bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2021‒08‒08
fifty-four papers selected by
Kelsey Fisher-Wellman
East Carolina University
  1. The human cytomegalovirus protein pUL13 targets mitochondrial cristae architecture to increase cellular respiration during infection.
  2. Impact of aging and exercise on skeletal muscle mitochondrial capacity, energy metabolism, and physical function.
  3. Insulin and IGF-1 receptors regulate complex-I dependent mitochondrial bioenergetics and supercomplexes via FoxOs in muscle.
  4. BRCA2 deficiency reveals that oxidative stress impairs RNaseH1 function to cripple mitochondrial DNA maintenance.
  5. Excess dietary carbohydrate affects mitochondrial integrity as observed in brown adipose tissue.
  6. Instability in NAD+ metabolism leads to impaired cardiac mitochondrial function and communication.
  7. Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer.
  8. The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder.
  9. Wild-type IDH2 protects nuclear DNA from oxidative damage and is a potential therapeutic target in colorectal cancer.
  10. UbiB proteins regulate cellular CoQ distribution in Saccharomyces cerevisiae.
  11. Minimal mitochondrial respiration is required to prevent cell death by inhibition of mTOR signaling in CoQ-deficient cells.
  12. Pomegranate Extract (POMx) Induces Mitochondrial Dysfunction and Apoptosis of Oral Cancer Cells.
  13. Ending on a sour note: Lipids orchestrate ferroptosis in cancer.
  14. Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation.
  15. Molecular Insights into Mitochondrial Protein Translocation and Human Disease.
  16. HPDL deficiency causes a neuromuscular disease by impairing the mitochondrial respiration.
  17. Myeloid specific deletion of ferroportin impairs macrophage bioenergetics but is disconnected from systemic insulin action in adult mice.
  18. Targeting RIOK2 ATPase activity leads to decreased protein synthesis and cell death in acute myeloid leukemia.
  19. Fraction B From Catfish Epidermal Secretions Kills Pancreatic Cancer Cells, Inhibits CD44 Expression and Stemness, and Alters Cancer Cell Metabolism.
  20. Physciosporin suppresses mitochondrial respiration, aerobic glycolysis, and tumorigenesis in breast cancer.
  21. Circulating Cell-Free Mitochondrial DNA in Cerebrospinal Fluid as a Biomarker for Mitochondrial Diseases.
  22. Azoxymethane Alters the Plasma Metabolome to a Greater Extent in Mice Fed a High-Fat Diet Compared to an AIN-93 Diet.
  23. Failure to Guard: Mitochondrial Protein Quality Control in Cancer.
  24. ENDOG Impacts on Tumor Cell Proliferation and Tumor Prognosis in the Context of PI3K/PTEN Pathway Status.
  25. Rapid interrogation of cancer cell of origin through CRISPR editing.
  26. Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis.
  27. Discovery of a CPS1-deficient HCC subtype with therapeutic potential via integrative genomic and experimental analysis.
  28. Preparation and antitumor activity of triphenylphosphine-based mitochondrial targeting polylactic acid nanoparticles loaded with 7-hydroxyl coumarin.
  29. FHL2 anchors mitochondria to actin and adapts mitochondrial dynamics to glucose supply.
  30. Protective Effect of Mitochondrial ND2 C5178A Gene Mutation on Cell and Mitochondrial Functions.
  31. Berberine elevates cardiolipin in heart of offspring from mouse dams with high fat diet-induced gestational diabetes mellitus.
  32. Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation.
  33. The Sustainability of Energy Conversion Inhibition for Tumor Ferroptosis Therapy and Chemotherapy.
  34. Reactive Oxygen Species: A Promising Therapeutic Target for SDHx-Mutated Pheochromocytoma and Paraganglioma.
  35. Matrix Stiffness Modulates Metabolic Interaction between Human Stromal and Breast Cancer Cells to Stimulate Epithelial Motility.
  36. Mitochondrial Genomic Landscape: A Portrait of the Mitochondrial Genome 40 Years after the First Complete Sequence.
  37. Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response.
  38. Targeting leukemia-specific dependence on the de novo purine synthesis pathway.
  39. When fat talks, the gut listens: IRONing out metabolism.
  40. A proteogenomic portrait of lung squamous cell carcinoma.
  41. Inhibition of BAG3 enhances the anticancer effect of shikonin in hepatocellular carcinoma.
  42. Unveiling a key role of oxaloacetate-glutamate interaction in regulation of respiration and ROS generation in nonsynaptic brain mitochondria using a kinetic model.
  43. Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3.
  44. iDeepSubMito: identification of protein submitochondrial localization with deep learning.
  45. Adipocytes Promote Breast Cancer Cell Survival and Migration through Autophagy Activation.
  46. The spectrum of mitochondrial DNA (mtDNA) mutations in pediatric CNS tumors.
  47. MICU1 opens the gates to cold-induced death.
  48. Hypothermia Promotes Mitochondrial Elongation In Cardiac Cells Via Inhibition Of Drp1.
  49. Mammalian Target of Rapamycin Signaling Pathway Regulates Mitochondrial Quality Control of Brown Adipocytes in Mice.
  50. Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation.
  51. Interrogating in vivo T-cell metabolism in mice using stable isotope labeling metabolomics and rapid cell sorting.
  52. Distinct Mitochondrial Pathologies Caused by Mutations of the Proximal Tubular Enzymes EHHADH and GATM.
  53. Thiol-disulphide independent in-cell trapping for the identification of peroxiredoxin 2 interactors.
  54. Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER.
  1. Proc Natl Acad Sci U S A. 2021 Aug 10. pii: e2101675118. [Epub ahead of print]118(32):
    The human cytomegalovirus protein pUL13 targets mitochondrial cristae architecture to increase cellular respiration during infection.
    Cora N Betsinger, Connor S R Jankowski, William A Hofstadter, Joel D Federspiel, Clayton J Otter, Pierre M Jean Beltran, Ileana M Cristea.
      Viruses modulate mitochondrial processes during infection to increase biosynthetic precursors and energy output, fueling virus replication. In a surprising fashion, although it triggers mitochondrial fragmentation, the prevalent pathogen human cytomegalovirus (HCMV) increases mitochondrial metabolism through a yet-unknown mechanism. Here, we integrate molecular virology, metabolic assays, quantitative proteomics, and superresolution confocal microscopy to define this mechanism. We establish that the previously uncharacterized viral protein pUL13 is required for productive HCMV replication, targets the mitochondria, and functions to increase oxidative phosphorylation during infection. We demonstrate that pUL13 forms temporally tuned interactions with the mitochondrial contact site and cristae organizing system (MICOS) complex, a critical regulator of cristae architecture and electron transport chain (ETC) function. Stimulated emission depletion superresolution microscopy shows that expression of pUL13 alters cristae architecture. Indeed, using live-cell Seahorse assays, we establish that pUL13 alone is sufficient to increase cellular respiration, not requiring the presence of other viral proteins. Our findings address the outstanding question of how HCMV targets mitochondria to increase bioenergetic output and expands the knowledge of the intricate connection between mitochondrial architecture and ETC function.
    Keywords:  HCMV; metabolism; mitochondria; pUL13; proteomics
    DOI:  https://doi.org/10.1073/pnas.2101675118
  2. Nat Commun. 2021 Aug 06. 12(1): 4773
    Impact of aging and exercise on skeletal muscle mitochondrial capacity, energy metabolism, and physical function.
    L Grevendonk, N J Connell, C McCrum, C E Fealy, L Bilet, Y M H Bruls, J Mevenkamp, V B Schrauwen-Hinderling, J A Jörgensen, E Moonen-Kornips, G Schaart, B Havekes, J de Vogel-van den Bosch, M C E Bragt, K Meijer, P Schrauwen, J Hoeks.
      The relationship between the age-associated decline in mitochondrial function and its effect on skeletal muscle physiology and function remain unclear. In the current study, we examined to what extent physical activity contributes to the decline in mitochondrial function and muscle health during aging and compared mitochondrial function in young and older adults, with similar habitual physical activity levels. We also studied exercise-trained older adults and physically impaired older adults. Aging was associated with a decline in mitochondrial capacity, exercise capacity and efficiency, gait stability, muscle function, and insulin sensitivity, even when maintaining an adequate daily physical activity level. Our data also suggest that a further increase in physical activity level, achieved through regular exercise training, can largely negate the effects of aging. Finally, mitochondrial capacity correlated with exercise efficiency and insulin sensitivity. Together, our data support a link between mitochondrial function and age-associated deterioration of skeletal muscle.
    DOI:  https://doi.org/10.1038/s41467-021-24956-2
  3. J Clin Invest. 2021 Aug 03. pii: 146415. [Epub ahead of print]
    Insulin and IGF-1 receptors regulate complex-I dependent mitochondrial bioenergetics and supercomplexes via FoxOs in muscle.
    Gourav Bhardwaj, Christie M Penniman, Jayashree Jena, Pablo A Suarez Beltran, Collin Foster, Kennedy Poro, Taylor L Junck, Antentor O Hinton, Rhonda Souvenir, Jordan D Fuqua, Pablo E Morales, Roberto Bravo-Sagua, William I Sivitz, Vitor A Lira, E Dale Abel, Brian T O'Neill.
      Decreased skeletal muscle strength and mitochondrial dysfunction are characteristic of diabetes. Action of insulin and IGF-1 through insulin receptor (IR) and IGF-1 receptor (IGF1R) maintain muscle mass via suppression of FoxOs, but whether FoxO activation coordinates atrophy in concert with mitochondrial dysfunction is unknown. We show that mitochondrial respiration and complex-I activity were decreased in streptozotocin (STZ) diabetic muscle, but these defects were reversed following muscle-specific FoxO1/3/4 triple knockout in STZ-FoxO TKO. In the absence of systemic glucose or lipid abnormalities, muscle-specific IR knockout (M-IR-/-) or combined IR/IGF1R knockout (MIGIRKO) impaired mitochondrial respiration, decreased ATP production, and increased ROS. These mitochondrial abnormalities were not present in muscle-specific IR/IGF1R and FoxO1/3/4 quintuple knockout mice (M-QKO). Acute tamoxifen-inducible deletion of IR/IGF1R also decreased muscle pyruvate respiration, complex-I activity, and supercomplex assembly. Although autophagy was increased when IR/IGF1R were deleted in muscle, mitophagy was not increased. Mechanistically, RNA-seq revealed that complex-I core subunits were decreased in STZ-diabetic and MIGIRKO muscle, and these changes were not present with FoxO knockout in STZ-FoxO TKO and M-QKO. Thus, insulin-deficient diabetes or loss of insulin/IGF-1 action in muscle decreases complex-I driven mitochondrial respiration and supercomplex assembly, in part by FoxO-mediated repression of Complex-I subunit expression.
    Keywords:  Endocrinology; Insulin; Mitochondria; Muscle
    DOI:  https://doi.org/10.1172/JCI146415
  4. Cell Rep. 2021 Aug 03. pii: S2211-1247(21)00905-0. [Epub ahead of print]36(5): 109478
    BRCA2 deficiency reveals that oxidative stress impairs RNaseH1 function to cripple mitochondrial DNA maintenance.
    Xavier Renaudin, Miyoung Lee, Mona Shehata, Eva-Maria Surmann, Ashok R Venkitaraman.
      Oxidative stress is a ubiquitous cellular challenge implicated in aging, neurodegeneration, and cancer. By studying pathogenic mutations in the tumor suppressor BRCA2, we identify a general mechanism by which oxidative stress restricts mitochondrial (mt)DNA replication. BRCA2 inactivation induces R-loop accumulation in the mtDNA regulatory region and diminishes mtDNA replication initiation. In BRCA2-deficient cells, intracellular reactive oxygen species (ROS) are elevated, and ROS scavengers suppress the mtDNA defects. Conversely, wild-type cells exposed to oxidative stress by pharmacologic or genetic manipulation phenocopy these defects. Mechanistically, we find that 8-oxoguanine accumulation in mtDNA caused by oxidative stress suffices to impair recruitment of the mitochondrial enzyme RNaseH1 to sites of R-loop accrual, restricting mtDNA replication initiation. Thus, oxidative stress impairs RNaseH1 function to cripple mtDNA maintenance. Our findings highlight a molecular mechanism that links oxidative stress to mitochondrial dysfunction and is elicited by the inactivation of genes implicated in neurodegeneration and cancer.
    Keywords:  BRCA2; PRPF8; R-loops; RNaseH1; SETX; cancer; mitochondrial DNA replication; neurodegeneration; oxidative stress
    DOI:  https://doi.org/10.1016/j.celrep.2021.109478
  5. Cell Rep. 2021 Aug 03. pii: S2211-1247(21)00915-3. [Epub ahead of print]36(5): 109488
    Excess dietary carbohydrate affects mitochondrial integrity as observed in brown adipose tissue.
    Althea N Waldhart, Brejnev Muhire, Ben Johnson, Dean Pettinga, Zachary B Madaj, Emily Wolfrum, Holly Dykstra, Vanessa Wegert, J Andrew Pospisilik, Xianlin Han, Ning Wu.
      Hyperglycemia affects over 400 million individuals worldwide. The detrimental health effects are well studied at the tissue level, but the in vivo effects at the organelle level are poorly understood. To establish such an in vivo model, we used mice lacking TXNIP, a negative regulator of glucose uptake. Examining mitochondrial function in brown adipose tissue, we find that TXNIP KO mice have a lower content of polyunsaturated fatty acids (PUFAs) in their membrane lipids, which affects mitochondrial integrity and electron transport chain efficiency and ultimately results in lower mitochondrial heat output. This phenotype can be rescued by a ketogenic diet, confirming the usefulness of this model and highlighting one facet of early cellular damage caused by excess glucose influx.
    Keywords:  BAT; PUFA; TXNIP; cold stress; glucose; ketogenic diet; lipid; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2021.109488
  6. Elife. 2021 Aug 03. pii: e59828. [Epub ahead of print]10
    Instability in NAD+ metabolism leads to impaired cardiac mitochondrial function and communication.
    Knut H Lauritzen, Maria Belland Olsen, Mohammed Shakil Ahmed, Kuan Yang, Johanne Egge Rinholm, Linda H Bergersen, Qin Ying Esbensen, Lars Jansen Sverkeli, Mathias Ziegler, Håvard Attramadal, Bente Halvorsen, Pål Aukrust, Arne Yndestad.
      Poly(ADP-ribose) polymerase (PARP) enzymes initiate (mt)DNA repair mechanisms and use nicotinamide adenine dinucleotide (NAD+) as energy source. Prolonged PARP activity can drain cellular NAD+ reserves, leading to de-regulation of important molecular processes. Here, we provide evidence of a pathophysiological mechanism that connects mtDNA damage to cardiac dysfunction via reduced NAD+ levels and loss of mitochondrial function and communication. Using a transgenic model, we demonstrate that high levels of mice cardiomyocyte mtDNA damage cause a reduction in NAD+ levels due to extreme DNA repair activity, causing impaired activation of NAD+-dependent SIRT3. In addition, we show that myocardial mtDNA damage in combination with high dosages of nicotinamideriboside (NR) causes an inhibition of sirtuin activity due to accumulation of nicotinamide (NAM), in addition to irregular cardiac mitochondrial morphology. Consequently, high doses of NR should be used with caution, especially when cardiomyopathic symptoms are caused by mitochondrial dysfunction and instability of mtDNA.
    Keywords:  DNA repair; NAD+; SIRT3; biochemistry; cardiovascular disease; chemical biology; human; mitochondrial dna; mouse; nicotinamide riboside
    DOI:  https://doi.org/10.7554/eLife.59828
  7. Int J Mol Sci. 2021 Aug 02. pii: 8312. [Epub ahead of print]22(15):
    Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer.
    Daniela Valenti, Rosa Anna Vacca, Loredana Moro, Anna Atlante.
      Mitochondria are complex intracellular organelles traditionally identified as the powerhouses of eukaryotic cells due to their central role in bioenergetic metabolism. In recent decades, the growing interest in mitochondria research has revealed that these multifunctional organelles are more than just the cell powerhouses, playing many other key roles as signaling platforms that regulate cell metabolism, proliferation, death and immunological response. As key regulators, mitochondria, when dysfunctional, are involved in the pathogenesis of a wide range of metabolic, neurodegenerative, immune and neoplastic disorders. Far more recently, mitochondria attracted renewed attention from the scientific community for their ability of intercellular translocation that can involve whole mitochondria, mitochondrial genome or other mitochondrial components. The intercellular transport of mitochondria, defined as horizontal mitochondrial transfer, can occur in mammalian cells both in vitro and in vivo, and in physiological and pathological conditions. Mitochondrial transfer can provide an exogenous mitochondrial source, replenishing dysfunctional mitochondria, thereby improving mitochondrial faults or, as in in the case of tumor cells, changing their functional skills and response to chemotherapy. In this review, we will provide an overview of the state of the art of the up-to-date knowledge on intercellular trafficking of mitochondria by discussing its biological relevance, mode and mechanisms underlying the process and its involvement in different pathophysiological contexts, highlighting its therapeutic potential for diseases with mitochondrial dysfunction primarily involved in their pathogenesis.
    Keywords:  bioenergetics; cancer; ccf-mtDNA; extracellular mitochondria; extracellular mitovesicles; immune-metabolic regulation; intercellular mitochondria trafficking; mitochondria; mitochondrial transplantation; neurodegenerative diseases; neurodevelopmental disorders; oxidative phosphorylation; tunneling nanotubes
    DOI:  https://doi.org/10.3390/ijms22158312
  8. EMBO Rep. 2021 Aug 05. e51991
    The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder.
    Esther Nuebel, Jeffrey T Morgan, Sarah Fogarty, Jacob M Winter, Sandra Lettlova, Jordan A Berg, Yu-Chan Chen, Chelsea U Kidwell, J Alan Maschek, Katie J Clowers, Catherine Argyriou, Lingxiao Chen, Ilka Wittig, James E Cox, Minna Roh-Johnson, Nancy Braverman, Joshua Bonkowsky, Steven P Gygi, Jared Rutter.
      Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs-Zellweger spectrum disorder (ZSD)-is caused by mutations in peroxin genes that result in both non-functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter-organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.
    Keywords:  mitochondria; mitochondrial quality control; peroxisomal biogenesis disorder; peroxisomal import; peroxisomes
    DOI:  https://doi.org/10.15252/embr.202051991
  9. Oncogene. 2021 Aug 04.
    Wild-type IDH2 protects nuclear DNA from oxidative damage and is a potential therapeutic target in colorectal cancer.
    Shuang Qiao, Wenhua Lu, Christophe Glorieux, Jiangjiang Li, Peiting Zeng, Ning Meng, Huiqin Zhang, Shijun Wen, Peng Huang.
      Although the role of isocitrate dehydrogenase (IDH) mutation in promoting cancer development has been well-characterized, the impact of wild-type IDH on cancer cells remains unclear. Here we show that the wild-type isocitrate dehydrogenase 2 (IDH2) is highly expressed in colorectal cancer (CRC) cells, and plays an unexpected role in protecting the cancer cells from oxidative damage. Genetic abrogation of IDH2 in CRC cells leads to reactive oxygen species (ROS)-mediated DNA damage and an accumulation of 8-oxoguanine with DNA strand breaks, which activates DNA damage response (DDR) with elevated γH2AX and phosphorylation of ataxia telangiectasia-mutated (ATM) protein, leading to a partial cell cycle arrest and eventually cell senescence. Mechanistically, the suppression of IDH2 results in a reduction of the tricarboxylic acid (TCA) cycle activity due to a decrease in the conversion of isocitrate to α-ketoglutarate (α-KG) with a concurrent decrease in NADPH production, leading to ROS accumulation and oxidative DNA damage. Importantly, abrogation of IDH2 inhibits CRC cell growth in vitro and in vivo, and renders CRC cells more vulnerable to DNA-damaging drugs. Screening of an FDA-approved drug library has identified oxaliplatin as a compound highly effective against CRC cells when IDH2 was suppressed. Our study has uncovered an important role of the wild-type IDH2 in protecting DNA from oxidative damage, and provides a novel biochemical basis for developing metabolic intervention strategy for cancer treatment.
    DOI:  https://doi.org/10.1038/s41388-021-01968-2
  10. Nat Commun. 2021 Aug 06. 12(1): 4769
    UbiB proteins regulate cellular CoQ distribution in Saccharomyces cerevisiae.
    Zachary A Kemmerer, Kyle P Robinson, Jonathan M Schmitz, Mateusz Manicki, Brett R Paulson, Adam Jochem, Paul D Hutchins, Joshua J Coon, David J Pagliarini.
      Beyond its role in mitochondrial bioenergetics, Coenzyme Q (CoQ, ubiquinone) serves as a key membrane-embedded antioxidant throughout the cell. However, how CoQ is mobilized from its site of synthesis on the inner mitochondrial membrane to other sites of action remains a longstanding mystery. Here, using a combination of Saccharomyces cerevisiae genetics, biochemical fractionation, and lipid profiling, we identify two highly conserved but poorly characterized mitochondrial proteins, Ypl109c (Cqd1) and Ylr253w (Cqd2), that reciprocally affect this process. Loss of Cqd1 skews cellular CoQ distribution away from mitochondria, resulting in markedly enhanced resistance to oxidative stress caused by exogenous polyunsaturated fatty acids, whereas loss of Cqd2 promotes the opposite effects. The activities of both proteins rely on their atypical kinase/ATPase domains, which they share with Coq8-an essential auxiliary protein for CoQ biosynthesis. Overall, our results reveal protein machinery central to CoQ trafficking in yeast and lend insights into the broader interplay between mitochondria and the rest of the cell.
    DOI:  https://doi.org/10.1038/s41467-021-25084-7
  11. Cell Death Discov. 2021 Aug 04. 7(1): 201
    Minimal mitochondrial respiration is required to prevent cell death by inhibition of mTOR signaling in CoQ-deficient cells.
    Ying Wang, Siegfried Hekimi.
      Coenzyme Q (CoQ) is a lipid-like mobile electron transporter of the mitochondrial respiratory chain. Patients with partial loss-of-function mutations in the CoQ biosynthesis pathway suffer from partial primary CoQ deficiency (MIM 607426). This leads to mitochondrial dysfunction, which presents like mitochondrial disease syndrome (MDS). In addition, many other conditions, including MDS itself, lead to secondary CoQ deficiency. We sought to identify drugs that can alleviate the consequences of the mitochondrial dysfunction that is associated with CoQ deficiency. Loss of the CoQ-biosynthetic enzyme COQ7 prevents CoQ synthesis but leads to the accumulation of the biosynthetic intermediate demethoxyubiquinone (DMQ). Coq7-knockout mouse embryonic fibroblasts (MEFs) die when rapid ATP generation from glycolysis is prevented. We screened for drugs that could rescue cell death under these conditions. All compounds that were identified inhibit mTOR signaling. In the CoQ-deficient cells, the beneficial action mTOR inhibition appears to be mediated by inhibition of protein translation rather than by stimulation of autophagy. We further studied the Coq7-knockout cells to better determine under which conditions mTOR inhibition could be beneficial. We established that Coq7-knockout cells remain capable of a low level of mitochondrial respiration mediated by DMQ. To obtain more profound mitochondrial dysfunction, we created double-knockout mutant MEFs lacking both Coq7, as well as Pdss2, which is required for sidechain synthesis. These cells make neither CoQ nor DMQ, and their extremely small residual respiration depends on uptake of CoQ from the culture medium. Although these cells are healthy in the presence of sufficient glucose for glycolysis and do not require uridine or pyruvate supplementation, mTOR inhibitors were unable to prevent their death in the absence of sufficient glycolysis. We conclude that, for reasons that remain to be elucidated, the energy-sparing benefits of the inhibition of mTOR signaling require a minimally functional respiratory chain.
    DOI:  https://doi.org/10.1038/s41420-021-00591-0
  12. Antioxidants (Basel). 2021 Jul 13. pii: 1117. [Epub ahead of print]10(7):
    Pomegranate Extract (POMx) Induces Mitochondrial Dysfunction and Apoptosis of Oral Cancer Cells.
    Sheng-Yao Peng, Li-Ching Lin, Shu-Rong Chen, Ammad A Farooqi, Yuan-Bin Cheng, Jen-Yang Tang, Hsueh-Wei Chang.
      The anticancer effect of pomegranate polyphenolic extract POMx in oral cancer cells has rarely been explored, especially where its impact on mitochondrial functioning is concerned. Here, we attempt to evaluate the proliferation modulating function and mechanism of POMx against human oral cancer (Ca9-22, HSC-3, and OC-2) cells. POMx induced ATP depletion, subG1 accumulation, and annexin V/Western blotting-detected apoptosis in these three oral cancer cell lines but showed no toxicity to normal oral cell lines (HGF-1). POMx triggered mitochondrial membrane potential (MitoMP) disruption and mitochondrial superoxide (MitoSOX) generation associated with the differential downregulation of several antioxidant gene mRNA/protein expressions in oral cancer cells. POMx downregulated mitochondrial mass, mitochondrial DNA copy number, and mitochondrial biogenesis gene mRNA/protein expression in oral cancer cells. Moreover, POMx induced both PCR-based mitochondrial DNA damage and γH2AX-detected nuclear DNA damage in oral cancer cells. In conclusion, POMx provides antiproliferation and apoptosis of oral cancer cells through mechanisms of mitochondrial impairment.
    Keywords:  DNA damage; apoptosis; mitochondrial DNA; oral cancer; pomegranate
    DOI:  https://doi.org/10.3390/antiox10071117
  13. Cell Metab. 2021 Aug 03. pii: S1550-4131(21)00327-2. [Epub ahead of print]33(8): 1507-1509
    Ending on a sour note: Lipids orchestrate ferroptosis in cancer.
    Mike Lange, James A Olzmann.
      Lipid metabolism is altered in the acidic tumor microenvironment. Here, the authors show that polyunsaturated fatty acid supplementation, together with concomitant inhibition of lipid droplet biogenesis, induces ferroptosis in acidic cancer cells. These findings highlight the potential to exploit cancer dependence on exogenous lipids as a therapeutic vulnerability.
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.011
  14. Development. 2021 Aug 06. pii: dev.199686. [Epub ahead of print]
    Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation.
    Grigor Varuzhanyan, Mark S Ladinsky, Shun-Ichi Yamashita, Manabu Abe, Kenji Sakimura, Tomotake Kanki, David C Chan.
      Male germline development involves choreographed changes to mitochondrial number, morphology, and organization. Mitochondrial reorganization during spermatogenesis was recently shown to require mitochondrial fusion and fission. Mitophagy, the autophagic degradation of mitochondria, is another mechanism for controlling mitochondrial number and physiology, but its role during spermatogenesis is largely unknown. During post-meiotic spermatid development, restructuring of the mitochondrial network results in packing of mitochondria into a tight array in the sperm midpiece to fuel motility. Here, we show that disruption of mouse Fis1 in the male germline results in early spermatid arrest that is associated with increased mitochondrial content. Mutant spermatids coalesce into multinucleated giant cells (GCs) that accumulate mitochondria of aberrant ultrastructure and numerous mitophagic and autophagic intermediates, suggesting a defect in mitophagy. We conclude that Fis1 regulates mitochondrial morphology and turnover to promote spermatid maturation.
    Keywords:  Autophagy; Mitochondrial dynamics; Mitophagy; Spermatid; Spermatogenesis
    DOI:  https://doi.org/10.1242/dev.199686
  15. Genes (Basel). 2021 Jul 01. pii: 1031. [Epub ahead of print]12(7):
    Molecular Insights into Mitochondrial Protein Translocation and Human Disease.
    Eduardo Ruiz-Pesini, Julio Montoya, David Pacheu-Grau.
      In human mitochondria, mtDNA encodes for only 13 proteins, all components of the OXPHOS system. The rest of the mitochondrial components, which make up approximately 99% of its proteome, are encoded in the nuclear genome, synthesized in cytosolic ribosomes and imported into mitochondria. Different import machineries translocate mitochondrial precursors, depending on their nature and the final destination inside the organelle. The proper and coordinated function of these molecular pathways is critical for mitochondrial homeostasis. Here, we will review molecular details about these pathways, which components have been linked to human disease and future perspectives on the field to expand the genetic landscape of mitochondrial diseases.
    Keywords:  disease; mitochondria; protein import
    DOI:  https://doi.org/10.3390/genes12071031
  16. J Genet Genomics. 2021 Jun 17. pii: S1673-8527(21)00162-4. [Epub ahead of print]
    HPDL deficiency causes a neuromuscular disease by impairing the mitochondrial respiration.
    Yu Sun, Xiujuan Wei, Fang Fang, Yiping Shen, Haiyan Wei, Jiuwei Li, Xianglai Ye, Yongkun Zhan, Xiantao Ye, Xiaomin Liu, Wei Yang, Yuhua Li, Xiangju Geng, Xuelin Huang, Yiyan Ruan, Zailong Qin, Shang Yi, Jianxin Lyu, Hezhi Fang, Yongguo Yu.
      Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes. A nuclear gene HPDL (4-hydroxyphenylpyruvate dioxygenase-like), which encodes an intermembrane mitochondrial protein, has been recently implicated in causing a neurodegenerative disease characterized by pediatric-onset spastic movement phenotypes. Here, we report six Chinese patients with bi-allelic HPDL pathogenic variants from four unrelated families showing neuropathic symptoms of variable severity, including developmental delay/intellectual disability, spasm, and hypertonia. Seven different pathogenic variants are identified, of which five are novel. Both fibroblasts and immortalized lymphocytes derived from patients show impaired mitochondrial respiratory function, which is also observed in HPDL-knockdown (KD) HeLa cells. In these HeLa cells, overexpression of a wild-type HPDL gene can rescue the respiratory phenotype of oxygen consumption rate. In addition, a decreased activity of the oxidative phosphorylation (OXPHOS) complex II is observed in patient-derived lymphocytes and HPDL-KD HeLa cells, further supporting an essential role of HPDL in the mitochondrial respiratory chain. Collectively, our data expand the clinical and mutational spectra of this mitochondrial neuropathy and further delineate the possible disease mechanism involving the impairment of the OXPHOS complex II activity due to the bi-allelic inactivations of HPDL.
    Keywords:  HPDL gene; Mitochondrial disease; OXPHOS; Respiration chain complex II; Respiration impairment
    DOI:  https://doi.org/10.1016/j.jgg.2021.01.009
  17. Am J Physiol Endocrinol Metab. 2021 08 02.
    Myeloid specific deletion of ferroportin impairs macrophage bioenergetics but is disconnected from systemic insulin action in adult mice.
    Nathan C Winn, Elysa M Wolf, Matthew A Cottam, Monica Bhanot, Alyssa H Hasty.
      Tissue iron overload is associated with insulin resistance and mitochondrial dysfunction in rodents and humans; however, the mechanisms or cell types that mediate this phenotype are not completely understood. Macrophages (Mɸ)s are known to contribute to iron handling; thus, we hypothesized that perturbed iron handling by Mɸs impairs mitochondrial energetics and evokes systemic insulin resistance in mice. Male and female mice with myeloid targeted (LysMCre) deletion of the canonical iron exporter, ferroportin (Fpn, encoded by Slc40a1), floxed littermates and C57BL/6J wild-type mice were used to test our hypotheses. Myeloid-targeted deletion of Fpn evoked multi-tissue iron accumulation and reduced mitochondrial respiration in bone marrow-derived Mɸs, liver leukocytes, and Mɸ-enriched populations from adipose tissue (AT). In addition, a single bolus of exogenous iron administered to C57BL/6J mice phenocopied the loss of Fpn, resulting in a reduction in maximal and mitochondrial reserve capacity in Mɸ-enriched cellular fractions from liver and AT. In vivo exogenous iron chelation restored mitochondrial reserve capacity in liver leukocytes from Fpn LysMCre mice, but had no effect in AT myeloid populations. However, despite the impairments in mitochondrial respiration, neither loss of myeloid-specific Fpn, nor exogenous iron overload, perturbed glucose homeostasis or systemic insulin action in lean or obese mice; whereas, aging coupled with lifelong loss of Fpn unmasked glucose intolerance. Together these data demonstrate that iron handling is critical for the maintenance of macrophage mitochondrial function but perturbing myeloid iron flux via the loss of Fpn action is not sufficient to evoke systemic insulin resistance in young adult mice. These findings also suggest that if Mɸs are capable of storing iron properly, they have a pronounced ability to withstand iron excess without evoking overt collateral damage and associated insulin resistance that may be age dependent.
    Keywords:  Adipose tissue; Insulin resistance; Iron handling; Macrophages; Obesity
    DOI:  https://doi.org/10.1152/ajpendo.00116.2021
  18. Blood. 2021 Aug 25. pii: blood.2021012629. [Epub ahead of print]
    Targeting RIOK2 ATPase activity leads to decreased protein synthesis and cell death in acute myeloid leukemia.
    Jan-Erik Messling, Karl Agger, Kasper L Andersen, Kristina Kromer, Hanna Maria Kuepper, Anders H Lund, Kristian Helin.
      Novel therapies for the treatment of acute myeloid leukemia (AML) are urgently needed as current treatments do not cure the majority of AML patients. Here, we report on a domain-focused, kinome-wide CRISPR-Cas9 screen to identify protein kinase targets for the treatment of AML, which led to the identification of Rio-kinase 2 (RIOK2) as a potential novel target. We show that loss of RIOK2 leads to a decrease in protein synthesis and to ribosomal instability followed by apoptosis in leukemic cells, but not in fibroblasts. Moreover, we demonstrate that the ATPase function of RIOK2 is required for cell survival. By using a small molecule inhibitor, we show that pharmacological inhibition of RIOK2 similarly leads to loss of protein synthesis and apoptosis and affects leukemic cell growth in vivo. Our results provide proof-of-concept for targeting RIOK2 as a potential treatment for AML patients.
    DOI:  https://doi.org/10.1182/blood.2021012629
  19. Front Pharmacol. 2021 ;12 659590
    Fraction B From Catfish Epidermal Secretions Kills Pancreatic Cancer Cells, Inhibits CD44 Expression and Stemness, and Alters Cancer Cell Metabolism.
    Jassim M Al-Hassan, Daoyan Wei, Sharmistha Chakraborty, Tara Conway, Patrea Rhea, Bo Wei, Megan Tran, Mihai Gagea, Mohammad Afzal, Sosamma Oommen, Divya Nair, Bincy M Paul, Peiying Yang.
      Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in western countries. The successful treatment of PDAC remains limited. We investigated the effect of Fraction B, which is a fraction purified from catfish (Arius bilineatus, Val.) skin secretions containing proteins and lipids, on PDAC biology both in-vivo and in-vitro. We report here that Fraction B potently suppressed the proliferation of both human and mouse pancreatic cancer cells in vitro and significantly reduced the growth of their relevant xenograft (Panc02) and orthotopic tumors (human Panc-1 cells) (p < 0.05). The Reverse Phase Protein Array (RPPA) data obtained from the tumor tissues derived from orthotopic tumor bearing mice treated with Fraction B showed that Fraction B altered the cancer stem cells related pathways and regulated glucose and glutamine metabolism. The down-regulation of the cancer stem cell marker CD44 expression was further confirmed in Panc-1 cells. CBC and blood chemistry analyses showed no systemic toxicity in Fraction B treated Panc-1 tumor bearing mice compared to that of control group. Our data support that Fraction B is a potential candidate for PDAC treatment.
    Keywords:  Fraction B; apoptosis; cancer metabolism; cancer stemness; catfish; pancreatic cancer
    DOI:  https://doi.org/10.3389/fphar.2021.659590
  20. Phytomedicine. 2021 Jul 18. pii: S0944-7113(21)00217-8. [Epub ahead of print]91 153674
    Physciosporin suppresses mitochondrial respiration, aerobic glycolysis, and tumorigenesis in breast cancer.
    İsa Taş, Mücahit Varlı, Yeseon Son, Jin Han, Dahye Kwak, Yi Yang, Rui Zhou, Chathurika D B Gamage, Sultan Pulat, So-Yeon Park, Young Hyun Yu, Kyung-Sub Moon, Kyung-Hwa Lee, Hyung-Ho Ha, Jae-Seoun Hur, Hangun Kim.
      BACKGROUND: Physciosporin (PHY) is one of the potent anticancer lichen compound. Recently, PHY was shown to suppress colorectal cancer cell proliferation, motility, and tumorigenesis through novel mechanisms of action.PURPOSE: We investigated the effects of PHY on energy metabolism and tumorigenicity of the human breast cancer (BC) cells MCF-7 (estrogen and progesterone positive BC) and MDA-MB-231 (triple negative BC).
    METHODS: The anticancer effect of PHY on cell viability, motility, cancer metabolism and tumorigenicity was evaluated by MTT assay, migration assay, clonogenic assay, anchorage-independent colony formation assay, glycolytic and mitochondrial metabolism analysis, qRT-PCR, flow cytometric analysis, Western blotting, immunohistochemistry in vitro; and by tumorigenicity study with orthotopic breast cancer xenograft model in vivo.
    RESULTS: PHY markedly inhibited BC cell viability. Cell-cycle profiling and Annexin V-FITC/PI double staining showed that a toxic dosage of PHY triggered apoptosis in BC cell lines by regulating the B-cell lymphoma-2 (Bcl-2) family proteins and the activity of caspase pathway. At non-toxic concentrations, PHY potently decreased migration, proliferation, and tumorigenesis of BC cells in vitro. Metabolic studies revealed that PHY treatment significantly reduced the bioenergetic profile by decreasing respiration, ATP production, and glycolysis capacity. In addition, PHY significantly altered the levels of mitochondrial (PGC-1α) and glycolysis (GLUT1, HK2 and PKM2) markers, and downregulated transcriptional regulators involved in cancer cell metabolism, including β-catenin, c-Myc, HIF-1α, and NF-κB. An orthotopic implantation mouse model of BC confirmed that PHY treatment suppressed BC growth in vivo and target genes were consistently suppressed in tumor specimens.
    CONCLUSION: The findings from our in vitro as well as in vivo studies exhibit that PHY suppresses energy metabolism as well as tumorigenesis in BC. Especially, PHY represents a promising therapeutic effect against hormone-insensitive BC (triple negative) by targeting energy metabolism.
    Keywords:  Anticancer; Breast cancer; Cancer metabolism; Energy metabolism; Lichen; Natural product
    DOI:  https://doi.org/10.1016/j.phymed.2021.153674
  21. Clin Chem. 2021 Aug 05. 67(8): 1113-1121
    Circulating Cell-Free Mitochondrial DNA in Cerebrospinal Fluid as a Biomarker for Mitochondrial Diseases.
    Selena Trifunov, Abraham J Paredes-Fuentes, Carmen Badosa, Anna Codina, Julio Montoya, Eduardo Ruiz-Pesini, Cristina Jou, Glòria Garrabou, Josep M Grau-Junyent, Dèlia Yubero, Raquel Montero, Jordi Muchart, Juan D Ortigoza-Escobar, Maria M O'Callaghan, Andrés Nascimento, Albert Català, Àngels Garcia-Cazorla, Cecilia Jimenez-Mallebrera, Rafael Artuch.
      BACKGROUND: Mitochondrial diseases (MD) are genetic metabolic disorders that impair normal mitochondrial structure or function. The aim of this study was to investigate the status of circulating cell-free mitochondrial DNA (ccfmtDNA) in cerebrospinal fluid (CSF), together with other biomarkers (growth differentiation factor-15 [GDF-15], alanine, and lactate), in a cohort of 25 patients with a molecular diagnosis of MD.METHODS: Measurement of ccfmtDNA was performed by using droplet digital PCR.
    RESULTS: The mean copy number of ccfmtDNA was approximately 6 times higher in the MD cohort compared to the control group; patients with mitochondrial deletion and depletion syndromes (MDD) had the higher levels. We also detected the presence of both wild-type mtDNA and mtDNA deletions in CSF samples of patients with single deletions. Patients with MDD with single deletions had significantly higher concentrations of GDF-15 in CSF than controls, whereas patients with point mutations in mitochondrial DNA presented no statistically significant differences. Additionally, we found a significant positive correlation between ccfmtDNA levels and GDF-15 concentrations (r = 0.59, P = 0.016).
    CONCLUSION: CSF ccfmtDNA levels are significantly higher in patients with MD in comparison to controls and, thus, they can be used as a novel biomarker for MD research. Our results could also be valuable to support the clinical outcome assessment of MD patients.
    Keywords:  cerebrospinal fluid; circulating cell-free mitochondrial DNA; droplet digital PCR; mitochondrial deletion and depletion syndromes; mitochondrial diseases
    DOI:  https://doi.org/10.1093/clinchem/hvab091
  22. Metabolites. 2021 Jul 09. pii: 448. [Epub ahead of print]11(7):
    Azoxymethane Alters the Plasma Metabolome to a Greater Extent in Mice Fed a High-Fat Diet Compared to an AIN-93 Diet.
    Huawei Zeng, Shahid Umar, Zhenhua Liu, Michael R Bukowski.
      Consumption of a high-fat diet (HFD) links obesity to colon cancer in humans. Our data show that a HFD (45% energy fat versus 16% energy fat in an AIN-93 diet (AIN)) promotes azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation in a mouse cancer model. However, the underlying metabolic basis remains to be determined. In the present study, we hypothesize that AOM treatment results in different plasma metabolomic responses in diet-induced obese mice. An untargeted metabolomic analysis was performed on the plasma samples by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We found that 53 of 144 identified metabolites were different between the 4 groups of mice (AIN, AIN + AOM, HFD, HFD + AOM), and sparse partial least-squares discriminant analysis showed a separation between the HFD and HFD + AOM groups but not the AIN and AIN + AOM groups. Moreover, the concentrations of dihydrocholesterol and cholesterol were inversely associated with AOM-induced colonic ACF formation. Functional pathway analyses indicated that diets and AOM-induced colonic ACF modulated five metabolic pathways. Collectively, in addition to differential plasma metabolomic responses, AOM treatment decreases dihydrocholesterol and cholesterol levels and alters the composition of plasma metabolome to a greater extent in mice fed a HFD compared to the AIN.
    Keywords:  aberrant crypt foci; azoxymethane; colon cancer; high-fat diet; inflammation; metabolome; obesity
    DOI:  https://doi.org/10.3390/metabo11070448
  23. Int J Mol Sci. 2021 Aug 02. pii: 8306. [Epub ahead of print]22(15):
    Failure to Guard: Mitochondrial Protein Quality Control in Cancer.
    Joseph E Friedlander, Ning Shen, Aozhuo Zeng, Sovannarith Korm, Hui Feng.
      Mitochondria are energetic and dynamic organelles with a crucial role in bioenergetics, metabolism, and signaling. Mitochondrial proteins, encoded by both nuclear and mitochondrial DNA, must be properly regulated to ensure proteostasis. Mitochondrial protein quality control (MPQC) serves as a critical surveillance system, employing different pathways and regulators as cellular guardians to ensure mitochondrial protein quality and quantity. In this review, we describe key pathways and players in MPQC, such as mitochondrial protein translocation-associated degradation, mitochondrial stress responses, chaperones, and proteases, and how they work together to safeguard mitochondrial health and integrity. Deregulated MPQC leads to proteotoxicity and dysfunctional mitochondria, which contributes to numerous human diseases, including cancer. We discuss how alterations in MPQC components are linked to tumorigenesis, whether they act as drivers, suppressors, or both. Finally, we summarize recent advances that seek to target these alterations for the development of anti-cancer drugs.
    Keywords:  MPQC; cancer; chaperone; mitochondria; oncogene; protease; proteostasis; therapeutic targeting; tumor suppressor; tumorigenesis
    DOI:  https://doi.org/10.3390/ijms22158306
  24. Cancers (Basel). 2021 Jul 28. pii: 3803. [Epub ahead of print]13(15):
    ENDOG Impacts on Tumor Cell Proliferation and Tumor Prognosis in the Context of PI3K/PTEN Pathway Status.
    Gisel Barés, Aida Beà, Luís Hernández, Raul Navaridas, Isidre Felip, Cristina Megino, Natividad Blasco, Ferran Nadeu, Elías Campo, Marta Llovera, Xavier Dolcet, Daniel Sanchis.
      EndoG influences mitochondrial DNA replication and is involved in somatic cell proliferation. Here, we investigated the effect of ENDOG/Endog expression on proliferation in different tumor models. Noteworthy, ENDOG deficiency reduced proliferation of endometrial tumor cells expressing low PTEN/high p-AKT levels, and Endog deletion blunted the growth of PTEN-deficient 3D endometrial cultures. Furthermore, ENDOG silencing reduced proliferation of follicular thyroid carcinoma and glioblastoma cell lines with high p-AKT expression. High ENDOG expression was associated with a short time to treatment in a cohort of patients with chronic lymphocytic leukemia (CLL), a B-cell lymphoid neoplasm with activation of PI3K/AKT. This clinical impact was observed in the less aggressive CLL subtype with mutated IGHV in which high ENDOG and low PTEN levels were associated with worse outcome. In summary, our results show that reducing ENDOG expression hinders growth of some tumors characterized by low PTEN activity and high p-AKT expression and that ENDOG has prognostic value for some cancer types.
    Keywords:  AKT; ENDOG; PTEN; chronic lymphocytic leukemia; endometrial carcinoma; glioblastoma
    DOI:  https://doi.org/10.3390/cancers13153803
  25. Proc Natl Acad Sci U S A. 2021 Aug 10. pii: e2110344118. [Epub ahead of print]118(32):
    Rapid interrogation of cancer cell of origin through CRISPR editing.
    Weiran Feng, Zhen Cao, Pei Xin Lim, Huiyong Zhao, Hanzhi Luo, Ninghui Mao, Young Sun Lee, Aura Agudelo Rivera, Danielle Choi, Chao Wu, Teng Han, Rodrigo Romero, Elisa de Stanchina, Brett S Carver, Qiao Wang, Maria Jasin, Charles L Sawyers.
      The increasing complexity of different cell types revealed by single-cell analysis of tissues presents challenges in efficiently elucidating their functions. Here we show, using prostate as a model tissue, that primary organoids and freshly isolated epithelial cells can be CRISPR edited ex vivo using Cas9-sgRNA (guide RNA) ribotnucleoprotein complex technology, then orthotopically transferred in vivo into immunocompetent or immunodeficient mice to generate cancer models with phenotypes resembling those seen in traditional genetically engineered mouse models. Large intrachromosomal (∼2 Mb) or multigenic deletions can be engineered efficiently without the need for selection, including in isolated subpopulations to address cell-of-origin questions.
    Keywords:  CRISPR; cancer modeling; editing; organoids
    DOI:  https://doi.org/10.1073/pnas.2110344118
  26. Cell Metab. 2021 Jul 27. pii: S1550-4131(21)00324-7. [Epub ahead of print]
    Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis.
    Alicia G Gómez-Valadés, Macarena Pozo, Luis Varela, Mehdi Boutagouga Boudjadja, Sara Ramírez, Iñigo Chivite, Elena Eyre, Roberta Haddad-Tóvolli, Arnaud Obri, Maria Milà-Guasch, Jordi Altirriba, Marc Schneeberger, Mónica Imbernón, Angela R Garcia-Rendueles, Pau Gama-Perez, Jonathan Rojo-Ruiz, Bence Rácz, Maria Teresa Alonso, Ramon Gomis, Antonio Zorzano, Giuseppe D'Agostino, Clara V Alvarez, Rubén Nogueiras, Pablo M Garcia-Roves, Tamas L Horvath, Marc Claret.
      Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance.
    Keywords:  OPA-1; POMC neurons; cristae; hypothalamus; lipolysis; mitochondria; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.008
  27. Hepatology. 2021 Aug 03.
    Discovery of a CPS1-deficient HCC subtype with therapeutic potential via integrative genomic and experimental analysis.
    Tong Wu, Guijuan Luo, Qiuyu Lian, Chengjun Sui, Jing Tang, Yanjing Zhu, Bo Zheng, Zhixuan Li, Yani Zhang, Yangqianwen Zhang, Jinxia Bao, Ji Hu, Siyun Shen, Zhao Yang, Jianmin Wu, Kaiting Wang, Yan Zhao, Shuai Yang, Shan Wang, Xinyao Qiu, Wenwen Wang, Xuan Wu, Hongyang Wang, Jin Gu, Lei Chen.
      BACKGROUND AND AIMS: Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack of in-depth study. Here, through analysis of big databases and clinical samples, we identified Carbamoyl phosphate synthetase I(CPS1)-deficient hepatocellular carcinoma(HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as target for HCC prevention.APPROACH AND RESULTS: Pan-cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas(TCGA) demonstrated that urea cycle(UC) was liver-specific and HCC-downregulated. A large-scale gene expression data analysis including a total of 2,596 HCC cases in 7 HCCDB datasets combined with a total of 17,444 hepatectomy cohort data identified a specific CPS1-deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed crucial role of CPS1 in HCC. LC-MS assay and Seahorse analysis revealed that UC dysregulation(UCD) led to the deceleration of the tricarboxylic acid(TCA) cycle, while excess ammonia caused by CPS1 deficiency activated fatty acid β-oxidation(FAO) through p-AMPK. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating FOXM1. Subcutaneous xenograft tumor models and patient-derived organoids(PDOs) were employed to identify that blocking FAO by Eto may provide therapeutic benefit to HCC patients with CPS1-deficiency.
    CONCLUSIONS: In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1-deficient HCC subtype through big-data mining, and provide insights for novel therapeutic for this type of HCC through targeting FAO.
    Keywords:  FAO; Metabolic reprogramming; Novel therapeutic target; Stem cell; Urea cycle
    DOI:  https://doi.org/10.1002/hep.32088
  28. J Biomater Appl. 2021 Aug 01. 8853282211037030
    Preparation and antitumor activity of triphenylphosphine-based mitochondrial targeting polylactic acid nanoparticles loaded with 7-hydroxyl coumarin.
    Lin Ye, Qing Yao, Fengnan Xu, Liu He, Jieqiong Ding, Ruolei Xiao, Liqiong Ding, Binhua Luo.
      Due to the low bioavailability and severe toxic side effects caused by the lack of selectivity of traditional chemotherapy drugs, the targeted delivery of chemotherapy drugs has become the key to tumor treatment. The activity and transmembrane potential of mitochondria in cancer cells were significantly higher than that of normal cells, making them a potential target for chemotherapeutic drug delivery. In this study, triphenylphosphine (TPP) based mitochondria targeting polylactic acid (PLLA) nanoparticles (TPP-PLLA NPs) were synthesized to improve the delivery efficiency of anticancer drugs. The carrier material was characterized by 1H NMR and FT-IR and 7-hydroxyl coumarin (7-HC) was successfully loaded into TPP-PLLA to form 7-HC/TPP-PLLA NPs. Further studies showed that TPP-PLLA NPs were primarily accumulated in the mitochondrial and 7-HC/TPP-PLLA NPs had higher antitumor activity. Taken together, our results indicated that TPP-PLLA NPs could be a promising mitochondria-targeted drug delivery system for cancer therapy.
    Keywords:  7-hydroxyl coumarin; Mitochondrial targeting; polylactic acid; triphenylphosphine
    DOI:  https://doi.org/10.1177/08853282211037030
  29. J Cell Biol. 2021 Oct 04. pii: e201912077. [Epub ahead of print]220(10):
    FHL2 anchors mitochondria to actin and adapts mitochondrial dynamics to glucose supply.
    Himanish Basu, Gulcin Pekkurnaz, Jill Falk, Wei Wei, Morven Chin, Judith Steen, Thomas L Schwarz.
      Mitochondrial movement and distribution are fundamental to their function. Here we report a mechanism that regulates mitochondrial movement by anchoring mitochondria to the F-actin cytoskeleton. This mechanism is activated by an increase in glucose influx and the consequent O-GlcNAcylation of TRAK (Milton), a component of the mitochondrial motor-adaptor complex. The protein four and a half LIM domains protein 2 (FHL2) serves as the anchor. FHL2 associates with O-GlcNAcylated TRAK and is both necessary and sufficient to drive the accumulation of F-actin around mitochondria and to arrest mitochondrial movement by anchoring to F-actin. Disruption of F-actin restores mitochondrial movement that had been arrested by either TRAK O-GlcNAcylation or forced direction of FHL2 to mitochondria. This pathway for mitochondrial immobilization is present in both neurons and non-neuronal cells and can thereby adapt mitochondrial dynamics to changes in glucose availability.
    DOI:  https://doi.org/10.1083/jcb.201912077
  30. Oxid Med Cell Longev. 2021 ;2021 4728714
    Protective Effect of Mitochondrial ND2 C5178A Gene Mutation on Cell and Mitochondrial Functions.
    Liuyang Tian, Chao Zhu, Huanwan Yang, Yang Li, Yuqi Liu.
      Background: Mitochondrial NADH dehydrogenase subunit 2 (MT-ND2) m. 5178C>A gene mutation has protective effects against various diseases, but the molecular mechanism is still unclear. In previous study, we found a heteroplasmy level of MT-ND2 m. 5178C>A mutation in normotensive controls. Peripheral blood samples were obtained from essential hypertension individuals carrying the mutation and healthy controls without gene mutation to establish immortalized lymphocyte lines. To investigate the effect of the MT-ND2 m. 5178C>A gene mutation, comparative analyses of the two group cell lines were performed, including measurements of cell proliferation, viability, ATP synthesis, mitochondrial oxidative stress, and oxidative phosphorylation.Results: The cell proliferation rate and viability of the MT-ND2 m. 5178C>A mutant lymphocyte line were higher than those of the control group. Mitochondrial functions of the MT-ND2 m. 5178C>A mutant lymphocyte were increased, including increased ATP synthesis, decreased ROS production, increased mitochondrial membrane potential and Bcl-2 gene transcription and protein translation, decreased Caspase 3/7 activity, and decreased early apoptosis and late apoptosis. The oxygen consumption rate (OCR) of the mutant lymphocyte line was higher than that of the control group, including basal OCR, ATP-linked OCR, maximal OCR, proton leak OCR, and reserve OCR, and there was no significant difference in nonmitochondrial OCR. The activity of Mitochondrial Complex I of the mutant group was increased than that of the control group.
    Conclusions: The MT-ND2 m. 5178C>A mutation is a protective mutation that may be related to improvement of mitochondrial functions and decrease in apoptosis.
    DOI:  https://doi.org/10.1155/2021/4728714
  31. Sci Rep. 2021 Aug 04. 11(1): 15770
    Berberine elevates cardiolipin in heart of offspring from mouse dams with high fat diet-induced gestational diabetes mellitus.
    Laura K Cole, Genevieve C Sparagna, Marilyne Vandel, Bo Xiang, Vernon W Dolinsky, Grant M Hatch.
      Berberine (BBR) is an isoquinoline alkaloid from plants known to improve cardiac mitochondrial function in gestational diabetes mellitus (GDM) offspring but the mechanism is poorly understood. We examined the role of the mitochondrial phospholipid cardiolipin (CL) in mediating this cardiac improvement. C57BL/6 female mice were fed either a Lean-inducing low-fat diet or a GDM-inducing high-fat diet for 6 weeks prior to breeding. Lean and GDM-exposed male offspring were randomly assigned a low-fat, high-fat, or high-fat diet containing BBR at weaning for 12 weeks. The content of CL was elevated in the heart of GDM offspring fed a high fat diet containing BBR. The increase in total cardiac CL was due to significant increases in the most abundant and functionally important CL species, tetralinoleoyl-CL and this correlated with an increase in the expression of the CL remodeling enzyme tafazzin. Additionally, BBR treatment increased expression of cardiac enzymes involved in fatty acid uptake and oxidation and electron transport chain subunits in high fat diet fed GDM offspring. Thus, dietary BBR protection from cardiac dysfunction in GDM exposed offspring involves improvement in mitochondrial function mediated through increased synthesis of CL.
    DOI:  https://doi.org/10.1038/s41598-021-95353-4
  32. Sci Adv. 2021 Aug;pii: eabf6580. [Epub ahead of print]7(32):
    Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation.
    Huihui Li, Zak Doric, Amandine Berthet, Danielle M Jorgens, Mai K Nguyen, Ivy Hsieh, Julia Margulis, Rebecca Fang, Jayanta Debnath, Hiromi Sesaki, Steve Finkbeiner, Eric Huang, Ken Nakamura.
      Altered mitochondrial quality control and dynamics may contribute to neurodegenerative diseases, including Parkinson's disease, but we understand little about these processes in neurons. We combined time-lapse microscopy and correlative light and electron microscopy to track individual mitochondria in neurons lacking the fission-promoting protein dynamin-related protein 1 (Drp1) and delineate the kinetics of PINK1-dependent pathways of mitochondrial quality control. Depolarized mitochondria recruit Parkin to the outer mitochondrial membrane, triggering autophagosome formation, rapid lysosomal fusion, and Parkin redistribution. Unexpectedly, these mitolysosomes are dynamic and persist for hours. Some are engulfed by healthy mitochondria, and others are deacidified before bursting. In other cases, Parkin is directly recruited to the matrix of polarized mitochondria. Loss of PINK1 blocks Parkin recruitment, causes LC3 accumulation within mitochondria, and exacerbates Drp1KO toxicity to dopamine neurons. These results define a distinct neuronal mitochondrial life cycle, revealing potential mechanisms of mitochondrial recycling and signaling relevant to neurodegeneration.
    DOI:  https://doi.org/10.1126/sciadv.abf6580
  33. Small. 2021 Aug 04. e2102695
    The Sustainability of Energy Conversion Inhibition for Tumor Ferroptosis Therapy and Chemotherapy.
    Wei Jiang, Xingyu Luo, Lulu Wei, Shanmei Yuan, Jianfeng Cai, Xiqun Jiang, Yong Hu.
      The hyperactive energy metabolism mostly contributes the tumor cells growth and proliferation. Herein, the intelligent nanoparticles (P-B-D NPs) obtained by loading BAY-876 and doxorubicin (Dox)-Duplex into nanoparticles composed of disulfide bond (SS) containing polymer are reported, which provide an efficient resistance of tumor cells energy metabolism and tumor growth to conquer malignant tumor. In response to the reducing microenvironment of tumor tissue, the SS bond can be disintegrated by intracellular glutathione to block the synthesis of lipid repair enzyme-glutathione peroxidase 4 for ferroptosis therapy. More importantly, the released BAY-876 can inhibit the functionality of glucose transporter 1, restricting the glucose uptake of tumor cells to a low energy metabolism status. Meanwhile, Dox-Duplex can interact with ATP to reduce intracellular ATP content and release Dox to kill tumor cells. Collectively, this work offers a new idea for restricting tumor cells energy metabolism to inhibit their proliferation.
    Keywords:  BAY-876; Glut1; ferroptosis; metabolic inhibition; self-assembly
    DOI:  https://doi.org/10.1002/smll.202102695
  34. Cancers (Basel). 2021 Jul 27. pii: 3769. [Epub ahead of print]13(15):
    Reactive Oxygen Species: A Promising Therapeutic Target for SDHx-Mutated Pheochromocytoma and Paraganglioma.
    Katerina Hadrava Vanova, Chunzhang Yang, Leah Meuter, Jiri Neuzil, Karel Pacak.
      Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors derived from neural crest cells. Germline variants in approximately 20 PHEO/PGL susceptibility genes are found in about 40% of patients, half of which are found in the genes that encode succinate dehydrogenase (SDH). Patients with SDH subunit B (SDHB)-mutated PHEO/PGL exhibit a higher likelihood of developing metastatic disease, which can be partially explained by the metabolic cell reprogramming and redox imbalance caused by the mutation. Reactive oxygen species (ROS) are highly reactive molecules involved in a multitude of important signaling pathways. A moderate level of ROS production can help regulate cellular physiology; however, an excessive level of oxidative stress can lead to tumorigenic processes including stimulation of growth factor-dependent pathways and the induction of genetic instability. Tumor cells effectively exploit antioxidant enzymes in order to protect themselves against harmful intracellular ROS accumulation, which highlights the essential balance between ROS production and scavenging. Exploiting ROS accumulation can be used as a possible therapeutic strategy in ROS-scavenging tumor cells. Here, we focus on the role of ROS production in PHEO and PGL, predominantly in SDHB-mutated cases. We discuss potential strategies and approaches to anticancer therapies by enhancing ROS production in these difficult-to-treat tumors.
    Keywords:  metastatic pheochromocytoma; paraganglioma; reactive oxygen species; succinate dehydrogenase
    DOI:  https://doi.org/10.3390/cancers13153769
  35. Metabolites. 2021 Jul 01. pii: 432. [Epub ahead of print]11(7):
    Matrix Stiffness Modulates Metabolic Interaction between Human Stromal and Breast Cancer Cells to Stimulate Epithelial Motility.
    Iván Ponce, Nelson Garrido, Nicolás Tobar, Francisco Melo, Patricio C Smith, Jorge Martínez.
      Breast tumors belong to the type of desmoplastic lesion in which a stiffer tissue structure is a determinant of breast cancer progression and constitutes a risk factor for breast cancer development. It has been proposed that cancer-associated stromal cells (responsible for this fibrotic phenomenon) are able to metabolize glucose via lactate production, which supports the catabolic metabolism of cancer cells. The aim of this work was to investigate the possible functional link between these two processes. To measure the effect of matrix rigidity on metabolic determinations, we used compliant elastic polyacrylamide gels as a substrate material, to which matrix molecules were covalently linked. We evaluated metabolite transport in stromal cells using two different FRET (Fluorescence Resonance Energy Transfer) nanosensors specific for glucose and lactate. Cell migration/invasion was evaluated using Transwell devices. We show that increased stiffness stimulates lactate production and glucose uptake by mammary fibroblasts. This response was correlated with the expression of stromal glucose transporter Glut1 and monocarboxylate transporters MCT4. Moreover, mammary stromal cells cultured on stiff matrices generated soluble factors that stimulated epithelial breast migration in a stiffness-dependent manner. Using a normal breast stromal cell line, we found that a stiffer extracellular matrix favors the acquisition mechanistical properties that promote metabolic reprograming and also constitute a stimulus for epithelial motility. This new knowledge will help us to better understand the complex relationship between fibrosis, metabolic reprogramming, and cancer malignancy.
    Keywords:  breast cancer; lactate; monocarboxylate transporters; stiffness
    DOI:  https://doi.org/10.3390/metabo11070432
  36. Life (Basel). 2021 Jul 06. pii: 663. [Epub ahead of print]11(7):
    Mitochondrial Genomic Landscape: A Portrait of the Mitochondrial Genome 40 Years after the First Complete Sequence.
    Alessandro Formaggioni, Andrea Luchetti, Federico Plazzi.
      Notwithstanding the initial claims of general conservation, mitochondrial genomes are a largely heterogeneous set of organellar chromosomes which displays a bewildering diversity in terms of structure, architecture, gene content, and functionality. The mitochondrial genome is typically described as a single chromosome, yet many examples of multipartite genomes have been found (for example, among sponges and diplonemeans); the mitochondrial genome is typically depicted as circular, yet many linear genomes are known (for example, among jellyfish, alveolates, and apicomplexans); the chromosome is normally said to be "small", yet there is a huge variation between the smallest and the largest known genomes (found, for example, in ctenophores and vascular plants, respectively); even the gene content is highly unconserved, ranging from the 13 oxidative phosphorylation-related enzymatic subunits encoded by animal mitochondria to the wider set of mitochondrial genes found in jakobids. In the present paper, we compile and describe a large database of 27,873 mitochondrial genomes currently available in GenBank, encompassing the whole eukaryotic domain. We discuss the major features of mitochondrial molecular diversity, with special reference to nucleotide composition and compositional biases; moreover, the database is made publicly available for future analyses on the MoZoo Lab GitHub page.
    Keywords:  Eukaryota; compositional bias; mitochondrial genome; mtDNA architecture; mtDNA expansion; mtDNA structure; nucleotide composition; strand asymmetry
    DOI:  https://doi.org/10.3390/life11070663
  37. Cancers (Basel). 2021 Jul 27. pii: 3762. [Epub ahead of print]13(15):
    Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response.
    Melissa Schwab, Katharina Thunborg, Omid Azimzadeh, Christine von Toerne, Caroline Werner, Maxim Shevtsov, Tommaso Di Genio, Masa Zdralevic, Jacques Pouyssegur, Kathrin Renner, Marina Kreutz, Gabriele Multhoff.
      The heightened energetic demand increases lactate dehydrogenase (LDH) activity, the corresponding oncometabolite lactate, expression of heat shock proteins (HSPs) and thereby promotes therapy resistance in many malignant tumor cell types. Therefore, we assessed the coregulation of LDH and the heat shock response with respect to radiation resistance in different tumor cells (B16F10 murine melanoma and LS174T human colorectal adenocarcinoma). The inhibition of LDH activity by oxamate or GNE-140, glucose deprivation and LDHA/B double knockout (LDH-/-) in B16F10 and LS174T cells significantly diminish tumor growth; ROS production and the cytosolic expression of different HSPs, including Hsp90, Hsp70 and Hsp27 concomitant with a reduction of heat shock factor 1 (HSF1)/pHSF1. An altered lipid metabolism mediated by a LDHA/B double knockout results in a decreased presence of the Hsp70-anchoring glycosphingolipid Gb3 on the cell surface of tumor cells, which, in turn, reduces the membrane Hsp70 density and increases the extracellular Hsp70 levels. Vice versa, elevated extracellular lactate/pyruvate concentrations increase the membrane Hsp70 expression in wildtype tumor cells. Functionally, an inhibition of LDH causes a generalized reduction of cytosolic and membrane-bound HSPs in tumor cells and significantly increases the radiosensitivity, which is associated with a G2/M arrest. We demonstrate that targeting of the lactate/pyruvate metabolism breaks the radioresistance by impairing the stress response.
    Keywords:  LDHA/B double knockout; lactate/pyruvate metabolism; membrane heat shock protein 70 (Hsp70); radiosensitivity; stress response
    DOI:  https://doi.org/10.3390/cancers13153762
  38. Leukemia. 2021 Aug 03.
    Targeting leukemia-specific dependence on the de novo purine synthesis pathway.
    Takuji Yamauchi, Kohta Miyawaki, Yuichiro Semba, Masatomo Takahashi, Yoshihiro Izumi, Jumpei Nogami, Fumihiko Nakao, Takeshi Sugio, Kensuke Sasaki, Luca Pinello, Daniel E Bauer, Takeshi Bamba, Koichi Akashi, Takahiro Maeda.
      Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.
    DOI:  https://doi.org/10.1038/s41375-021-01369-0
  39. Cell Metab. 2021 Aug 03. pii: S1550-4131(21)00328-4. [Epub ahead of print]33(8): 1505-1506
    When fat talks, the gut listens: IRONing out metabolism.
    Mirian Krystel De Siqueira, Claudio J Villanueva.
      In a new study, Zhang et al. (2021) show that reducing iron levels in adipose tissue improves metabolic function. This occurs through an interorgan communication system where signals from the adipocyte reduce intestinal lipid absorption.
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.012
  40. Cell. 2021 Aug 05. pii: S0092-8674(21)00857-6. [Epub ahead of print]184(16): 4348-4371.e40
    A proteogenomic portrait of lung squamous cell carcinoma.
    Shankha Satpathy, Karsten Krug, Pierre M Jean Beltran, Sara R Savage, Francesca Petralia, Chandan Kumar-Sinha, Yongchao Dou, Boris Reva, M Harry Kane, Shayan C Avanessian, Suhas V Vasaikar, Azra Krek, Jonathan T Lei, Eric J Jaehnig, Tatiana Omelchenko, Yifat Geffen, Erik J Bergstrom, Vasileios Stathias, Karen E Christianson, David I Heiman, Marcin P Cieslik, Song Cao, Xiaoyu Song, Jiayi Ji, Wenke Liu, Kai Li, Bo Wen, Yize Li, Zeynep H Gümüş, Myvizhi Esai Selvan, Rama Soundararajan, Tanvi H Visal, Maria G Raso, Edwin Roger Parra, Özgün Babur, Pankaj Vats, Shankara Anand, Tobias Schraink, MacIntosh Cornwell, Fernanda Martins Rodrigues, Houxiang Zhu, Chia-Kuei Mo, Yuping Zhang, Felipe da Veiga Leprevost, Chen Huang, Arul M Chinnaiyan, Matthew A Wyczalkowski, Gilbert S Omenn, Chelsea J Newton, Stephan Schurer, Kelly V Ruggles, David Fenyö, Scott D Jewell, Mathangi Thiagarajan, Mehdi Mesri, Henry Rodriguez, Sendurai A Mani, Namrata D Udeshi, Gad Getz, James Suh, Qing Kay Li, Galen Hostetter, Paul K Paik, Saravana M Dhanasekaran, Ramaswamy Govindan, Li Ding, Ana I Robles, Karl R Clauser, Alexey I Nesvizhskii, Pei Wang, Steven A Carr, Bing Zhang, D R Mani, Michael A Gillette, .
      Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.
    Keywords:  CPTAC; acetylation; genomics; lung cancer; phosphorylation; protein; proteogenomics; proteomics; squamous; ubiquitylation
    DOI:  https://doi.org/10.1016/j.cell.2021.07.016
  41. Am J Cancer Res. 2021 ;11(7): 3575-3593
    Inhibition of BAG3 enhances the anticancer effect of shikonin in hepatocellular carcinoma.
    Jie Lu, Shuang-Yu Liu, Jing Zhang, Guang-Ming Yang, Gui-Bin Gao, Nan-Nan Yu, Yan-Ping Li, Yi-Xiang Li, Zhong-Qi Ma, Yang Wang, Chun-Hua Lu.
      Human hepatocellular carcinoma (HCC) is the most frequent cancer worldwide with a poor prognosis. Tumor-specific pyruvate kinase M2 (PKM2) is essential for cancer metabolism and tumorigenesis. Shikonin, a specific inhibitor of PKM2, but not PKM1, exhibits significant anticancer effect in HCC, and was deemed as a promising drug for cancer therapy. However, shikonin-mediated bypass signaling in HCC remained unclear. Here, we performed forward/reverse stable isotope labeling with amino acids in cell culture (SILAC)-based proteomics to identify the early molecular events controlled by shikonin. We demonstrated for the first time that shikonin could induce the nuclear translocation of PKM2 for recruiting Nrf2, and transcriptionally activated Nrf2 downstream target gene BAG3, therefore increasing protective effect to sustain cell survival. Knockdown of BAG3 by si-RNA significantly potentiated the anticancer effect of shikonin. These findings provided the first evidence of a new noncanonical function of inhibited PKM2 could act as a transcriptional coactivator of Nrf2 in cancer survival, highlight that shikonin in combined with BAG3 inhibitor could be a promising therapeutic strategy for HCC therapy.
    Keywords:  BAG3; Nrf2; PKM2; Shikonin; human hepatocellular carcinoma
  42. PLoS One. 2021 ;16(8): e0255164
    Unveiling a key role of oxaloacetate-glutamate interaction in regulation of respiration and ROS generation in nonsynaptic brain mitochondria using a kinetic model.
    Vitaly A Selivanov, Olga A Zagubnaya, Yaroslav R Nartsissov, Marta Cascante.
      Glutamate plays diverse roles in neuronal cells, affecting cell energetics and reactive oxygen species (ROS) generation. These roles are especially vital for neuronal cells, which deal with high amounts of glutamate as a neurotransmitter. Our analysis explored neuronal glutamate implication in cellular energy metabolism and ROS generation, using a kinetic model that simulates electron transport details in respiratory complexes, linked ROS generation and metabolic reactions. The analysis focused on the fact that glutamate attenuates complex II inhibition by oxaloacetate, stimulating the latter's transformation into aspartate. Such a mechanism of complex II activation by glutamate could cause almost complete reduction of ubiquinone and deficiency of oxidized form (Q), which closes the main stream of electron transport and opens a way to massive ROS generating transfer in complex III from semiquinone radicals to molecular oxygen. In this way, under low workload, glutamate triggers the respiratory chain (RC) into a different steady state characterized by high ROS generation rate. The observed stepwise dependence of ROS generation on glutamate concentration experimentally validated this prediction. However, glutamate's attenuation of oxaloacetate's inhibition accelerates electron transport under high workload. Glutamate-oxaloacetate interaction in complex II regulation underlies the observed effects of uncouplers and inhibitors and acceleration of Ca2+ uptake. Thus, this theoretical analysis uncovered the previously unknown roles of oxaloacetate as a regulator of ROS generation and glutamate as a modifier of this regulation. The model predicted that this mechanism of complex II activation by glutamate might be operative in situ and responsible for excitotoxicity. Spatial-time gradients of synthesized hydrogen peroxide concentration, calculated in the reaction-diffusion model with convection under a non-uniform local approximation of nervous tissue, have shown that overproduction of H2O2 in a cell causes excess of its level in neighbor cells.
    DOI:  https://doi.org/10.1371/journal.pone.0255164
  43. Int J Mol Sci. 2021 Jul 29. pii: 8117. [Epub ahead of print]22(15):
    Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3.
    Nunzia D'Onofrio, Elisa Martino, Luigi Mele, Antonino Colloca, Martina Maione, Domenico Cautela, Domenico Castaldo, Maria Luisa Balestrieri.
      Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.
    Keywords:  PINK1/Parkin; colon cancer; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.3390/ijms22158117
  44. Brief Bioinform. 2021 Jul 30. pii: bbab288. [Epub ahead of print]
    iDeepSubMito: identification of protein submitochondrial localization with deep learning.
    Zilong Hou, Yuning Yang, Hui Li, Ka-Chun Wong, Xiangtao Li.
      Mitochondria are membrane-bound organelles containing over 1000 different proteins involved in mitochondrial function, gene expression and metabolic processes. Accurate localization of those proteins in the mitochondrial compartments is critical to their operation. A few computational methods have been developed for predicting submitochondrial localization from the protein sequences. Unfortunately, most of these computational methods focus on employing biological features or evolutionary information to extract sequence features, which greatly limits the performance of subsequent identification. Moreover, the efficiency of most computational models is still under explored, especially the deep learning feature, which is promising but requires improvement. To address these limitations, we propose a novel computational method called iDeepSubMito to predict the location of mitochondrial proteins to the submitochondrial compartments. First, we adopted a coding scheme using the ProteinELMo to model the probability distribution over the protein sequences and then represent the protein sequences as continuous vectors. Then, we proposed and implemented convolutional neural network architecture based on the bidirectional LSTM with self-attention mechanism, to effectively explore the contextual information and protein sequence semantic features. To demonstrate the effectiveness of our proposed iDeepSubMito, we performed cross-validation on two datasets containing 424 proteins and 570 proteins respectively, and consisting of four different mitochondrial compartments (matrix, inner membrane, outer membrane and intermembrane regions). Experimental results revealed that our method outperformed other computational methods. In addition, we tested iDeepSubMito on the M187, M983 and MitoCarta3.0 to further verify the efficiency of our method. Finally, the motif analysis and the interpretability analysis were conducted to reveal novel insights into subcellular biological functions of mitochondrial proteins. iDeepSubMito source code is available on GitHub at https://github.com/houzl3416/iDeepSubMito.
    Keywords:  deep learning; protein sequences; protein submitochondrial localization
    DOI:  https://doi.org/10.1093/bib/bbab288
  45. Cancers (Basel). 2021 Aug 03. pii: 3917. [Epub ahead of print]13(15):
    Adipocytes Promote Breast Cancer Cell Survival and Migration through Autophagy Activation.
    Dorine Bellanger, Cléa Dziagwa, Cyrille Guimaraes, Michelle Pinault, Jean-François Dumas, Lucie Brisson.
      White adipose tissue interacts closely with breast cancers through the secretion of soluble factors such as cytokines, growth factors or fatty acids. However, the molecular mechanisms of these interactions and their roles in cancer progression remain poorly understood. In this study, we investigated the role of fatty acids in the cooperation between adipocytes and breast cancer cells using a co-culture model. We report that adipocytes increase autophagy in breast cancer cells through the acidification of lysosomes, leading to cancer cell survival in nutrient-deprived conditions and to cancer cell migration. Mechanistically, the disturbance of membrane phospholipid composition with a decrease in arachidonic acid content is responsible for autophagy activation in breast cancer cells induced by adipocytes. Therefore, autophagy might be a central cellular mechanism of white adipose tissue interactions with cancer cells and thus participate in cancer progression.
    Keywords:  adipose tissue; autophagy; breast cancer; cell communication; fatty acid
    DOI:  https://doi.org/10.3390/cancers13153917
  46. Neurooncol Adv. 2021 Jan-Dec;3(1):3(1): vdab074
    The spectrum of mitochondrial DNA (mtDNA) mutations in pediatric CNS tumors.
    Kristiyana Kaneva, Katrina O'Halloran, Petr Triska, Xiyu Liu, Daria Merkurjev, Moiz Bootwalla, Alex Ryutov, Jennifer A Cotter, Dejerianne Ostrow, Jaclyn A Biegel, Xiaowu Gai.
      Background: We previously established the landscape of mitochondrial DNA (mtDNA) mutations in 23 subtypes of pediatric malignancies, characterized mtDNA mutation profiles among these subtypes, and provided statistically significant evidence for a contributory role of mtDNA mutations to pediatric malignancies.Methods: To further delineate the spectrum of mtDNA mutations in pediatric central nervous system (CNS) tumors, we analyzed 545 tumor-normal paired whole-genome sequencing datasets from the Children's Brain Tumor Tissue Consortium.
    Results: Germline mtDNA variants were used to determine the haplogroup, and maternal ancestry, which was not significantly different among tumor types. Among 166 (30.5%) tumors we detected 220 somatic mtDNA mutations, primarily missense mutations (36.8%), as well as 22 loss-of-function mutations. Different pediatric CNS tumor subtypes had distinct mtDNA mutation profiles. The number of mtDNA mutations per tumor ranged from 0.20 (dysembryoplastic neuroepithelial tumor [DNET]) to 0.75 (meningiomas). The average heteroplasmy was 10.7%, ranging from 4.6% in atypical teratoid/rhabdoid tumor (AT/RT) to 26% in diffuse intrinsic pontine glioma. High-grade gliomas had a significant higher number of mtDNA mutations per sample than low-grade gliomas (0.6 vs 0.27) (P = .004), with almost twice as many missense mtDNA mutations per sample (0.24 vs 0.11), and higher average heteroplasmy levels (16% vs 10%). Recurrent mtDNA mutations may represent hotspots which may serve as biologic markers of disease.
    Conclusions: Our findings demonstrate varying contributions of mtDNA mutations in different subtypes of CNS tumors. Sequencing the mtDNA genome may ultimately be used to characterize CNS tumors at diagnosis and monitor disease progression.
    Keywords:  CBTN; CBTTC; CNS tumors; brain tumors; mitochondrial DNA; pediatric
    DOI:  https://doi.org/10.1093/noajnl/vdab074
  47. Cell Calcium. 2021 Jul 27. pii: S0143-4160(21)00105-6. [Epub ahead of print]98 102451
    MICU1 opens the gates to cold-induced death.
    Felicia Dietsche, Li Zhang, John W Elrod, Axel Methner.
      Nakamura et al. recently discovered that the mitochondrial calcium uniporter gatekeeper, MICU1, is required for cold-induced ferroptotic cell death by modulating mitochondrial membrane potential. This function appears to be independent of its Ca2+-sensing ability. Here, we discuss their findings and suggest next steps to define MICU1's role in ferroptotic cell death.
    DOI:  https://doi.org/10.1016/j.ceca.2021.102451
  48. Cryobiology. 2021 Jul 28. pii: S0011-2240(21)00137-1. [Epub ahead of print]
    Hypothermia Promotes Mitochondrial Elongation In Cardiac Cells Via Inhibition Of Drp1.
    David Taylor, Juliana Germano, Yang Song, Hanane Hadj-Moussa, Stefanie Marek-Iannucci, Raeesa Dhanji, Jon Sin, Lawrence S C Czer, Kenneth B Storey, Roberta A Gottlieb.
      Hypothermia is a valuable clinical tool in mitigating against the consequences of ischemia in surgery, stroke, cardiac arrest and organ preservation. Protection is afforded principally by a reduction of metabolism, manifesting as reduced rates of oxygen uptake, preservation of ATP levels, and a curtailing of ischemic calcium overload. The effects of non-ischemic hypothermic stress are relatively unknown. We sought to investigate the effects of clinically mild-to-severe hypothermia on mitochondrial morphology, oxygen consumption and protein expression in normoxic hearts and cardiac cells. Normoxic perfusion of rat hearts at 28-32°C was associated with inhibition of mitochondrial fission, evidenced by a reduced abundance of the active phosphorylated form of the fission receptor Drp1 (pDrp1S616). Abundance of the same residue was reduced in H9c2 cells subjected to hypothermic culture (25-32°C), in addition to a reduced abundance of the Drp1 receptor MFF. Hypothermia-treated H9c2 cardiomyocytes exhibited elongated mitochondria and depressed rates of mitochondrial-associated oxygen consumption, which persisted upon rewarming. Hypothermia also promoted a reduction in mRNA expression of the capsaicin receptor TRPV1 in H9c2 cells. When normothermic H9c2 cells were transfected with TRPV1 siRNA we observed reduced pDrp1S616 and MFF abundance, elongated mitochondria, and reduced rates of mitochondrial-associated oxygen consumption, mimicking the effects of hypothermic culture. In conclusion hypothermia promoted elongation of cardiac mitochondria via reduced pDrp1S616 abundance which was also associated with suppression of cellular oxygen consumption. Silencing of TRPV1 in H9c2 cardiomyocytes reproduced the morphological and respirometric phenotype of hypothermia. This report demonstrates a novel mechanism of cold-induced inhibition of mitochondrial fission.
    Keywords:  Drp1; Mitochondria; TRPV1; hypothermia; mitochondrial fission
    DOI:  https://doi.org/10.1016/j.cryobiol.2021.07.013
  49. Front Physiol. 2021 ;12 638352
    Mammalian Target of Rapamycin Signaling Pathway Regulates Mitochondrial Quality Control of Brown Adipocytes in Mice.
    Bahetiyaer Huwatibieke, Wenzhen Yin, Lingchao Liu, Yuxin Jin, Xinxin Xiang, Jingyan Han, Weizhen Zhang, Yin Li.
      The mammalian target of rapamycin (mTOR) is an important protein kinase that senses changes in extracellular and intracellular energy levels and plays a key role in regulating energy metabolism. Brown adipose tissue, which can be converted to white adipose tissue, contains a large number of mitochondria and regulates energy expenditure through thermogenesis. Because obesity is a process of fat accumulation due to chronic excessive energy intake, we attempted to determine whether the mTOR signaling pathway can affect the mitochondrial quality control of brown adipocytes through sensing energy status, thereby regulating brown/white adipocyte transformation. In the present study, through activation or inhibition of mTOR signaling, we detected mitochondrial biogenesis, dynamics, and autophagy-related markers in brown adipocytes. We found that activation of mTOR signaling downregulated the expression of mitochondrial biogenesis, dynamics, and autophagy-relevant markers and inhibited the mitochondrial quality control of brown adipocytes, indicating a phenotypic transformation of brown to white adipocytes. In contrast, inhibition of mTOR signaling upregulated the expression of mitochondrial biogenesis, dynamics, and mitophagy-relevant markers and strengthened mitochondrial quality control, suggesting an inhibition of the phenotypic transformation of brown to white adipocytes. In conclusion, the mTOR signaling pathway plays an important role in modulating the transformation of adipocytes by regulating mitochondrial quality control.
    Keywords:  brown adipose tissue; mammalian target of rapamycin; mitochondria; obesity; white adipose tissue
    DOI:  https://doi.org/10.3389/fphys.2021.638352
  50. Cell Rep. 2021 Aug 03. pii: S2211-1247(21)00914-1. [Epub ahead of print]36(5): 109487
    Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation.
    Kevin B Koronowski, Carolina M Greco, He Huang, Jin-Kwang Kim, Jennifer L Fribourgh, Priya Crosby, Lavina Mathur, Xuelian Ren, Carrie L Partch, Cholsoon Jang, Feng Qiao, Yingming Zhao, Paolo Sassone-Corsi.
      Ketone bodies are bioactive metabolites that function as energy substrates, signaling molecules, and regulators of histone modifications. β-hydroxybutyrate (β-OHB) is utilized in lysine β-hydroxybutyrylation (Kbhb) of histones, and associates with starvation-responsive genes, effectively coupling ketogenic metabolism with gene expression. The emerging diversity of the lysine acylation landscape prompted us to investigate the full proteomic impact of Kbhb. Global protein Kbhb is induced in a tissue-specific manner by a variety of interventions that evoke β-OHB. Mass spectrometry analysis of the β-hydroxybutyrylome in mouse liver revealed 891 sites of Kbhb within 267 proteins enriched for fatty acid, amino acid, detoxification, and one-carbon metabolic pathways. Kbhb inhibits S-adenosyl-L-homocysteine hydrolase (AHCY), a rate-limiting enzyme of the methionine cycle, in parallel with altered metabolite levels. Our results illuminate the role of Kbhb in hepatic metabolism under ketogenic conditions and demonstrate a functional consequence of this modification on a central metabolic enzyme.
    Keywords:  AHCY; S-adenosyl-L-homocysteine hydrolase; ketogenesis; ketogenic diet; liver metabolism; lysine acylation; methionine cycle; β-hydroxybutyrate; β-hydroxybutyrylation
    DOI:  https://doi.org/10.1016/j.celrep.2021.109487
  51. Nat Protoc. 2021 Aug 04.
    Interrogating in vivo T-cell metabolism in mice using stable isotope labeling metabolomics and rapid cell sorting.
    Ryan D Sheldon, Eric H Ma, Lisa M DeCamp, Kelsey S Williams, Russell G Jones.
      T cells are integral players in the adaptive immune system that readily adapt their metabolism to meet their energetic and biosynthetic needs. A major hurdle to understand physiologic T-cell metabolism has been the differences between in vitro cell culture conditions and the complex in vivo milieu. To address this, we have developed a protocol that merges traditional immunology infection models with whole-body metabolite infusion and mass-spectrometry-based metabolomic profiling to assess T-cell metabolism in vivo. In this protocol, pathogen-infected mice are infused via the tail vein with an isotopically labeled metabolite (2-6 h), followed by rapid magnetic bead isolation to purify T-cell populations (<1 h) and then stable isotope labeling analysis conducted by mass spectrometry (~1-2 d). This procedure enables researchers to evaluate metabolic substrate utilization into central carbon metabolic pathways (i.e., glycolysis and the tricarboxylic acid cycle) by specific T-cell subpopulations in the context of physiological immune responses in vivo.
    DOI:  https://doi.org/10.1038/s41596-021-00586-2
  52. Front Physiol. 2021 ;12 715485
    Distinct Mitochondrial Pathologies Caused by Mutations of the Proximal Tubular Enzymes EHHADH and GATM.
    Anna-Lena Forst, Markus Reichold, Robert Kleta, Richard Warth.
      The mitochondria of the proximal tubule are essential for providing energy in this nephron segment, whose ATP generation is almost exclusively oxygen dependent. In addition, mitochondria are involved in a variety of metabolic processes and complex signaling networks. Proximal tubular mitochondrial dysfunction can therefore affect renal function in very different ways. Two autosomal dominantly inherited forms of renal Fanconi syndrome illustrate how multifaceted mitochondrial pathology can be: Mutation of EHHADH, an enzyme in fatty acid metabolism, results in decreased ATP synthesis and a consecutive transport defect. In contrast, mutations of GATM, an enzyme in the creatine biosynthetic pathway, leave ATP synthesis unaffected but do lead to mitochondrial protein aggregates, inflammasome activation, and renal fibrosis with progressive renal failure. In this review article, the distinct pathophysiological mechanisms of these two diseases are presented, which are examples of the spectrum of proximal tubular mitochondrial diseases.
    Keywords:  autosomal dominant mutation; inflammasome; mitochondrial damage associated molecular patterns; peroxisome; protein aggregates; renal fibrosis
    DOI:  https://doi.org/10.3389/fphys.2021.715485
  53. Redox Biol. 2021 Jul 25. pii: S2213-2317(21)00225-1. [Epub ahead of print]46 102066
    Thiol-disulphide independent in-cell trapping for the identification of peroxiredoxin 2 interactors.
    Ting Luo, Julia Malo Pueyo, Khadija Wahni, Charlotte Yvanoff, Tamas Lazar, Sébastien Pyr Dit Ruys, Didier Vertommen, Daria Ezeriņa, Joris Messens.
      Hydrogen peroxide (H2O2) acts as a signalling molecule by oxidising cysteine thiols in proteins. Recent evidence has established a role for cytosolic peroxiredoxins in transmitting H2O2-based oxidation to a multitude of target proteins. Moreover, it is becoming clear that peroxiredoxins fulfil their function in organised microdomains, where not all interactors are covalently bound. However, most studies aimed at identifying peroxiredoxin interactors were based on methods that only detect covalently linked partners. Here, we explore the applicability of two thiol-disulphide independent in-cell trapping methodological approaches in combination with mass spectrometry for the identification of interaction partners of peroxiredoxin 2 (Prdx2). The first is biotin-dependent proximity-labelling (BioID) with a biotin ligase A (BirA*)-fused Prdx2, which has never been applied on redox-active proteins. The second is crosslinker co-immunoprecipitation with an N-terminally His-tagged Prdx2. During the initial characterisation of the tagged Prdx2 constructs, we found that the His-tag, but not BirA*, compromises the peroxidase and signalling activities of Prdx2. Further, the Prdx2 interactors identified with each approach showed little overlap. We therefore concluded that BioID is a more reliable method than crosslinker co-immunoprecipitation. After a stringent mass spec data filtering, BioID identified 13 interactors under elevated H2O2 conditions, including subunit five of the COP9 signalosome complex (CSN5). The Prdx2:CSN5 interaction was further confirmed in a proximity ligation assay. Taken together, our results demonstrate that BioID can be used as a method for the identification of interactors of Prdxs, and that caution should be exercised when interpreting protein-protein interaction results using tagged Prdxs.
    Keywords:  BioID; Peroxiredoxin; Prdx2; Protein-protein interactions; Proximity labelling; Redox signalling
    DOI:  https://doi.org/10.1016/j.redox.2021.102066
  54. Mol Cell. 2021 Jul 27. pii: S1097-2765(21)00583-9. [Epub ahead of print]
    Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER.
    David M Booth, Péter Várnai, Suresh K Joseph, György Hajnóczky.
      The emerging role of mitochondria as signaling organelles raises the question of whether individual mitochondria can initiate heterotypic communication with neighboring organelles. Using fluorescent probes targeted to the endoplasmic-reticulum-mitochondrial interface, we demonstrate that single mitochondria generate oxidative bursts, rapid redox oscillations, confined to the nanoscale environment of the interorganellar contact sites. Using probes fused to inositol 1,4,5-trisphosphate receptors (IP3Rs), we show that Ca2+ channels directly sense oxidative bursts and respond with Ca2+ transients adjacent to active mitochondria. Application of specific mitochondrial stressors or apoptotic stimuli dramatically increases the frequency and amplitude of the oxidative bursts by enhancing transient permeability transition pore openings. Conversely, blocking interface Ca2+ transport via elimination of IP3Rs or mitochondrial calcium uniporter channels suppresses ER-mitochondrial Ca2+ feedback and cell death. Thus, single mitochondria initiate local retrograde signaling by miniature oxidative bursts and, upon metabolic or apoptotic stress, may also amplify signals to the rest of the cell.
    Keywords:  Ca2+ microdomain; Inositol-1,4,5-trisphosphate receptor; Mitochondrial retrograde signaling; Organelle contacts; Redox nanodomain
    DOI:  https://doi.org/10.1016/j.molcel.2021.07.014
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