bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2020‒04‒19
thirty-two papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit


  1. Science. 2020 Apr 17. 368(6488): 283-290
    Pareek V, Tian H, Winograd N, Benkovic SJ.
      Metabolons, multiprotein complexes consisting of sequential enzymes of a metabolic pathway, are proposed to be biosynthetic "hotspots" within the cell. However, experimental demonstration of their presence and functions has remained challenging. We used metabolomics and in situ three-dimensional submicrometer chemical imaging of single cells by gas cluster ion beam secondary ion mass spectrometry (GCIB-SIMS) to directly visualize de novo purine biosynthesis by a multienzyme complex, the purinosome. We found that purinosomes comprise nine enzymes that act synergistically, channeling the pathway intermediates to synthesize purine nucleotides, increasing the pathway flux, and influencing the adenosine monophosphate/guanosine monophosphate ratio. Our work also highlights the application of high-resolution GCIB-SIMS for multiplexed biomolecular analysis at the level of single cells.
    DOI:  https://doi.org/10.1126/science.aaz6465
  2. Semin Nephrol. 2020 Mar;pii: S0270-9295(20)30002-4. [Epub ahead of print]40(2): 101-113
    Clark AJ, Parikh SM.
      The kidney is a highly metabolic organ that requires substantial adenosine triphosphate for the active transport required to maintain water and solute reabsorption. Aberrations in energy availability and energy utilization can lead to cellular dysfunction and death. Mitochondria are essential for efficient energy production. The pathogenesis of acute kidney injury is complex and varies with different types of injury. However, multiple distinct acute kidney injury syndromes share a common dysregulation of energy metabolism. Pathways of energy metabolism and mitochondrial dysfunction are emerging as critical drivers of acute kidney injury and represent new potential targets for treatment. This review shows the basic metabolic pathways that all cells depend on for life; describes how the kidney optimizes those pathways to meet its anatomic, physiologic, and metabolic needs; summarizes the importance of metabolic and mitochondrial dysfunction in acute kidney injury; and analyzes the mitochondrial processes that become dysregulated in acute kidney injury including mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and changes in mitochondrial energy metabolism.
    Keywords:  Acute kidney injury; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.semnephrol.2020.01.002
  3. Biochem J. 2020 Apr 16. pii: BCJ20190754. [Epub ahead of print]
    Martin SB, Reiche WS, Fifelski NA, Schultz AJ, Stanford SJ, Martin AA, Nack DL, Radlwimmer B, Boyer MP, Ananieva E.
      Osteosarcoma and chondrosarcoma are sarcomas of the bone and the cartilage that are primarily treated by surgical intervention combined with high toxicity chemotherapy. In search of alternative metabolic approaches to address the challenges in treating bone sarcomas, we assessed the growth dependence of these cancers on leucine, one of the branched chain amino acids (BCAAs), and BCAA metabolism. Tumor biopsies from bone sarcoma patients revealed differential expression of BCAA metabolic enzymes. The cytosolic branched chain aminotransferase (BCATc) that is commonly overexpressed in cancer cells, was downregulated in chondrosarcoma (SW1353) in contrast to osteosarcoma (143B) cells that expressed both BCATc and its mitochondrial isoform BCATm. Treating SW1353cells with gabapentin, a selective inhibitor of BCATc, further revealed that these cells failed to respond to gabapentin. Application of the structural analog of leucine, N-acetyl-leucine amide (NALA) to disrupt leucine uptake, indicated that all bone sarcoma cells used leucine to support their energy metabolism and biosynthetic demands. This was evident from the increased activity of the energy sensor AMP-activated protein kinase (AMPK), downregulation of complex 1 of the mammalian target of rapamycin (mTORC1), and reduced cell viability in response to NALA.  The observed changes were most profound in the 143B cells, which appeared highly dependent on cytosolic and mitochondrial BCAA metabolism. This study thus demonstrates that bone sarcomas rely on leucine and BCAA metabolism for energy and growth; however, the differential expression of BCAA enzymes and the presence of other carbon sources may dictate how efficiently these cancer cells take advantage of BCAA metabolism.
    Keywords:  BCAAs; BCATc; BCATm; Leucine; chondrosarcoma; osteosarcoma
    DOI:  https://doi.org/10.1042/BCJ20190754
  4. Autophagy. 2020 Apr 15. 1-3
    Heimbucher T, Qi W, Baumeister R.
      Macroautophagy/autophagy is an evolutionarily conserved cellular degradation and recycling process that is tightly regulated by external stimuli, diet, and stress. Our recent findings suggest that in C. elegans, a nutrient sensing pathway mediated by MTORC2 (mechanistic target of rapamycin kinase complex 2) and its downstream effector kinase SGK-1 (serum- and glucocorticoid-inducible kinase homolog 1) suppresses autophagy, involving mitophagy. Induced autophagy/mitophagy in MTORC2-deficient animals slows down development and impairs reproduction independently of the SGK-1 effectors DAF-16/FOXO and SKN-1/NFE2L2/NRF2. In this punctum, we discuss how TORC2-SGK-1 signaling might regulate autophagic turnover and its impact on mitochondrial homeostasis via linking mitochondria-derived reactive oxygen species (mtROS) production to mitophagic turnover.
    Keywords:  Autophagy; MTORC (mechanistic target of rapamycin kinase complex); ROS (reactive oxygen species); SGK-1 (serum- and glucocorticoid-inducible kinase homolog 1); VDAC1 (voltage dependent anion channel 1); mitophagy
    DOI:  https://doi.org/10.1080/15548627.2020.1749368
  5. Biol Chem. 2020 Apr 01. pii: /j/bchm.just-accepted/hsz-2020-0135/hsz-2020-0135.xml. [Epub ahead of print]
    Bader V, Winklhofer KF.
      Mitochondria are highly vulnerable organelles based on their complex biogenesis, entailing dependence on nuclear gene expression and efficient import strategies. They are implicated in a wide spectrum of vital cellular functions, including oxidative phosphorylation, iron-sulfur cluster synthesis, regulation of calcium homeostasis and apoptosis. Moreover, damaged mitochondria can release mitochondrial components, such as mtDNA or cardiolipin, which are sensed as danger-associated molecular patterns and trigger innate immune signaling. Thus, dysfunctional mitochondria pose a thread not only to the cellular but also to the organismal integrity. The elimination of dysfunctional and damaged mitochondria by selective autophagy, called mitophagy, is a major mechanism of mitochondrial quality control. Certain types of stress-induced mitophagy are regulated by the mitochondrial kinase PINK1 and the E3 ubiquitin ligase Parkin, which are both linked to autosomal recessive Parkinson's disease.
    Keywords:  Parkinson; mitochondria; quality control; selective autophagy; ubiquitin
    DOI:  https://doi.org/10.1515/hsz-2020-0135
  6. Hum Mol Genet. 2020 Apr 13. pii: ddaa066. [Epub ahead of print]
    Berenguer-Escuder C, Grossmann D, Antony P, Arena G, Wasner K, Massart F, Jarazo J, Walter J, Schwamborn JC, Grünewald A, Krüger R.
      BACKGROUND: Mitochondrial Rho GTPase 1 (Miro1) protein is a well-known adaptor for mitochondrial transport, and also regulates mitochondrial quality control and function. Furthermore, Miro1 was associated with mitochondria-endoplasmic reticulum (ER) contact sites (MERCs), which are key regulators of cellular calcium homeostasis and the initiation of autophagy. Impairments of these mechanisms were linked to neurodegeneration in Parkinson's disease (PD). We recently revealed that PD fibroblasts harboring Miro1 mutations displayed dysregulations in MERC organization and abundance, affecting mitochondrial homeostasis and clearance. We hypothesize that mutant Miro1 impairs the function of MERCs and mitochondrial dynamics, altering neuronal homeostasis and integrity in PD.METHODS: PD skin fibroblasts harboring the Miro1-R272Q mutation were differentiated into patient-derived neurons. Live-cell imaging and immunocytochemistry were used to study mitophagy and the organization and function of MERCs. Markers of autophagy or mitochondrial function were assessed by Western blotting.
    RESULTS: Quantification of organelle juxtapositions revealed an increased number of MERCs in patient-derived neurons. Live-cell imaging results showed alterations of mitochondrial dynamics and increased sensitivity to calcium stress, as well as reduced mitochondrial clearance. Finally, Western blot analysis indicated a blockage of the autophagy flux in Miro1-mutant neurons.
    CONCLUSIONS: Miro1-mutant neurons display altered ER-mitochondrial tethering compared to control neurons. This alteration likely interferes with proper MERC function, contributing to a defective autophagic flux and cytosolic calcium handling capacity. Moreover, mutant Miro1 affects mitochondrial dynamics in neurons, which may result in disrupted mitochondrial turnover and altered mitochondrial movement.
    DOI:  https://doi.org/10.1093/hmg/ddaa066
  7. Nat Cell Biol. 2020 Apr 13.
    Singh S, Kumar S, Srivastava RK, Nandi A, Thacker G, Murali H, Kim S, Baldeon M, Tobias J, Blanco MA, Saffie R, Zaidi MR, Sinha S, Busino L, Fuchs SY, Chakrabarti R.
      Triple-negative breast cancer (TNBC) is characterized by a high degree of immune infiltrate in the tumour microenvironment, which may influence the fate of TNBC cells. We reveal that loss of the tumour suppressive transcription factor Elf5 in TNBC cells activates intrinsic interferon-γ (IFN-γ) signalling, promoting tumour progression and metastasis. Mechanistically, we find that loss of the Elf5-regulated ubiquitin ligase FBXW7 ensures stabilization of its putative protein substrate IFN-γ receptor 1 (IFNGR1) at the protein level in TNBC. Elf5low tumours show enhanced IFN-γ signalling accompanied by an increase of immunosuppressive neutrophils within the tumour microenvironment and increased programmed death ligand 1 expression. Inactivation of either programmed death ligand 1 or IFNGR1 elicited a robust anti-tumour and/or anti-metastatic effect. A positive correlation between ELF5 and FBXW7 expression and a negative correlation between ELF5, FBXW7 and IFNGR1 expression in the tumours of patients with TNBC strongly suggest that this signalling axis could be exploited for patient stratification and immunotherapeutic treatment strategies for Elf5low patients with TNBC.
    DOI:  https://doi.org/10.1038/s41556-020-0495-y
  8. Biochem Pharmacol. 2020 Apr 13. pii: S0006-2952(20)30188-X. [Epub ahead of print] 113960
    Feng J, Jiang W, Liu Y, Huang W, Hu K, Li K, Chen J, Ma C, Sun Z, Pang X.
      Signal transducer and activator of transcription 3 (STAT3) exerts a profound role in regulating mitochondrial function and cellular metabolism. Mitochondrial STAT3 supports RAS-dependent malignant transformation and tumor growth. However, whether pharmacological blockade of STAT3 leads to metabolic lethality in KRAS-mutant lung cancer remains unclear. Pyrvinium pamoate, a clinical antihelminthic drug, preferentially inhibited the growth of KRAS-mutant lung cancer cells in vitro and in vivo. Mechanistic study revealed that pyrvinium dose-dependently suppressed STAT3 phosphorylation at tyrosine 705 and serine 727. Overexpression mitochondrial STAT3 prominently weakened the therapeutic efficacy of pyrvinium. As a result of targeting STAT3, pyrvinium selectively triggered reactive oxygen species release, depolarized mitochondrial membrane potential and suppressed aerobic glycolysis in KRAS-mutant lung cancer cells. Importantly, the cytotoxic effects of pyrvinium could be significantly augmented by glucose deprivation both in vitro and in a patient-derived lung cancer xenograft mouse model in vivo. The combined efficacy significantly correlated with intratumoural STAT3 suppression. Our findings reveal that KRAS-mutant lung cancer cells are vulnerable to STAT3 inhibition exerted by pyrvinium, providing a promising direction for developing therapies targeting STAT3 and metabolic synthetic lethality for the treatment of KRAS-mutant lung cancer.
    Keywords:  KRAS; Metabolism; Pyrvinium pamoate; STAT3; Synthetic lethality
    DOI:  https://doi.org/10.1016/j.bcp.2020.113960
  9. Redox Rep. 2020 Dec;25(1): 26-32
    Hadrava Vanova K, Kraus M, Neuzil J, Rohlena J.
      Increasing evidence points to the respiratory Complex II (CII) as a source and modulator of reactive oxygen species (ROS). Both functional loss of CII as well as its pharmacological inhibition can lead to ROS generation in cells, with a relevant impact on the development of pathophysiological conditions, i.e. cancer and neurodegenerative diseases. While the basic framework of CII involvement in ROS production has been defined, the fine details still await clarification. It is important to resolve these aspects to fully understand the role of CII in pathology and to explore its therapeutic potential in cancer and other diseases.
    Keywords:  OXPHOS; Respiratory complex II; cancer; mitochondria; reactive oxygen species; succinate; succinate dehydrogenase; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1080/13510002.2020.1752002
  10. Semin Nephrol. 2020 Mar;pii: S0270-9295(20)30010-3. [Epub ahead of print]40(2): 199-205
    Quinn GZ, Dhillon P, Susztak K.
      Acute kidney injury is a major contributor of chronic kidney disease development. The pathogenesis of acute kidney injury and chronic kidney disease shows significant similarities. Both conditions are associated with a defect in cellular metabolism, such as fatty acid oxidation and mitochondrial oxidative phosphorylation in kidney tubule cells and a marked increase in infiltrating immune cells. Here, we discuss how inflammatory cytokines and macrophages contribute to epithelial injury and metabolic defects. In addition, we discuss the role of mitochondrial damage and cytosolic leakage of the mitochondrial DNA activating the innate immune pathway such as cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes. The interplay between inflammation and metabolism appears to be critical for kidney disease development.
    Keywords:  cGAS-STING; inflammation; innate immune system; kidney injury; metabolic dysregulation
    DOI:  https://doi.org/10.1016/j.semnephrol.2020.01.010
  11. Front Oncol. 2020 ;10 409
    Läsche M, Emons G, Gründker C.
      Since the earliest findings of Otto Warburg, who discovered the first metabolic differences between lactate production of cancer cells and non-malignant tissues in the 1920s, much time has passed. He explained the increased lactate levels with dysfunctional mitochondria and aerobic glycolysis despite adequate oxygenation. Meanwhile, we came to know that mitochondria remain instead functional in cancer cells; hence, metabolic drift, rather than being linked to dysfunctional mitochondria, was found to be an active act of direct response of cancer cells to cell proliferation and survival signals. This metabolic drift begins with the use of sugars and the full oxidative phosphorylation via the mitochondrial respiratory chain to form CO2, and it then leads to the formation of lactic acid via partial oxidation. In addition to oncogene-driven metabolic reprogramming, the oncometabolites themselves alter cell signaling and are responsible for differentiation and metastasis of cancer cells. The aberrant metabolism is now considered a major characteristic of cancer within the past 15 years. However, the proliferating anabolic growth of a tumor and its spread to distal sites of the body is not explainable by altered glucose metabolism alone. Since a tumor consists of malignant cells and its tumor microenvironment, it was important for us to understand the bilateral interactions between the primary tumor and its microenvironment and the processes underlying its successful metastasis. We here describe the main metabolic pathways and their implications in tumor progression and metastasis. We also portray that metabolic flexibility determines the fate of the cancer cell and ultimately the patient. This flexibility must be taken into account when deciding on a therapy, since singular cancer therapies only shift the metabolism to a different alternative path and create resistance to the medication used. As with Otto Warburg in his days, we primarily focused on the metabolism of mitochondria when dealing with this scientific question.
    Keywords:  cancer; metabolism; metastasis; microenvironment; therapy
    DOI:  https://doi.org/10.3389/fonc.2020.00409
  12. Trends Cell Biol. 2020 Apr 14. pii: S0962-8924(20)30058-1. [Epub ahead of print]
    Harris IS, DeNicola GM.
      Reactive oxygen species (ROS) play important roles in tissue homeostasis, cellular signaling, differentiation, and survival. In this review, we discuss the types of ROS, their impact on cellular processes, and their pro- and antitumorigenic effects. Further, we discuss recent advances in our understanding of both endogenous and exogenous antioxidants in tumorigenic processes. Finally, we discuss how aberrant activation of antioxidant programs by the transcription factor NFE2-related factor 2 (NRF2) influences tumorigenesis and metastasis, and where the current gaps in our knowledge remain.
    Keywords:  NRF2; ROS; antioxidant; cancer; glutathione
    DOI:  https://doi.org/10.1016/j.tcb.2020.03.002
  13. Sci Rep. 2020 Apr 14. 10(1): 6289
    Morone D, Autilia F, Schorn T, Erreni M, Doni A.
      Acidic pH occurs in acute wounds progressing to healing as consequence of a cell metabolic adaptation in response to injury-induced tissue hypoperfusion. In tumours, high metabolic rate leads to acidosis affecting cancer progression. Acidic pH affects activities of remodelling cells in vitro. The pH measurement predicts healing in pathological wounds and success of surgical treatment of burns and chronic ulcers. However, current methods are limited to skin surface or based on detection of fluorescence intensity of specific sensitive probes that suffer of microenvironment factors. Herein, we ascertained relevance in vivo of cell metabolic adaptation in skin repair by interfering with anaerobic glycolysis. Moreover, a custom-designed skin imaging chamber, 2-Photon microscopy (2PM), fluorescence lifetime imaging (FLIM) and data mapping analyses were used to correlate maps of glycolytic activity in vivo as measurement of NADH intrinsic lifetime with areas of hypoxia and acidification in models of skin injury and cancer. The method was challenged by measuring the NADH profile by interfering with anaerobic glycolysis and oxidative phosphorylation in the mitochondrial respiratory chain. Therefore, intravital NADH FLIM represents a tool for investigating cell metabolic adaptation occurring in wounds, as well as the relationship between cell metabolism and cancer.
    DOI:  https://doi.org/10.1038/s41598-020-63203-4
  14. Best Pract Res Clin Endocrinol Metab. 2020 Mar 10. pii: S1521-690X(20)30043-9. [Epub ahead of print] 101416
    Buffet A, Burnichon N, Favier J, Gimenez-Roqueplo AP.
      Paragangliomas and pheochromocytomas (PPGL) are rare neuroendocrine tumours characterized by a strong genetic determinism. Over the past 20 years, evolution of PPGL genetics has revealed that around 40% of PPGL are genetically determined, secondary to a germline mutation in one of more than twenty susceptibility genes reported so far. More than half of the mutations occur in one of the SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), which encode the different subunits and assembly protein of a mitochondrial enzyme, succinate dehydrogenase. These susceptibility genes predispose to early forms (VHL, RET, SDHD, EPAS1, DLST), syndromic (RET, VHL, EPAS1, NF1, FH), multiple (SDHD, TMEM127, MAX, DLST, MDH2, GOT2) or malignant (SDHB, FH, SLC25A11) PPGL. The discovery of a germline mutation in one of these genes changes the patient's follow-up and allows genetic screening of affected families and the presymptomatic follow-up of relatives carrying a mutation.
    Keywords:  SDHx; VHL; familial genetic screening; genetic; paraganglioma; pheochromocytoma
    DOI:  https://doi.org/10.1016/j.beem.2020.101416
  15. Aging (Albany NY). 2020 Apr 14. 12
    Wang Y, Yu T, Zhou Y, Wang S, Zhou X, Wang L, Ou T, Chen Y, Zhou Y, Zhang H, Wang Y, Fan X, Chen P, Gonzalez FJ, Yu A, Huang P, Huang M, Bi H.
      Stable transfection manipulation with antibiotic selection and passaging induces progressive cellular senescence phenotypes. However, the underlying mechanisms remain poorly understood. This study demonstrated that stable transfection of the empty vector induced PANC-1 cells into cellular senescence. Metabolomics revealed several acylcarnitines and their upstream regulatory gene, carnitine palmitoyltransferase 1C (CPT1C) involved in fatty acid β-oxidation in mitochondria, were strikingly decreased in senescent PANC-1 cells. Low CPT1C expression triggered mitochondrial dysfunction, inhibited telomere elongation, impaired cell survival under metabolic stress, and hindered the malignance and tumorigenesis of senescent cells. On the contrary, mitochondrial activity was restored by CPT1C gain-of-function in senescent vector PANC-1 cells. PPARα and TP53/CDKN1A, crucial signaling components in cellular senescence, were downregulated in senescent PANC-1 cells. This study identifies CPT1C as a key regulator of stable transfection-induced progressive PANC-1 cell senescence that inhibits mitochondrial function-associated metabolic reprogramming. These findings confirm the need to identify cell culture alterations after stable transfection, particularly when cells are used for metabolomics and mitochondria-associated studies, and suggest inhibition of CPT1C could be a promising target to intervene pancreatic tumorigenesis.
    Keywords:  carnitine palmitoyltransferase 1C; metabolic reprogramming; mitochondria; senescence; stable transfection
    DOI:  https://doi.org/10.18632/aging.103033
  16. Trends Cell Biol. 2020 May;pii: S0962-8924(20)30040-4. [Epub ahead of print]30(5): 408-424
    Kurmi K, Haigis MC.
      As one of the fundamental requirements for cell growth and proliferation, nitrogen acquisition and utilization must be tightly regulated. Nitrogen can be generated from amino acids (AAs) and utilized for biosynthetic processes through transamination and deamination reactions. Importantly, limitations of nitrogen availability in cells can disrupt the synthesis of proteins, nucleic acids, and other important nitrogen-containing compounds. Rewiring cellular metabolism to support anabolic processes is a feature common to both cancer and proliferating immune cells. In this review, we discuss how nitrogen is utilized in biosynthetic pathways and highlight different metabolic and oncogenic programs that alter the flow of nitrogen to sustain biomass production and growth, an important emerging feature of cancer and immune cell proliferation.
    Keywords:  T cells; ammonia; cancer cells; nitrogen metabolism; non-essential amino acids; transaminases; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tcb.2020.02.005
  17. Proc Natl Acad Sci U S A. 2020 Apr 17. pii: 201917948. [Epub ahead of print]
    Tavallaie M, Voshtani R, Deng X, Qiao Y, Jiang F, Collman JP, Fu L.
      Deregulation of mitochondrial dynamics leads to the accumulation of oxidative stress and unhealthy mitochondria; consequently, this accumulation contributes to premature aging and alterations in mitochondria linked to metabolic complications. We postulate that restrained mitochondrial ATP synthesis might alleviate age-associated disorders and extend healthspan in mammals. Herein, we prepared a previously discovered mitochondrial complex IV moderate inhibitor in drinking water and orally administered to standard-diet-fed, wild-type C57BL/6J mice every day for up to 16 mo. No manifestation of any apparent toxicity or deleterious effect on studied mouse models was observed. The impacts of an added inhibitor on a variety of mitochondrial functions were analyzed, such as respiratory activity, mitochondrial bioenergetics, and biogenesis, and a few age-associated comorbidities, including reactive oxygen species (ROS) production, glucose abnormalities, and obesity in mice. It was found that mitochondrial quality, dynamics, and oxidative metabolism were greatly improved, resulting in lean mice with a specific reduction in visceral fat plus superb energy and glucose homeostasis during their aging period compared to the control group. These results strongly suggest that a mild interference in ATP synthesis through moderation of mitochondrial activity could effectively up-regulate mitogenesis, reduce ROS production, and preserve mitochondrial integrity, thereby impeding the onset of metabolic syndrome. We conclude that this inhibitory intervention in mitochondrial respiration rectified the age-related physiological breakdown in mice by protecting mitochondrial function and markedly mitigated certain undesired primary outcomes of metabolic syndrome, such as obesity and type 2 diabetes. This intervention warrants further research on the treatment of metabolic syndrome of aging in humans.
    Keywords:  aging; cytochrome c oxidase; metabolic syndrome; mitochondria; mitogenesis
    DOI:  https://doi.org/10.1073/pnas.1917948117
  18. Trends Biochem Sci. 2020 Apr 11. pii: S0968-0004(20)30086-4. [Epub ahead of print]
    Sabouny R, Shutt TE.
      The dynamic processes of mitochondrial fission and fusion are tightly regulated, determine mitochondrial shape, and influence mitochondrial functions. For example, fission and fusion mediate energy output, production of reactive oxygen species (ROS), and mitochondrial quality control. As our understanding of the molecular machinery and mechanisms regulating dynamic changes in the mitochondrial network continues to grow, we are beginning to unravel important signaling pathways that integrate physiological cues to modulate mitochondrial morphology and function. Here, we highlight reciprocal regulation of mitochondrial fusion and fission as an emerging trend in the regulation of mitochondrial function.
    Keywords:  fragmentation; hyperfusion; mitochondrial dynamics; reciprocal regulation
    DOI:  https://doi.org/10.1016/j.tibs.2020.03.009
  19. Oncogene. 2020 Apr 14.
    Wu PK, Hong SK, Starenki D, Oshima K, Shao H, Gestwicki JE, Tsai S, Park JI.
      The mitochondrial HSP70 chaperone mortalin (HSPA9/GRP75) is often upregulated and mislocalized in MEK/ERK-deregulated tumors. Here, we show that mortalin depletion can selectively induce death of immortalized normal fibroblasts IMR90E1A when combined with K-RasG12V expression, but not with wild-type K-Ras expression, and that K-RasG12V-driven MEK/ERK activity is necessary for this lethality. This cell death was attenuated by knockdown or inhibition of adenine nucleotide translocase (ANT), cyclophilin D (CypD), or mitochondrial Ca2+ uniporter (MCU), which implicates a mitochondria-originated death mechanism. Indeed, mortalin depletion increased mitochondrial membrane permeability and induced cell death in KRAS-mutated human pancreatic ductal adenocarcinoma (PDAC) and colon cancer lines, which were attenuated by knockdown or inhibition of ANT, CypD, or MCU, and occurred independently of TP53 and p21CIP1. Intriguingly, JG-98, an advanced MKT-077 derivative, phenocopied the lethal effects of mortalin depletion in K-RasG12V-expressing IMR90E1A and KRAS-mutated tumor cell lines in vitro. Moreover, JG-231, a JG-98 analog with improved microsomal stability effectively suppressed the xenograft of MIA PaCa-2, a K-RasG12C-expressing human PDAC line, in athymic nude mice. These data demonstrate that oncogenic KRAS activity sensitizes cells to the effects of mortalin depletion, suggesting that mortalin has potential as a selective therapeutic target for KRAS-mutated tumors.
    DOI:  https://doi.org/10.1038/s41388-020-1285-5
  20. Cell Chem Biol. 2020 Apr 16. pii: S2451-9456(20)30112-4. [Epub ahead of print]27(4): 463-471
    Zou Y, Schreiber SL.
      Ferroptosis is an iron-dependent cell-death modality driven by oxidative phospholipid damage. In contrast to apoptosis, which enables organisms to eliminate targeted cells purposefully at specific times, ferroptosis appears to be a vulnerability of cells that otherwise use high levels of polyunsaturated lipids to their advantage. Cells in this high polyunsaturated lipid state generally have safeguards that mitigate ferroptotic risk. Since its recognition, ferroptosis has been implicated in degenerative diseases in tissues including kidney and brain, and is a targetable vulnerability in multiple cancers-each likely characterized by the high polyunsaturated lipid state with insufficient or overwhelmed ferroptotic safeguards. In this Perspective, we present progress toward defining the essential roles and key mediators of lipid peroxidation and ferroptosis in disease contexts. Moreover, we discuss gaps in our understanding of ferroptosis and list key challenges that have thus far limited the full potential of targeting ferroptosis for improving human health.
    DOI:  https://doi.org/10.1016/j.chembiol.2020.03.015
  21. Nat Rev Mol Cell Biol. 2020 Apr 16.
    Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, Campbell K, Cano A, Casanova J, Christofori G, Dedhar S, Derynck R, Ford HL, Fuxe J, García de Herreros A, Goodall GJ, Hadjantonakis AK, Huang RJY, Kalcheim C, Kalluri R, Kang Y, Khew-Goodall Y, Levine H, Liu J, Longmore GD, Mani SA, Massagué J, Mayor R, McClay D, Mostov KE, Newgreen DF, Nieto MA, Puisieux A, Runyan R, Savagner P, Stanger B, Stemmler MP, Takahashi Y, Takeichi M, Theveneau E, Thiery JP, Thompson EW, Weinberg RA, Williams ED, Xing J, Zhou BP, Sheng G, .
      Epithelial-mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by 'the EMT International Association' (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT.
    DOI:  https://doi.org/10.1038/s41580-020-0237-9
  22. Br J Cancer. 2020 Apr 15.
    Han S, Liu Y, Cai SJ, Qian M, Ding J, Larion M, Gilbert MR, Yang C.
      Isocitrate dehydrogenase (IDH) enzymes catalyse the oxidative decarboxylation of isocitrate and therefore play key roles in the Krebs cycle and cellular homoeostasis. Major advances in cancer genetics over the past decade have revealed that the genes encoding IDHs are frequently mutated in a variety of human malignancies, including gliomas, acute myeloid leukaemia, cholangiocarcinoma, chondrosarcoma and thyroid carcinoma. A series of seminal studies further elucidated the biological impact of the IDH mutation and uncovered the potential role of IDH mutants in oncogenesis. Notably, the neomorphic activity of the IDH mutants establishes distinctive patterns in cancer metabolism, epigenetic shift and therapy resistance. Novel molecular targeting approaches have been developed to improve the efficacy of therapeutics against IDH-mutated cancers. Here we provide an overview of the latest findings in IDH-mutated human malignancies, with a focus on glioma, discussing unique biological signatures and proceedings in translational research.
    DOI:  https://doi.org/10.1038/s41416-020-0814-x
  23. Front Oncol. 2020 ;10 360
    Gozzelino L, De Santis MC, Gulluni F, Hirsch E, Martini M.
      The phosphatidylinositide 3 kinases (PI3Ks) and their downstream mediators AKT and mammalian target of rapamycin (mTOR) are central regulators of glycolysis, cancer metabolism, and cancer cell proliferation. At the molecular level, PI3K signaling involves the generation of the second messenger lipids phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] and phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2]. There is increasing evidence that PI(3,4)P2 is not only the waste product for the removal of PI(3,4,5)P3 but can also act as a signaling molecule. The selective cellular functions for PI(3,4)P2 independent of PI(3,4,5)P3 have been recently described, including clathrin-mediated endocytosis and mTOR regulation. However, the specific spatiotemporal dynamics and signaling role of PI3K minor lipid messenger PI(3,4)P2 are not well-understood. This review aims at highlighting the biological functions of this lipid downstream of phosphoinositide kinases and phosphatases and its implication in cancer metabolism.
    Keywords:  AKT; INPP4; PI3K; PTEN; cancer biology; cancer metabolism; phosphatases; phosphoinositide
    DOI:  https://doi.org/10.3389/fonc.2020.00360
  24. Circ Res. 2020 Apr 17.
    Huo J, Lu S, Kwong JQ, Bround MJ, Grimes KM, Sargent MA, Brown ME, Davis ME, Bers DM, Molkentin JD.
      Rationale: Mitochondrial Ca2+ loading augments oxidative metabolism to match functional demands during times of increased work or injury. However, mitochondrial Ca2+ overload also directly causes mitochondrial rupture and cardiomyocyte death during ischemia-reperfusion injury by inducing mitochondrial permeability transition pore opening. The mitochondrial Ca2+ uniporter (MCU) mediates mitochondrial Ca2+ influx, and its activity is modulated by partner proteins in its molecular complex, including the MCUb subunit. Objective: Here we sought to examine the function of the MCUb subunit of the MCU-complex in regulating mitochondria Ca2+ influx dynamics, acute cardiac injury and long-term adaptation after ischemic injury. Methods and Results:Cardiomyocyte-specific MCUb overexpressing transgenic mice and Mcub gene-deleted (Mcub-/-) mice were generated to dissect the molecular function of this protein in the heart. We observed that MCUb protein is undetectable in the adult mouse heart at baseline, but mRNA and protein are induced after ischemia-reperfusion injury. MCUb overexpressing mice demonstrated inhibited mitochondrial Ca2+ uptake in cardiomyocytes and partial protection from ischemia-reperfusion injury by reducing mitochondrial permeability transition pore opening. Antithetically, deletion of the Mcub gene exacerbated pathologic cardiac remodeling and infarct expansion after ischemic injury in association with greater mitochondrial Ca2+ uptake. Furthermore, hindlimb remote ischemic pre-conditioning induced MCUb expression in the heart, which was associated with decreased mitochondrial Ca2+ uptake, collectively suggesting that induction of MCUb protein in the heart is protective. Similarly, mouse embryonic fibroblasts from Mcub-/- mice were more sensitive to Ca2+ overload. Conclusions: Our studies suggest that Mcub is a protective cardiac inducible gene that reduces mitochondrial Ca2+ influx and permeability transition pore opening after ischemic injury to reduce ongoing pathological remodeling.
    Keywords:  Ca2+ handling; ischemic injury; mitochondrial calcium; reperfusion injury
    DOI:  https://doi.org/10.1161/CIRCRESAHA.119.316369
  25. Mitochondrion. 2020 Apr 08. pii: S1567-7249(19)30342-3. [Epub ahead of print]
    Igamberdiev AU.
      While in heterotrophic cells and in darkness mitochondria serve as main producers of energy, during photosynthesis this function is transferred to chloroplasts and the main role of mitochondria in bioenergetics turns to be the balance of the level of phosphorylation of adenylates and of reduction of pyridine nucleotides to avoid over-energization of the cell and optimize major metabolic fluxes. This is achieved via the establishment and regulation of local equilibria of the tricarboxylic acid (TCA) cycle enzymes malate dehydrogenase and fumarase in one branch and aconitase and isocitrate dehydrogenase in another branch. In the conditions of elevation of redox level, the TCA cycle is transformed into a non-cyclic open structure (hemicycle) leading to the export of the tricarboxylic acid (citrate) to the cytosol and to the accumulation of the dicarboxylic acids (malate and fumarate). While the buildup of NADPH in chloroplasts provides operation of the malate valve leading to establishment of NADH/NAD+ ratios in different cell compartments, the production of NADH by mitochondria drives citrate export by establishing conditions for the operation of the citrate valve. The latter regulates the intercompartmental NADPH/NADP+ ratio and contributes to the biosynthesis of amino acids and other metabolic products during photosynthesis.
    Keywords:  citrate hemicycle; citrate valve; isocitrate dehydrogenase; malate valve; plant mitochondria; redox regulation; thermodynamic buffering
    DOI:  https://doi.org/10.1016/j.mito.2020.04.003
  26. Nat Chem Biol. 2020 Apr 13.
    Lynch JH, Qian Y, Guo L, Maoz I, Huang XQ, Garcia AS, Louie G, Bowman ME, Noel JP, Morgan JA, Dudareva N.
      In plants, phenylalanine biosynthesis occurs via two compartmentally separated pathways. Overexpression of petunia chorismate mutase 2 (PhCM2), which catalyzes the committed step of the cytosolic pathway, increased flux in cytosolic phenylalanine biosynthesis, but paradoxically decreased the overall levels of phenylalanine and phenylalanine-derived volatiles. Concomitantly, the levels of auxins, including indole-3-acetic acid and its precursor indole-3-pyruvic acid, were elevated. Biochemical and genetic analyses revealed the existence of metabolic crosstalk between the cytosolic phenylalanine biosynthesis and tryptophan-dependent auxin biosynthesis mediated by an aminotransferase that uses a cytosolic phenylalanine biosynthetic pathway intermediate, phenylpyruvate, as an amino acceptor for auxin formation.
    DOI:  https://doi.org/10.1038/s41589-020-0519-8
  27. Br J Pharmacol. 2020 Apr 15.
    Forte M, Schirone L, Ameri P, Basso C, Catalucci D, Modica J, Chimenti C, Crotti L, Frati G, Rubattu S, Schiattarella GG, Torella D, Perrino C, Indolfi C, Sciarretta S, .
      The process of mitochondrial dynamics is emerging as a core player in cardiovascular homeostasis. This process refers to the coordinated cycles of biogenesis, fusion, fission and degradation to which mitochondria constantly undergo to maintain their integrity, distribution and size. These mechanisms represent an early response to mitochondrial stress, confining organelle portions that are irreversibly damaged and preserving mitochondrial function. Accumulating evidence demonstrates that impairment in mitochondrial dynamics leads to myocardial damage and cardiac disease progression in a variety of disease models, including pressure overload, ischemia/reperfusion and metabolic disturbance. These findings suggest that modulation of mitochondrial dynamics may be considered as a valid therapeutic strategy in cardiovascular diseases. In this review, we discuss the current evidence about the role of mitochondrial dynamics in cardiac pathophysiology, with a particular focus on the mechanisms underlying the development of cardiac hypertrophy and heart failure, metabolic and genetic cardiomyopathies, ischemia/reperfusion injury, atherosclerosis and ischemic stroke.
    Keywords:  fission; fusion; mitochondrial dynamics; cardiovascular diseases; mitophagy
    DOI:  https://doi.org/10.1111/bph.15068
  28. DNA Cell Biol. 2020 Apr 13.
    La P, Oved JH, Ghiaccio V, Rivella S.
      Iron-sulfur (Fe-S) clusters are required for mitochondrial function. Fe-S cluster synthesis occurs in the mitochondria and iron uptake is required for mitochondrial biogenesis. However, Fe-S clusters inhibit the expression of the iron importer transferrin receptor 1 (TfR1), whereas lack of the Fe-S cluster stimulates TfR1 expression. Yet, it is unclear whether Fe-S cluster synthesis increases with mitochondria biogenesis and, in turn, whether this negatively modulates TfR1 expression. We manipulated peroxisome proliferator-activated receptor-gamma coactivator-1α expression to control mitochondrial biogenesis in a variety of cell types, including erythroid cells. We demonstrated that Fe-S cluster synthesis increases with mitochondria biogenesis but does not interfere with increasing TfR1 expression. In fact, TfR1 expression is stimulated through alternative means to meet iron requirement for mitochondria biogenesis. Furthermore, under enhanced mitochondria biogenesis, increased Fe-S cluster synthesis inhibits the function of iron-regulating protein (IRP)1 and hence stimulates the expression of 5'-aminolevulinate synthase 2 (ALAS2), a target of IRP1 and rate-limiting enzyme in erythroid heme biogenesis. Increased ALAS2 expression leads to enhanced heme production, hemoglobinization, and erythropoiesis. Therefore, our study also provides a mechanism to link mitochondrial biogenesis with erythropoiesis and has a potential therapeutic value in the treatment of blood disorders.
    Keywords:  TfR1; erythropoiesis; heme; iron–sulfur cluster; mitochondria biogenesis
    DOI:  https://doi.org/10.1089/dna.2019.5123
  29. Proc Natl Acad Sci U S A. 2020 Apr 14. pii: 201920612. [Epub ahead of print]
    Hartley AM, Meunier B, Pinotsis N, Maréchal A.
      The organization of the mitochondrial electron transport chain proteins into supercomplexes (SCs) is now undisputed; however, their assembly process, or the role of differential expression isoforms, remain to be determined. In Saccharomyces cerevisiae, cytochrome c oxidase (CIV) forms SCs of varying stoichiometry with cytochrome bc 1 (CIII). Recent studies have revealed, in normoxic growth conditions, an interface made exclusively by Cox5A, the only yeast respiratory protein that exists as one of two isoforms depending on oxygen levels. Here we present the cryo-EM structures of the III2-IV1 and III2-IV2 SCs containing the hypoxic isoform Cox5B solved at 3.4 and 2.8 Å, respectively. We show that the change of isoform does not affect SC formation or activity, and that SC stoichiometry is dictated by the level of CIII/CIV biosynthesis. Comparison of the CIV5B- and CIV5A-containing SC structures highlighted few differences, found mainly in the region of Cox5. Additional density was revealed in all SCs, independent of the CIV isoform, in a pocket formed by Cox1, Cox3, Cox12, and Cox13, away from the CIII-CIV interface. In the CIV5B-containing hypoxic SCs, this could be confidently assigned to the hypoxia-induced gene 1 (Hig1) type 2 protein Rcf2. With conserved residues in mammalian Hig1 proteins and Cox3/Cox12/Cox13 orthologs, we propose that Hig1 type 2 proteins are stoichiometric subunits of CIV, at least when within a III-IV SC.
    Keywords:  Hig1 proteins; bioenergetics; cytochrome c oxidase; electron transport chain; respiratory supercomplexes
    DOI:  https://doi.org/10.1073/pnas.1920612117
  30. Cell Chem Biol. 2020 Apr 02. pii: S2451-9456(20)30110-0. [Epub ahead of print]
    Stockwell BR, Jiang X.
      Ferroptosis is a recently described form of cell death driven by iron-dependent lipid peroxidation. This type of cell death was first observed in response to treatment of tumor cells with a small-molecule chemical probe named erastin. Most subsequent advances in understanding the mechanisms governing ferroptosis involved the use of genetic screens and small-molecule probes. We describe herein the utility and limitations of chemical probes that have been used to analyze and perturb ferroptosis, as well as mechanistic studies of ferroptosis that benefitted from the use of these probes and genetic screens. We also suggest probes for ferroptosis and highlight mechanistic questions surrounding this form of cell death that will be a high priority for exploration in the future.
    Keywords:  ROS; cancer; cell death; chemical probe; cysteine; ferroptosis; glutathione; iron; lipid peroxidation; metabolism
    DOI:  https://doi.org/10.1016/j.chembiol.2020.03.013
  31. Elife. 2020 Apr 15. pii: e56214. [Epub ahead of print]9
    Wallings RL, Herrick MK, Tansey MG.
      A gene associated with Parkinson's disease regulates mitochondrial homeostasis, thus affecting innate immunity.
    Keywords:  DRP1; Parkinson's disease; bacterial pathogenesis; cGAS; human; immunology; infectious disease; inflammation; metabolism; microbiology; mouse; purine biosynthesis
    DOI:  https://doi.org/10.7554/eLife.56214
  32. Biol Chem. 2020 Apr 01. pii: /j/bchm.just-accepted/hsz-2020-0118/hsz-2020-0118.xml. [Epub ahead of print]
    Ren M, Yang X, Bie J, Wang Z, Liu M, Li Y, Shao G, Luo J.
      Citrate synthase (CS), the rate-limiting enzyme in the TCA cycle, catalyzes the first step of the cycle, namely, the condensation of oxaloacetate and acetyl-CoA to produce citrate. The expression and enzymatic activity of CS are altered in cancers, but posttranslational modification (PTM) of CS and its regulation in tumorigenesis remain largely obscure. SIRT5 belongs to the nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase sirtuin family and plays vital roles in multiple biological processes via modulating various substrates. Here, we show that SIRT5 interacts with CS and that SIRT5 desuccinylates CS at the evolutionarily conserved residues K393 and K395. Moreover, hypersuccinylation of CS at K393 and K395 dramatically reduces its enzymatic activity and suppresses colon cancer cell proliferation and migration. These results provide experimental evidence in support of a potential therapeutic approach for colon cancer.
    Keywords:  SIRT5; cancer; citrate synthase; succinylation
    DOI:  https://doi.org/10.1515/hsz-2020-0118