox Biol. 2021 Jul 11. pii: S2213-2317(21)00224-X. [Epub ahead of print]46 102065
      Although glucose, through pentose phosphate pathway (PPP), is the main source to generate NADPH, solid tumors are often deprived of glucose, hence alternative metabolic pathways to maintain NADPH homeostasis in cancer cells are required. Here, we report that lactate and glutamine support NADPH production via isocitrate dehydrogenase 1 (IDH1) and malic enzyme 1 (ME1), respectively, under glucose-deprived conditions. Isotopic tracing demonstrates that lactate participates in the formation of isocitrate. Malate derived from glutamine in mitochondria shuttles to cytosol to produce NADPH. In cells cultured in the absence of glucose, knockout of IDH1 and ME1 decreases NADPH/NADP+ and GSH/GSSG, increases ROS level and facilitates cell necrosis. In 4T1 murine breast tumors, knockout of ME1 retards tumor growth in vivo, with combined ME1/IDH1 knockout more strongly suppressing tumor growth. Our findings reveal two alternative NADPH-producing pathways that cancer cells use to resist glucose starvation, reflecting the metabolic plasticity and flexibility of cancer cells adapting to nutrition stress.
    Keywords:  Glucose deprivation; Glutamine; IDH1; Lactate; ME1; NADPH
    DOI:  https://doi.org/10.1016/j.redox.2021.102065
  3. Nature. 2021 Jul 21.
      The mTOR complex 1 (mTORC1) controls cell growth in response to amino acid levels1. Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its activator GATOR2. In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. SAR1B-GATOR2-mTORC1 signalling is conserved in nematodes and has a role in the regulation of lifespan. Bioinformatic analysis reveals that SAR1B deficiency correlates with the development of lung cancer. The silencing of SAR1B and its paralogue SAR1A promotes mTORC1-dependent growth of lung tumours in mice. Our results reveal that SAR1B is a conserved leucine sensor that has a potential role in the development of lung cancer.
    DOI:  https://doi.org/10.1038/s41586-021-03768-w
  4. Front Oncol. 2021 ;11 694526
      Amino acid (AA) metabolism plays an important role in many cellular processes including energy production, immune function, and purine and pyrimidine synthesis. Cancer cells therefore require increased AA uptake and undergo metabolic reprogramming to satisfy the energy demand associated with their rapid proliferation. Like many other cancers, myeloid leukemias are vulnerable to specific therapeutic strategies targeting metabolic dependencies. Herein, our review provides a comprehensive overview and TCGA data analysis of biosynthetic enzymes required for non-essential AA synthesis and their dysregulation in myeloid leukemias. Furthermore, we discuss the role of the general control nonderepressible 2 (GCN2) and-mammalian target of rapamycin (mTOR) pathways of AA sensing on metabolic vulnerability and drug resistance.
    Keywords:  GCN2; general control non-derepressible 2; mTORC1; myeloid leukemias; non-essential amino acid
    DOI:  https://doi.org/10.3389/fonc.2021.694526
  5. Autophagy. 2021 Jul 18. 1-3
      Mitophagy, the clearance of surplus or damaged mitochondria or mitochondrial parts by autophagy, is important for maintenance of cellular homeostasis. Whereas knowledge on programmed and stress-induced mitophagy is increasing, much less is known about mechanisms of basal mitophagy. Recently, we identified SAMM50 (SAMM50 sorting and assembly machinery component) as a receptor for piecemeal degradation of components of the sorting and assembly machinery (SAM) complex and mitochondrial contact site and cristae organizing system (MICOS) complexes. SAMM50 interacts directly with Atg8-family proteins through a canonical LIR motif and with SQSTM1/p62 to mediate basal piecemeal mitophagy. During a metabolic switch to oxidative phosphorylation (OXPHOS), SAMM50 cooperates with SQSTM1 to mediate efficient piecemeal mitophagy.
    Keywords:  Atg8; MICOS; OXPHOS; SAMM50; SQSTM1; basal; metabolic switch; p62; piecemeal mitophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1953846
  6. J Immunol. 2021 Jul 21. pii: ji2100230. [Epub ahead of print]
      Metabolic programming is integrally linked to immune cell function. Nowhere is this clearer than in the differentiation of macrophages. Proinflammatory M1 macrophages primarily use glycolysis as a rapid energy source but also to generate antimicrobial compounds, whereas alternatively activated M2 macrophages primarily rely on oxidative phosphorylation for the longevity required for proper wound healing. mTOR signaling has been demonstrated to be a key regulator of immune cell metabolism and function. mTORC2 signaling is required for the generation of M2 macrophages, whereas the role of mTORC1 signaling, a key regulator of glycolysis, has been controversial. By using genetic deletion of mTORC1 signaling in C57BL/6 mouse macrophages, we observed enhanced M1 macrophage function in vitro and in vivo. Surprisingly, this enhancement occurred despite a significant defect in M1 macrophage glycolytic metabolism. Mechanistically, enhanced M1 function occurred because of inhibition of the class III histone deacetylases the sirtuins, resulting in enhanced histone acetylation. Our findings provide a counterpoint to the paradigm that enhanced immune cell function must occur in the presence of increased cellular metabolism and identifies a potential, pharmacologic target for the regulation of inflammatory responses.
    DOI:  https://doi.org/10.4049/jimmunol.2100230
  7. Amino Acids. 2021 Jul 20.
      Proline metabolic reprogramming is intimately involved in cancer progression. We recently identified a critical role of PINCH-1, a cell-extracellular matrix (ECM) adhesion protein whose expression is elevated in lung adenocarcinoma, in the promotion of proline biosynthesis, fibrosis and lung adenocarcinoma growth. How PINCH-1 promotes proline biosynthesis, however, was incompletely understood. In this study, we show that PINCH-1 promotes the expression of Δ1-pyrroline-5-carboxylate synthase (P5CS), a key enzyme that links glutamate metabolism to proline biosynthesis. Depletion of PINCH-1 from lung adenocarcinoma cells reduced the protein but not mRNA level of P5CS, resulting in down-regulation of the cellular level of P5C and cell proliferation. Treatment of the cells with protease inhibitor leupeptin effectively reversed PINCH-1 deficiency-induced reduction of the P5CS level. At the molecular level, PINCH-1, through its LIM2 domain, physically associated with P5CS in lung adenocarcinoma cells. Re-expression of wild type PINCH-1, but not that of the PINCH-1 LIM2 deletion mutant, in PINCH-1 deficient lung adenocarcinoma cells restored P5CS expression, proline biosynthesis and cell proliferation. Finally, P5CS expression, like that of PINCH-1, is elevated in human and mouse lung adenocarcinoma. Using a mouse model of lung adenocarcinoma in which PINCH-1 is conditionally ablated, we show that knockout of PINCH-1 from lung adenocarcinoma effectively reduced the P5CS level in vivo. Our results reveal an important role of PINCH-1 in the promotion of P5CS expression, which likely contributes to proline metabolic reprogramming and consequently lung adenocarcinoma progression.
    Keywords:  Fibrosis; Lung adenocarcinoma; PINCH-1; Proline synthesis; Pyrroline-5-carboxylate synthase
    DOI:  https://doi.org/10.1007/s00726-021-03050-3
  8. Oncogene. 2021 Jul 21.
      Epidemiologic studies in diabetic patients as well as research in model organisms have indicated the potential of metformin as a drug candidate for the treatment of various types of cancer, including breast cancer. To date most of the anti-cancer properties of metformin have, in large part, been attributed either to the inhibition of mitochondrial NADH oxidase complex (Complex I in the electron transport chain) or the activation of AMP-activated kinase (AMPK). However, it is becoming increasingly clear that AMPK activation may be critical to alleviate metabolic and energetic stresses associated with tumor progression suggesting that it may, in fact, attenuate the toxicity of metformin instead of promoting it. Here, we demonstrate that AMPK opposes the detrimental effects of mitochondrial complex I inhibition by enhancing glycolysis at the expense of, and in a manner dependent on, pyruvate availability. We also found that metformin forces cells to rewire their metabolic grid in a manner that depends on AMPK, with AMPK-competent cells upregulating glycolysis and AMPK-deficient cell resorting to ketogenesis. In fact, while the killing effects of metformin were largely rescued by pyruvate in AMPKcompetent cells, AMPK-deficient cells required instead acetoacetate, a product of fatty acid catabolism indicating a switch from sugar to fatty acid metabolism as a central resource for ATP production in these cells. In summary, our results indicate that AMPK activation is not responsible for metformin anticancer activity and may instead alleviate energetic stress by activating glycolysis.
    DOI:  https://doi.org/10.1038/s41388-021-01943-x
  9. Nat Commun. 2021 07 21. 12(1): 4447
      Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-L-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-γ mediated STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1β, IFN-γ, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance.
    DOI:  https://doi.org/10.1038/s41467-021-24785-3
  10. Nat Metab. 2021 Jul;3(7): 940-953
      Males and females exhibit striking differences in the prevalence of metabolic traits including hepatic steatosis, a key driver of cardiometabolic morbidity and mortality. RNA methylation is a widespread regulatory mechanism of transcript turnover. Here, we show that presence of the RNA modification N6-methyladenosine (m6A) triages lipogenic transcripts for degradation and guards against hepatic triglyceride accumulation. In male but not female mice, this protective checkpoint stalls under lipid-rich conditions. Loss of m6A control in male livers increases hepatic triglyceride stores, leading to a more 'feminized' hepatic lipid composition. Crucially, liver-specific deletion of the m6A complex protein Mettl14 from male and female mice significantly diminishes sex-specific differences in steatosis. We further surmise that the m6A installing machinery is subject to transcriptional control by the sex-responsive BCL6-STAT5 axis in response to dietary conditions. These data show that m6A is essential for precise and synchronized control of lipogenic enzyme activity and provide insights into the molecular basis for the existence of sex-specific differences in hepatic lipid traits.
    DOI:  https://doi.org/10.1038/s42255-021-00427-2
  11. Annu Rev Nutr. 2021 Jul 20.
      Dietary fat absorption is required for health but also contributes to hyperlipidemia and metabolic disease when dysregulated. One step in the process of dietary fat absorption is the formation of cytoplasmic lipid droplets (CLDs) in small intestinal enterocytes; these CLDs serve as dynamic triacylglycerol storage organelles that influence the rate at which dietary fat is absorbed. Recent studies have uncovered novel factors regulating enterocyte CLD metabolism that in turn influence the absorption of dietary fat. These include peroxisome proliferator-activated receptor α activation, compartmentalization of different lipid pools, the gut microbiome, liver X receptor and farnesoid X receptor activation, obesity, and physiological factors stimulating CLD mobilization. Understanding how enterocyte CLD metabolism is regulated is key in modulating the absorption of dietary fat in the prevention of hyperlipidemia and its associated metabolic disorders. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-nutr-110320-013657
  12. EMBO Rep. 2021 Jul 23. e51954
      Mfn2 is a mitochondrial fusion protein with bioenergetic functions implicated in the pathophysiology of neuronal and metabolic disorders. Understanding the bioenergetic mechanism of Mfn2 may aid in designing therapeutic approaches for these disorders. Here we show using endoplasmic reticulum (ER) or mitochondria-targeted Mfn2 that Mfn2 stimulation of the mitochondrial metabolism requires its localization in the ER, which is independent of its fusion function. ER-located Mfn2 interacts with mitochondrial Mfn1/2 to tether the ER and mitochondria together, allowing Ca2+ transfer from the ER to mitochondria to enhance mitochondrial bioenergetics. The physiological relevance of these findings is shown during neurite outgrowth, when there is an increase in Mfn2-dependent ER-mitochondria contact that is necessary for correct neuronal arbor growth. Reduced neuritic growth in Mfn2 KO neurons is recovered by the expression of ER-targeted Mfn2 or an artificial ER-mitochondria tether, indicating that manipulation of ER-mitochondria contacts could be used to treat pathologic conditions involving Mfn2.
    Keywords:  Ca2+; ER-mitochondria tethering; Mfn2; neuritic growth
    DOI:  https://doi.org/10.15252/embr.202051954
  13. Oncogene. 2021 Jul 23.
      Cancer is the most complex genetic disease known, with mutations implicated in more than 250 genes. However, it is still elusive which specific mutations found in human patients lead to tumorigenesis. Here we show that a combination of oncogenes that is characteristic of liver cancer (CTNNB1, TERT, MYC) induces senescence in human fibroblasts and primary hepatocytes. However, reprogramming fibroblasts to a liver progenitor fate, induced hepatocytes (iHeps), makes them sensitive to transformation by the same oncogenes. The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. These results show that tumorigenesis is triggered by a combination of three elements: the set of driver mutations, the cellular lineage, and the state of differentiation of the cells along the lineage. Our results provide direct support for the role of cell identity as a key determinant in transformation and establish a paradigm for studying the dynamic role of oncogenic drivers in human tumorigenesis.
    DOI:  https://doi.org/10.1038/s41388-021-01940-0
  14. J Hematol Oncol. 2021 Jul 22. 14(1): 114
      Metabolic rewiring offers novel therapeutic opportunities in cancer. Until recently, there was scant information regarding soft tissue sarcomas, due to their heterogeneous tissue origin, histological definition and underlying genetic history. Novel large-scale genomic and metabolomics approaches are now helping stratify their physiopathology. In this review, we show how various genetic alterations skew activation pathways and orient metabolic rewiring in sarcomas. We provide an update on the contribution of newly described mechanisms of metabolic regulation. We underscore mechanisms that are relevant to sarcomagenesis or shared with other cancers. We then discuss how diverse metabolic landscapes condition the tumor microenvironment, anti-sarcoma immune responses and prognosis. Finally, we review current attempts to control sarcoma growth using metabolite-targeting drugs.
    Keywords:  Metabolism; Metabolite-targeted therapies; Metabolomics; Microenvironment; Sarcoma; Transcriptomics
    DOI:  https://doi.org/10.1186/s13045-021-01125-y
  15. Nat Commun. 2021 Jul 23. 12(1): 4493
      Neuronal function relies on careful coordination of organelle organization and transport. Kinesin-1 mediates transport of the endoplasmic reticulum (ER) and lysosomes into the axon and it is increasingly recognized that contacts between the ER and lysosomes influence organelle organization. However, it is unclear how organelle organization, inter-organelle communication and transport are linked and how this contributes to local organelle availability in neurons. Here, we show that somatic ER tubules are required for proper lysosome transport into the axon. Somatic ER tubule disruption causes accumulation of enlarged and less motile lysosomes at the soma. ER tubules regulate lysosome size and axonal translocation by promoting lysosome homo-fission. ER tubule - lysosome contacts often occur at a somatic pre-axonal region, where the kinesin-1-binding ER-protein P180 binds microtubules to promote kinesin-1-powered lysosome fission and subsequent axonal translocation. We propose that ER tubule - lysosome contacts at a pre-axonal region finely orchestrate axonal lysosome availability for proper neuronal function.
    DOI:  https://doi.org/10.1038/s41467-021-24713-5
  16. Int J Mol Sci. 2021 Jul 14. pii: 7525. [Epub ahead of print]22(14):
      Mitochondria are vital to life and provide biological energy for other organelles and cell physiological processes. On the mitochondrial double layer membrane, there are a variety of channels and transporters to transport different metal ions, such as Ca2+, K+, Na+, Mg2+, Zn2+ and Fe2+/Fe3+. Emerging evidence in recent years has shown that the metal ion transport is essential for mitochondrial function and cellular metabolism, including oxidative phosphorylation (OXPHOS), ATP production, mitochondrial integrity, mitochondrial volume, enzyme activity, signal transduction, proliferation and apoptosis. The homeostasis of mitochondrial metal ions plays an important role in maintaining mitochondria and cell functions and regulating multiple diseases. In particular, channels and transporters for transporting mitochondrial metal ions are very critical, which can be used as potential targets to treat neurodegeneration, cardiovascular diseases, cancer, diabetes and other metabolic diseases. This review summarizes the current research on several types of mitochondrial metal ion channels/transporters and their functions in cell metabolism and diseases, providing strong evidence and therapeutic strategies for further insights into related diseases.
    Keywords:  cell metabolism; disease; mitochondrial function; mitochondrial metal ion homeostasis; mitochondrial metal ion transport
    DOI:  https://doi.org/10.3390/ijms22147525
  17. Amino Acids. 2021 Jul 22.
      Proline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources, generated de novo within cells, and released from protein structures; a noteworthy source being collagen. Its catabolism within cells can generate ATP and reactive oxygen species (ROS). Recent findings suggest that proline biosynthesis and catabolism are essential processes in disease; not only due to the role in new protein synthesis as part of pathogenic processes but also due to the impact of proline metabolism on the wider metabolic network through its significant role in redox homeostasis. This is particularly clear in cancer proliferation and metastatic outgrowth. Nevertheless, the precise identity of the drivers of cellular proline catabolism and biosynthesis, and the overall cost of maintaining appropriate balance is not currently known. In this review, we explore the major drivers of proline availability and consumption at a local and systemic level with a focus on cancer. Unraveling the main factors influencing proline metabolism in normal physiology and disease will shed light on new effective treatment strategies.
    Keywords:  Cancer; Disease; Proline; Redox
    DOI:  https://doi.org/10.1007/s00726-021-03051-2
  18. Cancer Res. 2021 Jul 21. pii: canres.1723.2020. [Epub ahead of print]
      Elevated infiltration of immunosuppressive alternatively polarized (M2) macrophages is associated with poor prognosis in cancer patients. The tumor microenvironment remarkably orchestrates molecular mechanisms that program these macrophages. Here we identify a novel role for oncogenic Hedgehog (Hh) signaling in programming signature metabolic circuitries that regulate alternative polarization of tumor-associated macrophages. Two immunocompetent orthotopic mouse models of mammary tumors were used to test the effect of inhibiting Hh signaling on tumor-associated macrophages. Treatment with the pharmacological Hh inhibitor Vismodegib induced a significant shift in the profile of tumor-infiltrating macrophages. Mass spectrometry-based metabolomic analysis showed Hh inhibition induced significant alterations in metabolic processes, including metabolic sensing, mitochondrial adaptations, and lipid metabolism. In particular, inhibition of Hh in M2 macrophages reduced flux through the UDP-GlcNAc biosynthesis pathway. Consequently, O-GlcNAc-modification of STAT6 decreased, mitigating the immune suppressive program of M2 macrophages, and the metabolically demanding M2 macrophages shifted their metabolism and bioenergetics from fatty acid oxidation to glycolysis. M2 macrophages enriched from Vismodegib-treated mammary tumors showed characteristically decreased O-GlcNAcylation and altered mitochondrial dynamics. These Hh-inhibited macrophages are reminiscent of inflammatory (M1) macrophages, phenotypically characterized by fragmented mitochondria. This is the first report highlighting the relevance of Hh signaling in controlling a complex metabolic network in immune cells. These data describe a novel immunometabolic function of Hh signaling that can be clinically exploited.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1723
  19. Oncogene. 2021 Jul 17.
      Epigenetic alterations have been previously shown to contribute to multiple myeloma (MM) pathogenesis via DNA methylations and histone modifications. RNA methylation, a novel epigenetic modification, is required for cancer cell survival, and targeting this pathway has been proposed as a new therapeutic strategy. The extent to the N6-methyladenosine (m6A)-regulatory pathway functions in MM remains unknown. Here, we show that an imbalance of RNA methylation may underlies the tumorigenesis of MM. Mechanistically, isocitrate dehydrogenase 2 (IDH2) is highly expressed in CD138+ cells from MM and its levels appear a progressive increase in the progression of plasma cell dyscrasias. Downregulation of IDH2 increases global m6A RNA levels and reduces myeloma cell growth in vitro, decreases the burden of disease and prolongs overall survival in vivo. IDH2 regulates RNA methylation by activating the RNA demethylase FTO, which is an α-KG-dependent dioxygenase. Furthermore, IDH2-mediated FTO activation decreases the m6A level on WNT7B transcripts, then increases WNT7B expression and thus activated Wnt signaling pathway. Moreover, survival analysis indicates that the elevated expression of IDH2 predicts a poor prognosis. Higher expression of FTO is related to higher International Staging System (ISS) stage and higher Revised-ISS (R-ISS) stage of MM. Collectively, our studies reveal that IDH2 regulates global m6A RNA modification in MM via targeting RNA demethylases FTO. The imbalance of m6A methylation activates the Wnt signaling pathway by enhancing the WNT7B expression, and thus promoting tumorigenesis and progression of MM. IDH2 might be used as a therapeutic target and a possible prognostic factor for MM.
    DOI:  https://doi.org/10.1038/s41388-021-01939-7
  20. Cell Rep. 2021 Jul 20. pii: S2211-1247(21)00825-1. [Epub ahead of print]36(3): 109412
      In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1-mutated (BRCA1mut) tumors are thus T cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine is identified as a potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1mut cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance and tumor progression. Tumor-intrinsic STING elimination reduces neoangiogenesis, increases CD8+ T cell infiltration, and reverts therapeutic resistance to dual immune checkpoint blockade (ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with ICB and/or poly(ADP-ribose) polymerase (PARP) inhibitors to control the outgrowth of Trp53-/-Brca1-/- but not Brca1+/+ ovarian tumors in vivo, offering rational combinatorial therapies for HRD cancers.
    Keywords:  BRCA1; CTLA-4; DNA sensing; ICB; PARPi; PD-L1; STING; T cells; VEGF-A; angiogenesis; dual immune checkpoint blockade; ovarian cancer; type I IFN
    DOI:  https://doi.org/10.1016/j.celrep.2021.109412
  21. Amino Acids. 2021 Jul 20.
      L-proline catabolism is emerging as a key pathway that is critical to cellular metabolism, growth, survival, and death. Proline dehydrogenase (PRODH) enzyme, which catalyzes the first step of proline catabolism, has diverse functional roles in regulating many pathophysiological processes, including apoptosis, autophagy, cell senescence, and cancer metastasis. Notably, accumulated evidence demonstrated that PRODH plays complex role in many types of cancers. In this review, we briefly introduce the function of PRODH, then its expression in different types of cancer. We next discuss the regulation of PRODH in cancer, the downstream pathways of PRODH and the therapies that are under investigation. Finally, we propose novel insights for future perspectives on the modulation of PRODH.
    Keywords:  Apoptosis; Autophagy; Cancer; L-proline; PRODH; p53
    DOI:  https://doi.org/10.1007/s00726-021-03032-5
  22. Cell. 2021 Jul 14. pii: S0092-8674(21)00796-0. [Epub ahead of print]
      The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known to be required for pore formation after GSDMD cleavage. Herein, we report a forward genetic screen that identified the Ragulator-Rag complex as being necessary for GSDMD pore formation and pyroptosis in macrophages. Mechanistic analysis revealed that Ragulator-Rag is not required for GSDMD cleavage upon inflammasome activation but rather promotes GSDMD oligomerization in the plasma membrane. Defects in GSDMD oligomerization and pore formation can be rescued by mitochondrial poisons that stimulate reactive oxygen species (ROS) production, and ROS modulation impacts the ability of inflammasome pathways to promote pore formation downstream of GSDMD cleavage. These findings reveal an unexpected link between key regulators of immunity (inflammasome-GSDMD) and metabolism (Ragulator-Rag).
    Keywords:  gasdermin D; inflammasomes; inflammation; innate immunity; macrophages; mtorc1; pyroptosis; ragulator; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cell.2021.06.028
  23. Elife. 2021 Jul 20. pii: e65484. [Epub ahead of print]10
      Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including α-synuclein and amyloid β. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases.
    Keywords:  C. elegans; S. cerevisiae; biochemistry; chemical biology
    DOI:  https://doi.org/10.7554/eLife.65484
  24. Biochim Biophys Acta Mol Cell Res. 2021 Jul 15. pii: S0167-4889(21)00153-1. [Epub ahead of print] 119099
      Cellular senescence generates a permanent cell cycle arrest, characterized by apoptosis resistance and a pro-inflammatory senescence-associated secretory phenotype (SASP). Physiologically, senescent cells promote tissue remodeling during development and after injury. However, when accumulated over a certain threshold as happens during aging or after cellular stress, senescent cells contribute to the functional decline of tissues, participating in the generation of several diseases. Cellular senescence is accompanied by increased mitochondrial metabolism. How mitochondrial function is regulated and what role it plays in senescent cell homeostasis is poorly understood. Mitochondria are functionally and physically coupled to the endoplasmic reticulum (ER), the major calcium (Ca2+) storage organelle in mammalian cells, through special domains known as mitochondria-ER contacts (MERCs). In this domain, the release of Ca2+ from the ER is mainly regulated by inositol 1,4,5-trisphosphate receptors (IP3Rs), a family of three Ca2+ release channels activated by a ligand (IP3). IP3R-mediated Ca2+ release is transferred to mitochondria through the mitochondrial Ca2+ uniporter (MCU), where it modulates the activity of several enzymes and transporters impacting its bioenergetic and biosynthetic function. Here, we review the possible connection between ER to mitochondria Ca2+ transfer and senescence. Understanding the pathways that contribute to senescence is essential to reveal new therapeutic targets that allow either delaying senescent cell accumulation or reduce senescent cell burden to alleviate multiple diseases.
    Keywords:  MERCs; calcium; metabolism; mitochondria; senescence
    DOI:  https://doi.org/10.1016/j.bbamcr.2021.119099
  25. Elife. 2021 Jul 19. pii: e69344. [Epub ahead of print]10
      Selection against deleterious mitochondrial mutations is facilitated by germline processes, lowering the risk of genetic diseases. How selection works is disputed: experimental data are conflicting and previous modelling work has not clarified the issues. Here we develop computational and evolutionary models that compare the outcome of selection at the level of individuals, cells and mitochondria. Using realistic de novo mutation rates and germline development parameters from mouse and humans, the evolutionary model predicts the observed prevalence of mitochondrial mutations and diseases in human populations. We show the importance of organelle-level selection, seen in the selective pooling of mitochondria into the Balbiani body, in achieving high-quality mitochondria at extreme ploidy in mature oocytes. Alternative mechanisms debated in the literature, bottlenecks and follicular atresia, are unlikely to account for the clinical data, because neither process effectively eliminates mitochondrial mutations under realistic conditions. Our findings explain the major features of female germline architecture, notably the longstanding paradox of over-proliferation of primordial germ cells followed by massive loss. The near-universality of these processes across animal taxa makes sense in light of the need to maintain mitochondrial quality at extreme ploidy in mature oocytes, in the absence of sex and recombination.
    Keywords:  evolutionary biology; none
    DOI:  https://doi.org/10.7554/eLife.69344
  26. Nature. 2021 Jul 21.
      
    Keywords:  Cancer; Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-021-01943-7
  27. Elife. 2021 Jul 19. pii: e68603. [Epub ahead of print]10
      Overwhelming lipid peroxidation induces ferroptotic stress and ferroptosis, a non-apoptotic form of regulated cell death that has been implicated in maladaptive renal repair in mice and humans. Using single-cell transcriptomic and mouse genetic approaches, we show that proximal tubular (PT) cells develop a molecularly distinct, pro-inflammatory state following injury. While these inflammatory PT cells transiently appear after mild injury and return to their original state without inducing fibrosis, after severe injury they accumulate and contribute to persistent inflammation. This transient inflammatory PT state significantly downregulates glutathione metabolism genes, making the cells vulnerable to ferroptotic stress. Genetic induction of high ferroptotic stress in these cells after mild injury leads to the accumulation of the inflammatory PT cells, enhancing inflammation and fibrosis. Our study broadens the roles of ferroptotic stress from being a trigger of regulated cell death to include the promotion and accumulation of proinflammatory cells that underlie maladaptive repair.
    Keywords:  cell biology; mouse; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.68603
  28. Int J Biochem Cell Biol. 2021 Jul 20. pii: S1357-2725(21)00130-8. [Epub ahead of print] 106050
      Classical mitochondrial disease (MD) represents a group of complex metabolic syndromes primarily linked to dysfunction of the mitochondrial ATP-generating oxidative phosphorylation (OXPHOS) system. To date, effective therapies for these diseases are lacking. Here we discuss the ketogenic diet (KD), being a high-fat, moderate protein, and low carbohydrate diet, as a potential intervention strategy. We concisely review the impact of the KD on bioenergetics, ROS/redox metabolism, mitochondrial dynamics and mitophagy. Next, the consequences of the KD in (models of) MD, as well as KD adverse effects, are described. It is concluded that the current experimental evidence suggests that the KD can positively impact on mitochondrial bioenergetics, mitochondrial ROS/redox metabolism and mitochondrial dynamics. However, more information is required on the bioenergetic consequences and mechanistic mode-of-action aspects of the KD at the cellular level and in MD patients.
    Keywords:  bioenergetics; ketone bodies; mitochondria; mitochondrial disease
    DOI:  https://doi.org/10.1016/j.biocel.2021.106050
  29. Methods Mol Biol. 2021 ;2353 137-154
      Iron-Sulfur (Fe-S) clusters function as core prosthetic groups known to modulate the activity of metalloenzymes, act as trafficking vehicles for biological iron and sulfur, and participate in several intersecting metabolic pathways. The formation of these clusters is initiated by a class of enzymes called cysteine desulfurases, whose primary function is to shuttle sulfur from the amino acid L-cysteine to a variety of sulfur transfer proteins involved in Fe-S cluster synthesis as well as in the synthesis of other thiocofactors. Thus, sulfur and Fe-S cluster metabolism are connected through shared enzyme intermediates, and defects in their associated pathways cause a myriad of pleiotropic phenotypes, which are difficult to dissect. Post-transcriptionally modified transfer RNA (tRNA) represents a large class of analytes whose synthesis often requires the coordinated participation of sulfur transfer and Fe-S enzymes. Therefore, these molecules can be used as biologically relevant readouts for cellular Fe and S status. Methods employing LC-MS technology provide a valuable experimental tool to determine the relative levels of tRNA modification in biological samples and, consequently, to assess genetic, nutritional, and environmental factors modulating reactions dependent on Fe-S clusters. Herein, we describe a robust method for extracting RNA and analytically evaluating the degree of Fe-S-dependent and -independent tRNA modifications via an LC-MS platform.
    Keywords:  Bacteria; Iron-sulfur cluster; LC-MS; RNA extraction; Sulfur metabolism; Thionucleosides; tRNA; tRNA modification
    DOI:  https://doi.org/10.1007/978-1-0716-1605-5_8
  30. J Inherit Metab Dis. 2021 Jul 23.
      Propionic aciduria (PA) is caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). Due to inefficient propionate catabolism patients are endangered by life-threatening ketoacidotic crisis. Protein and amino acid restriction are major therapeutic pillars. However, long-term complications like neurological deterioration and cardiac abnormalities cannot be prevented. Chronic kidney disease (CKD), which is a well-known characteristic of methylmalonic aciduria two enzymatic steps down-stream from PCC, has been recognized as a novel late-onset complication in PA. The pathophysiology of CKD in PA is unclear. We investigated mitochondrial structure and metabolism in human renal tubular cells of healthy controls and PA patients. The cells were exposed to either standard cell culture conditions (NT), high protein (HP) or high concentrations of isoleucine and valine (I/V). Mitochondrial morphology changed to condensed, fractured morphology in PA cells irrespective of the cell culture medium. HP and I/V exposure, however, potentiated oxidative stress in PA cells. Mitochondrial mass was enriched in PA cells, and further increased by HP and I/V exposure suggesting a need for compensation. Alterations in the tricarboxylic acid cycle intermediates and accumulation of medium- and long-chain acylcarnitines pointed to altered mitochondrial energy metabolism. Mitophagy was silenced while autophagy as cellular defense mechanisms was highly active in PA cells. The data demonstrate that PA is associated with renal mitochondrial damage which is aggravated by protein and I/V load. Preservation of mitochondrial energy homeostasis in renal cells may be a potential future therapeutic target. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/jimd.12419
  31. Cancers (Basel). 2021 Jul 03. pii: 3351. [Epub ahead of print]13(13):
      Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries with the potential to improve cancer patient care. However, an increasing understanding of the crosstalk between cancer hallmarks has highlighted the complexity of the mechanisms of drug resistance, co-opting pathways outside of the canonical "cell death" machinery to facilitate cell survival in the face of cytotoxic stress. Rewiring of cellular metabolism is vital to drive and support increased proliferative demands in cancer cells, and recent discoveries in the field of cancer metabolism have uncovered a novel role for these programs in facilitating drug resistance. As a key organelle in both metabolic and apoptotic homeostasis, the mitochondria are at the forefront of these mechanisms of resistance, coordinating crosstalk in the event of cellular stress, and promoting cellular survival. Importantly, the appreciation of this role metabolism plays in the cytotoxic response to therapy, and the ability to profile metabolic adaptions in response to treatment, has encouraged new avenues of investigation into the potential of exploiting metabolic addictions to improve therapeutic efficacy and overcome drug resistance in cancer. Here, we review the role cancer metabolism can play in mediating drug resistance, and the exciting opportunities presented by imposed metabolic vulnerabilities.
    Keywords:  cancer metabolism; cell death; drug resistance; mitochondria
    DOI:  https://doi.org/10.3390/cancers13133351
  32. Cancers (Basel). 2021 Jul 15. pii: 3541. [Epub ahead of print]13(14):
      Arginine is an amino acid critically involved in multiple cellular processes including the syntheses of nitric oxide and polyamines, and is a direct activator of mTOR, a nutrient-sensing kinase strongly implicated in carcinogenesis. Yet, it is also considered as a non- or semi-essential amino acid, due to normal cells' intrinsic ability to synthesize arginine from citrulline and aspartate via ASS1 (argininosuccinate synthase 1) and ASL (argininosuccinate lyase). As such, arginine can be used as a dietary supplement and its depletion as a therapeutic strategy. Strikingly, in over 70% of tumors, ASS1 transcription is suppressed, rendering the cells addicted to external arginine, forming the basis of arginine-deprivation therapy. In this review, we will discuss arginine as a signaling metabolite, arginine's role in cancer metabolism, arginine as an epigenetic regulator, arginine as an immunomodulator, and arginine as a therapeutic target. We will also provide a comprehensive summary of ADI (arginine deiminase)-based arginine-deprivation preclinical studies and an update of clinical trials for ADI and arginase. The different cell killing mechanisms associated with various cancer types will also be described.
    Keywords:  ADI; arginase; arginine; arginine-deprivation therapy; cancer metabolism; epigenetics
    DOI:  https://doi.org/10.3390/cancers13143541
  33. J Biol Chem. 2021 Jul 16. pii: S0021-9258(21)00774-2. [Epub ahead of print] 100972
      Heme plays a critical role in catalyzing life-essential redox reactions in all cells, and its synthesis must be tightly balanced with cellular requirements. Heme synthesis in eukaryotes is tightly regulated by the mitochondrial AAA+ unfoldase CLPX (caseinolytic mitochondrial matrix peptidase chaperone subunit X), which promotes heme synthesis by activation of δ-aminolevulinate synthase (ALAS/Hem1) in yeast and regulates turnover of ALAS1 in human cells. However, the specific mechanisms by which CLPX regulates heme synthesis are unclear. In this study, we interrogated the mechanisms by which CLPX regulates heme synthesis in erythroid cells. Quantitation of enzyme activity and protein degradation showed that ALAS2 stability and activity were both increased in the absence of CLPX, suggesting that CLPX primarily regulates ALAS2 by control of its turnover, rather than its activation. However, we also showed that CLPX is required for PPOX (protoporphyinogen IX oxidase) activity and maintenance of FECH (ferrochelatase) levels, which are the terminal enzymes in heme synthesis, likely accounting for the heme deficiency and porphyrin accumulation observed in Clpx-/- cells. Lastly, CLPX is required for iron utilization for hemoglobin synthesis during erythroid differentiation. Collectively, our data show that the role of CLPX in yeast ALAS/Hem1 activation is not conserved in vertebrates as vertebrates rely on CLPX to regulate ALAS turnover as well as PPOX and FECH activity. Our studies reveal that CLPX mutations may cause anemia and porphyria via dysregulation of ALAS, FECH and PPOX activities, as well as of iron metabolism.
    DOI:  https://doi.org/10.1016/j.jbc.2021.100972
  34. Mol Cell. 2021 Jul 12. pii: S1097-2765(21)00507-4. [Epub ahead of print]
      Mutant isocitrate dehydrogenase (IDH) 1 and 2 play a pathogenic role in cancers, including acute myeloid leukemia (AML), by producing oncometabolite 2-hydroxyglutarate (2-HG). We recently reported that tyrosine phosphorylation activates IDH1 R132H mutant in AML cells. Here, we show that mutant IDH2 (mIDH2) R140Q commonly has K413 acetylation, which negatively regulates mIDH2 activity in human AML cells by attenuating dimerization and blocking binding of substrate (α-ketoglutarate) and cofactor (NADPH). Mechanistically, K413 acetylation of mitochondrial mIDH2 is achieved through a series of hierarchical phosphorylation events mediated by tyrosine kinase FLT3, which phosphorylates mIDH2 to recruit upstream mitochondrial acetyltransferase ACAT1 and simultaneously activates ACAT1 and inhibits upstream mitochondrial deacetylase SIRT3 through tyrosine phosphorylation. Moreover, we found that the intrinsic enzyme activity of mIDH2 is much higher than mIDH1, thus the inhibitory K413 acetylation optimizes leukemogenic ability of mIDH2 in AML cells by both producing sufficient 2-HG for transformation and avoiding cytotoxic accumulation of intracellular 2-HG.
    Keywords:  2-HG; ACAT1; AML; FLT3; K413 acetylation; SIRT3; dimerization; mutant IDH2
    DOI:  https://doi.org/10.1016/j.molcel.2021.06.027
  35. Cancers (Basel). 2021 Jul 01. pii: 3311. [Epub ahead of print]13(13):
      Carcinogenesis is a multi-step process that refers to transformation of a normal cell into a tumoral neoplastic cell. The mechanisms that promote tumor initiation, promotion and progression are varied, complex and remain to be understood. Studies have highlighted the involvement of oncogenic mutations, genomic instability and epigenetic alterations as well as metabolic reprogramming, in different processes of oncogenesis. However, the underlying mechanisms still have to be clarified. Mitochondria are central organelles at the crossroad of various energetic metabolisms. In addition to their pivotal roles in bioenergetic metabolism, they control redox homeostasis, biosynthesis of macromolecules and apoptotic signals, all of which are linked to carcinogenesis. In the present review, we discuss how mitochondria contribute to the initiation of carcinogenesis through gene mutations and production of oncometabolites, and how they promote tumor progression through the control of metabolic reprogramming and mitochondrial dynamics. Finally, we present mitochondrial metabolism as a promising target for the development of novel therapeutic strategies.
    Keywords:  ROS; Warburg effect; carcinogenesis; metabolic reprogramming; mitochondria; mitochondrial oxidative respiration; mitophagy; mtDNA mutations; oncometabolites; therapy
    DOI:  https://doi.org/10.3390/cancers13133311
  36. J Mol Med (Berl). 2021 Jul 17.
      Mutations in BCS1L are the most frequent cause of human mitochondrial disease linked to complex III deficiency. Different forms of BCS1L-related diseases and more than 20 pathogenic alleles have been reported to date. Clinical symptoms are highly heterogenous, and multisystem involvement is often present, with liver and brain being the most frequently affected organs. BCS1L encodes a mitochondrial AAA + -family member with essential roles in the latest steps in the biogenesis of mitochondrial respiratory chain complex III. Since Bcs1 has been investigated mostly in yeast and mammals, its function in invertebrates remains largely unknown. Here, we describe the phenotypical, biochemical and metabolic consequences of Bcs1 genetic manipulation in Drosophila melanogaster. Our data demonstrate the fundamental role of Bcs1 in complex III biogenesis in invertebrates and provide novel, reliable models for BCS1L-related human mitochondrial diseases. These models recapitulate several features of the human disorders, collectively pointing to a crucial role of Bcs1 and, in turn, of complex III, in development, organismal fitness and physiology of several tissues.
    Keywords:  BCS1L; Drosophila melanogaster; Mitochondrial disease; Mitochondrial respiratory chain; Respiratory chain complex III
    DOI:  https://doi.org/10.1007/s00109-021-02110-1
  37. Trends Endocrinol Metab. 2021 Jul 20. pii: S1043-2760(21)00133-8. [Epub ahead of print]
      There has been an explosion of interest in the signaling capacity of energy metabolites. A prime example is the Krebs cycle substrate succinate, an archetypal respiratory substrate with functions beyond energy production as an intracellular and extracellular signaling molecule. Long associated with inflammation, emerging evidence supports a key role for succinate in metabolic processes relating to energy management. As the natural ligand for SUCNR1, a G protein-coupled receptor, succinate is akin to hormones and likely functions as a reporter of metabolism and stress. In this review, we reconcile new and old observations to outline a regulatory role for succinate in metabolic homeostasis. We highlight the importance of the succinate-SUCNR1 axis in metabolic diseases as an integrator of macrophage immune response, and we discuss new metabolic functions recently ascribed to succinate in specific tissues. Because circulating succinate has emerged as a promising biomarker in chronic metabolic diseases, a better understanding of the physiopathological role of the succinate-SUCNR1 axis in metabolism might open new avenues for clinical use in patients with obesity or diabetes.
    Keywords:  SUCNR1; energy metabolite; metabolic diseases; metabolic function; succinate
    DOI:  https://doi.org/10.1016/j.tem.2021.06.003
  38. PLoS Comput Biol. 2021 Jul 23. 17(7): e1009234
      Metabolic adaptations to complex perturbations, like the response to pharmacological treatments in multifactorial diseases such as cancer, can be described through measurements of part of the fluxes and concentrations at the systemic level and individual transporter and enzyme activities at the molecular level. In the framework of Metabolic Control Analysis (MCA), ensembles of linear constraints can be built integrating these measurements at both systemic and molecular levels, which are expressed as relative differences or changes produced in the metabolic adaptation. Here, combining MCA with Linear Programming, an efficient computational strategy is developed to infer additional non-measured changes at the molecular level that are required to satisfy these constraints. An application of this strategy is illustrated by using a set of fluxes, concentrations, and differentially expressed genes that characterize the response to cyclin-dependent kinases 4 and 6 inhibition in colon cancer cells. Decreases and increases in transporter and enzyme individual activities required to reprogram the measured changes in fluxes and concentrations are compared with down-regulated and up-regulated metabolic genes to unveil those that are key molecular drivers of the metabolic response.
    DOI:  https://doi.org/10.1371/journal.pcbi.1009234
  39. Front Cell Dev Biol. 2021 ;9 655731
      The mechanistic target of rapamycin (mTOR), master regulator of cellular metabolism, exists in two distinct complexes: mTOR complex 1 and mTOR complex 2 (mTORC1 and 2). MTORC1 is a master switch for most energetically onerous processes in the cell, driving cell growth and building cellular biomass in instances of nutrient sufficiency, and conversely, allowing autophagic recycling of cellular components upon nutrient limitation. The means by which the mTOR kinase blocks autophagy include direct inhibition of the early steps of the process, and the control of the lysosomal degradative capacity of the cell by inhibiting the transactivation of genes encoding structural, regulatory, and catalytic factors. Upon inhibition of mTOR, autophagic recycling of cellular components results in the reactivation of mTORC1; thus, autophagy lies both downstream and upstream of mTOR. The functional relationship between the mTOR pathway and autophagy involves complex regulatory loops that are significantly deciphered at the cellular level, but incompletely understood at the physiological level. Nevertheless, genetic evidence stemming from the use of engineered strains of mice has provided significant insight into the overlapping and complementary metabolic effects that physiological autophagy and the control of mTOR activity exert during fasting and nutrient overload.
    Keywords:  autophagy; lysosome; mechanistic target of rapamycin; metabolism; nutrients
    DOI:  https://doi.org/10.3389/fcell.2021.655731
  40. Semin Cell Dev Biol. 2021 Jul 16. pii: S1084-9521(21)00195-6. [Epub ahead of print]
      Intrinsic circadian clocks are present in all forms of photosensitive life, enabling daily anticipation of the light/dark cycle and separation of energy storage and utilization cycles on a 24-h timescale. The core mechanism underlying circadian rhythmicity involves a cell-autonomous transcription/translation feedback loop that in turn drives rhythmic organismal physiology. In mammals, genetic studies have established that the core clock plays an essential role in maintaining metabolic health through actions within both brain pacemaker neurons and peripheral tissues and that disruption of the clock contributes to disease. Peripheral clocks, in turn, can be entrained by metabolic cues. In this review, we focus on the role of the nucleotide NAD(P)(H) and NAD+-dependent sirtuin deacetylases as integrators of circadian and metabolic cycles, as well as the implications for this interrelationship in healthful aging.
    Keywords:  Aging; Circadian clock; Metabolism; Nicotinamide adenine dinucleotide (NAD(+)); Sirtuins
    DOI:  https://doi.org/10.1016/j.semcdb.2021.07.008
  41. Front Physiol. 2021 ;12 689747
      Lactate, a metabolite produced when the glycolytic flux exceeds mitochondrial oxidative capacities, is now viewed as a critical regulator of metabolism by acting as both a carbon and electron carrier and a signaling molecule between cells and tissues. In recent years, increasing evidence report its key role in white, beige, and brown adipose tissue biology, and highlights new mechanisms by which lactate participates in the maintenance of whole-body energy homeostasis. Lactate displays a wide range of biological effects in adipose cells not only through its binding to the membrane receptor but also through its transport and the subsequent effect on intracellular metabolism notably on redox balance. This study explores how lactate regulates adipocyte metabolism and plasticity by balancing intracellular redox state and by regulating specific signaling pathways. We also emphasized the contribution of adipose tissues to the regulation of systemic lactate metabolism, their roles in redox homeostasis, and related putative physiopathological repercussions associated with their decline in metabolic diseases and aging.
    Keywords:  adipose tissues; beige adipocytes; brown adipocytes; lactate; metabolic dialogs; redox metabolism; white adipocytes
    DOI:  https://doi.org/10.3389/fphys.2021.689747
  42. Mult Scler Relat Disord. 2021 Jul 03. pii: S2211-0348(21)00399-0. [Epub ahead of print]54 103132
      Succinate dehydrogenase (SDH), or respiratory complex II, consists of four nuclear-encoded subunits. The chaperone protein succinate dehydrogenase assembly factor 1 (SDHAF1) plays an essential role in the assembly of SDH, and in the incorporation of iron-sulfur clusters into the SDHB subunit. SDHB couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol. Previously reported mutations in SDHAF1 have been associated with infantile leukoencephalopathy. We report an adult case with a homozygous variant of uncertain significance (VUS) mutation in SDHAF1, presenting with dementia, spastic paraparesis, and cardiomyopathy, initially diagnosed as multiple sclerosis.
    Keywords:  Leukoencephalopathy; Multiple sclerosis; Respiratory chain; Succinate dehydrogenase assembly factor 1
    DOI:  https://doi.org/10.1016/j.msard.2021.103132
  43. Cancer Res. 2021 Jul 23. pii: canres.0345.2021. [Epub ahead of print]
      Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of RCC, and its progression has been linked to chronic inflammation. About 70% of the ccRCC cases are associated with inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. However, it is still not clear how mutations in VHL, encoding the substrate-recognition subunit of an E3 ubiquitin ligase that targets the alpha subunit of hypoxia-inducible factor (HIF-α), can coordinate tissue inflammation and tumorigenesis. We previously generated mice with conditional Vhlh knockout in kidney tubules, which resulted in severe inflammation and fibrosis in addition to hyperplasia and the appearance of transformed clear cells. Interestingly, the endothelial cells (ECs), although not subject to genetic manipulation, nonetheless showed profound changes in gene expression that suggest a role in promoting inflammation and tumorigenesis. Oncostatin M (OSM) mediated the interaction between VHL-deficient renal tubule cells and the ECs, where the activated ECs in turn induce macrophage recruitment and polarization. The OSM-dependent microenvironment also promoted metastasis of exogenous tumors. Thus, OSM signaling initiates reconstitution of an inflammatory and tumorigenic microenvironment by VHL-deficient renal tubule cells, which plays a critical role in ccRCC initiation and progression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0345
  44. Sci Rep. 2021 Jul 21. 11(1): 14827
      Inactivation of the tumor suppressor von Hippel-Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC). The mechanistic target of rapamycin (mTOR) signaling pathway is a fundamental regulator of cell growth and proliferation, and hyperactivation of mTOR signaling is a common finding in VHL-dependent ccRCC. Deregulation of mTOR signaling correlates with tumor progression and poor outcome in patients with ccRCC. Here, we report that the regulatory-associated protein of mTOR (RAPTOR) is strikingly repressed by VHL. VHL interacts with RAPTOR and increases RAPTOR degradation by ubiquitination, thereby inhibiting mTORC1 signaling. Consistent with hyperactivation of mTORC1 signaling in VHL-deficient ccRCC, we observed that loss of vhl-1 function in C. elegans increased mTORC1 activity, supporting an evolutionary conserved mechanism. Our work reveals important new mechanistic insight into deregulation of mTORC1 signaling in ccRCC and links VHL directly to the control of RAPTOR/mTORC1. This may represent a novel mechanism whereby loss of VHL affects organ integrity and tumor behavior.
    DOI:  https://doi.org/10.1038/s41598-021-94132-5