bims-camemi Biomed news
on Mitochondrial metabolism in cancer
Issue of 2018‒08‒19
twelve papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit


  1. Mitochondrion. 2018 Aug 08. pii: S1567-7249(18)30087-4. [Epub ahead of print]
    Koref MS, Griffin H, Turnbull DM, Chinnery PF, Herbert M, Hudson G.
      The mitochondrial genome has recently become the focus of several high-impact next-generation sequencing studies investigating the effect of mutations in disease and assessing the efficacy of mitochondrial replacement therapies. However, these studies have failed to take into consideration the capture of recurring translocations of mitochondrial DNA to the nuclear genome, known as nuclear mitochondrial sequences (NUMTs), continuing to align sequence data to the revised Cambridge reference sequence alone. Here, using different mtDNA enrichment techniques and a variety of tissues, we demonstrate that NUMTs are present in sequence data and that, dependent upon downstream analysis, are at a level which affects variant calling.
    Keywords:  Bioinformatic analysis; Heteroplasmy; Mitochondrial DNA; Next-generation sequencing
    DOI:  https://doi.org/10.1016/j.mito.2018.08.003
  2. Mol Metab. 2018 Jul 25. pii: S2212-8778(18)30486-1. [Epub ahead of print]
    Taddeo EP, Stiles L, Sereda S, Ritou E, Wolf DM, Abdullah M, Swanson Z, Wilhelm J, Bellin M, McDonald P, Caradonna K, Neilson A, Liesa M, Shirihai OS.
      OBJECTIVE: Islets from the same pancreas show remarkable variability in glucose sensitivity. While mitochondrial respiration is essential for glucose-stimulated insulin secretion, little is known regarding heterogeneity in mitochondrial function at the individual islet level. This is due in part to a lack of high-throughput and non-invasive methods for detecting single islet function.METHODS: We have developed a novel non-invasive, high-throughput methodology capable of assessing mitochondrial respiration in large-sized individual islets using the XF96 analyzer (Agilent Technologies).
    RESULTS: By increasing measurement sensitivity, we have reduced the minimal size of mouse and human islets needed to assess mitochondrial respiration to single large islets of >35,000 μm2 area (∼210 μm diameter). In addition, we have measured heterogeneous glucose-stimulated mitochondrial respiration among individual human and mouse islets from the same pancreas, allowing population analyses of islet mitochondrial function for the first time.
    CONCLUSIONS: We have developed a novel methodology capable of analyzing mitochondrial function in large-sized individual islets. By highlighting islet functional heterogeneity, we hope this methodology can significantly advance islet research.
    Keywords:  Glucose; Islets; Mitochondria; Respirometry
    DOI:  https://doi.org/10.1016/j.molmet.2018.07.003
  3. J Photochem Photobiol B. 2018 Aug 03. pii: S1011-1344(18)30467-6. [Epub ahead of print]187 41-47
    Tatmatsu-Rocha JC, Tim CR, Avo L, Bernardes-Filho R, Brassolatti P, Kido HW, Hamblin MR, Parizotto NA.
      OBJECTIVE: Mitochondrial dysfunction has been associated with the development of diabetes mellitus which is characterized by disorders of collagen production and impaired wound healing. This study analyzed the effects of photobiomodulation (PBM) mediated by laser and light-emitting diode (LED) on the production and organization of collagen fibers in an excisional wound in an animal model of diabetes, and the correlation with inflammation and mitochondrial dynamics.METHODS: Twenty Wistar rats were randomized into 4 groups of 5 animals. Groups: (SHAM) a control non-diabetic wounded group with no treatment; (DC) a diabetic wounded group with no treatment; (DLASER) a diabetic wounded group irradiated by 904 nm pulsed laser (40 mW, 9500 Hz, 1 min, 2.4 J); (DLED) a diabetic wounded group irradiated by continuous wave LED 850 nm (48 mW, 22 s, 1.0 J). Diabetes was induced by injection with streptozotocin (70 mg/kg). PBM was carried out daily for 5 days followed by sacrifice and tissue removal.
    RESULTS: Collagen fibers in diabetic wounded skin were increased by DLASER but not by DLED. Both groups showed increased blood vessels by atomic force microscopy. Vascular endothelial growth factor (VEGF) was higher and cyclooxygenase (COX2) was lower in the DLED group. Mitochondrial fusion was higher and mitochondrial fusion was lower in DLED compared to DLASER.
    CONCLUSION: Differences observed between DLASER and DLED may be due to the pulsed laser and CW LED, and to the higher dose of laser. Regulation of mitochondrial homeostasis may be an important mechanism for PBM effects in diabetes.
    Keywords:  Atomic force microscopy; Collagen fibers; Diabetes mellitus; Diabetic wound healing; Laser versus LED; Mitochondrial fission and fusion; Photobiomodulation therapy
    DOI:  https://doi.org/10.1016/j.jphotobiol.2018.07.032
  4. J Physiol. 2018 Aug 12.
    Lee H, Kim K, Kim B, Shin J, Rajan S, Wu J, Chen X, Brown MD, Lee S, Park JY.
      KEY POINTS: Referring to the muscle memory theory, previously trained muscles acquire strength and volume much faster than naive muscles. Using extreme experimental models such as synergist ablation or steroid administration, previous studies have demonstrated that the number of nuclei increases when a muscle becomes enlarged, which serves as a cellular muscle memory mechanism for the muscle. In the present study, we found that, when rats were subjected to physiologically relevant resistance training, the number of myonuclei increased and was retained during a long-term detraining period. The acquired myonuclei were related to a greater degree of muscle hypertrophic and mitochondrial biogenesis processes following subsequent hypertrophic conditions. Our data suggest a cellular mechanism supporting the notion that exposing young muscles to resistance training would help to restore age-related muscle loss coupled with mitochondrial dysfunction in later life.ABSTRACT: Muscle hypertrophy induced by resistance training is accompanied by an increase in the number of myonuclei. The acquired myonuclei are viewed as a cellular component of muscle memory by which muscle enlargement is promoted during a re-training period. In the present study, we investigated the effect of exercise preconditioning on mitochondrial remodelling induced by resistance training. Sprague-Dawley rats were divided into four groups: untrained control, training, pre-training or re-training. The training groups were subjected to weight loaded-ladder climbing exercise training. Myonuclear numbers were significantly greater (up to 20%) in all trained muscles compared to untrained controls. Muscle mass was significantly higher in the re-training group compared to the training group (∼2-fold increase). Mitochondrial content, mitochondrial biogenesis gene expression levels and mitochondrial DNA copy numbers were significantly higher in re-trained muscles compared to the others. Oxidative myofibres (type I) were significantly increased only in the re-trained muscles. Furthermore, in vitro studies using insulin-like growth factor-1-treated L6 rat myotubes demonstrated that myotubes with a higher myonuclear number confer greater expression levels of both mitochondrial and nuclear genes encoding for constitutive and regulatory mitochondrial proteins, which also showed a greater mitochondrial respiratory function. These data suggest that myonuclei acquired from previous training facilitate mitochondrial biogenesis in response to subsequent retraining by (at least in part) enhancing cross-talk between mitochondria and myonuclei in the pre-conditioned myofibres.
    Keywords:  mitochondrial biogenesis; muscle memory; myonuclei; resistance training
    DOI:  https://doi.org/10.1113/JP275308
  5. Mol Aspects Med. 2018 Aug 08. pii: S0098-2997(18)30042-6. [Epub ahead of print]
    van der Vliet A, Janssen-Heininger YMW, Anathy V.
      The lung is a delicate organ with a large surface area that is continuously exposed to the external environment, and is therefore highly vulnerable to exogenous sources of oxidative stress. In addition, each of its approximately 40 cell types can also generate reactive oxygen species (ROS), as byproducts of cellular metabolism and in a more regulated manner by NOX enzymes with functions in host defense, immune regulation, and cell proliferation or differentiation. To effectively regulate the biological actions of exogenous and endogenous ROS, various enzymatic and non-enzymatic antioxidant defense systems are present in all lung cell types to provide adequate protection against their injurious effects and to allow for appropriate ROS-mediated biological signaling. Acute and chronic lung diseases are commonly thought to be associated with increased oxidative stress, evidenced by altered cellular or extracellular redox status, increased irreversible oxidative modifications in proteins or DNA, mitochondrial dysfunction, and altered expression or activity of NOX enzymes and antioxidant enzyme systems. However, supplementation strategies with generic antioxidants has proven minimally successful in prevention or treatment of lung disease, most likely due to their inability to distinguish between harmful and beneficial actions of ROS. Recent studies have attempted to identify specific redox-based mechanisms that may mediate chronic lung disease, such as allergic asthma or pulmonary fibrosis, which provide opportunities for selective redox-based therapeutic strategies that may be useful in treatment of these diseases. (229 words).
    Keywords:  Asthma; ER stress; Epithelium; Fibrosis; NOX; S-glutathionylation; Sulfenylation
    DOI:  https://doi.org/10.1016/j.mam.2018.08.001
  6. Mitochondrion. 2018 Aug 08. pii: S1567-7249(18)30101-6. [Epub ahead of print]
    Lowes H, Pyle A, Duddy M, Hudson G.
      Recent studies have linked cell-free mitochondrial DNA (ccf-mtDNA) to neurodegeneration in both Alzheimer's and Parkinson's disease, raising the possibility that the same phenomenon could be seen in other diseases which manifest a neurodegenerative component. Here, we assessed the role of circulating cell-free mitochondrial DNA (ccf-mtDNA) in end-stage progressive multiple sclerosis (PMS), where neurodegeneration is evident, contrasting both ventricular cerebral spinal fluid ccf-mtDNA abundance and integrity between PMS cases and controls, and correlating ccf-mtDNA levels to known protein markers of neurodegeneration and PMS. Our data indicate that reduced ccf-mtDNA is a component of PMS, concluding that it may indeed be a hallmark of broader neurodegeneration.
    Keywords:  Cell-free mitochondrial DNA; Neurodegeneration; Next-Generation Sequencing; Progressive Multiple Sclerosis
    DOI:  https://doi.org/10.1016/j.mito.2018.07.008
  7. Exp Cell Res. 2018 Aug 08. pii: S0014-4827(18)30669-4. [Epub ahead of print]
    Wang Y, Liu Q, Huan Y, Li R, Li C, Sun S, Guo N, Yang M, Liu S, Shen Z.
      Recently, SIRT5 was reported to be a predominant desuccinylase and demalonylase in mitochondria. Ablation of SIRT5 enhances the systemic succinylation and malonylation of mitochondrial proteins, including various metabolic enzymes; however, its function in pancreatic β cells has not yet been clarified. In this study, we evaluated the effects of SIRT5 overexpression on glucolipotoxicity-induced apoptosis in β cell lines. Full-length SIRT5, which preferentially targeted to mitochondria and partially to the nucleus and cytoplasm, was overexpressed in NIT-1 cells. Chronic exposure to excess palmitate and glucose (High-PA-G) induced apoptosis and suppressed glucose-stimulated insulin secretion in β cells. SIRT5 overexpression significantly alleviated apoptosis under the High-PA-G condition, accompanied by suppressed Caspase 3 activity and reduced malondialdehyde levels. SIRT5 overexpression also improved β cell secretory capacity in response to glucose under the High-PA-G condition, suggesting its protective role in β cell function. Furthermore, SIRT5 overexpression reversed the decreasing trend of anti-apoptotic factors BCL-2 and BCL-XL expression under High-PA-G condition. Further regulation mechanisms between SIRT5 and these anti-apoptotic factors remains to be explored in future studies. Our data reveal that SIRT5 is a potentially protective factor for pancreatic β cells against glucolipotoxicity-induced apoptosis and cell dysfunction.
    Keywords:  SIRT5; apoptosis; glucolipotoxicity; insulin secretion; β cell
    DOI:  https://doi.org/10.1016/j.yexcr.2018.08.011
  8. Redox Biol. 2018 Aug 04. pii: S2213-2317(18)30532-9. [Epub ahead of print]19 37-45
    Konovalova S, Liu X, Manjunath P, Baral S, Neupane N, Hilander T, Yang Y, Balboa D, Terzioglu M, Euro L, Varjosalo M, Tyynismaa H.
      Mitochondria are central organelles to cellular metabolism. Their function relies largely on nuclear-encoded proteins that must be imported from the cytosol, and thus the protein import pathways are important for the maintenance of mitochondrial proteostasis. Mitochondrial HSP70 (mtHsp70) is a key component in facilitating the translocation of proteins through the inner membrane into the mitochondrial matrix. Its protein folding cycle is regulated by the nucleotide-exchange factor GrpE, which triggers the release of folded proteins by ATP rebinding. Vertebrates have two mitochondrial GrpE paralogs, GRPEL1 and 2, but without clearly defined roles. Using BioID proximity labeling to identify potential binding partners of the GRPELs in the mitochondrial matrix, we obtained results supporting a model where both GRPELs regulate mtHsp70 as homodimers. We show that GRPEL2 is not essential in human cultured cells, and its absence does not prevent mitochondrial protein import. Instead we find that GRPEL2 is redox regulated in oxidative stress. In the presence of hydrogen peroxide, GRPEL2 forms dimers through intermolecular disulfide bonds in which Cys87 is the thiol switch. We propose that the dimerization of GRPEL2 may activate the folding machinery responsible for protein import into mitochondrial matrix or enhance the chaperone activity of mtHSP70, thus protecting mitochondrial proteostasis in oxidative stress.
    Keywords:  GRPEL2; Mitochondrial protein import; Oxidative stress; Protein folding; Redox regulation; mtHSP70
    DOI:  https://doi.org/10.1016/j.redox.2018.07.024
  9. J Mol Cell Cardiol. 2018 Aug 09. pii: S0022-2828(18)30773-9. [Epub ahead of print]122 58-68
    Huang CY, Lai CH, Kuo CH, Chiang SF, Pai PY, Lin JY, Chang CF, Viswanadha VP, Kuo WW, Huang CY.
      Mitochondrial dysfunction is a major contributor to myocyte loss and the development of heart failure. Myocytes have quality control mechanisms to retain functional mitochondria by removing damaged mitochondria via specialized autophagy, i.e., mitophagy. The underlying mechanisms of fission affect the survival of cardiomyocytes, and left ventricular function in the heart is poorly understood. Here, we demonstrated the direct effect and potential mechanisms of mitochondrial functional defects associated with abnormal mitochondrial dynamics in heart failure. We observed that IGF-IIR signaling produced significant changes in mitochondrial morphology and function; such changes were associated with the altered expression and distribution of dynamin-related protein (Drp1) and mitofusin (Mfn2). IGF-IIR signaled extracellular signal-regulated kinase (ERK) activation to promote Drp1 phosphorylation and translocation to mitochondria for mitochondrial fission and mitochondrial dysfunction. Moreover, IGF-IIR signaling triggered Rab9-dependent autophagosome formation by the JNK-mediated phosphorylation of Bcl-2 at serine 87 and promoted ULK1/Beclin 1-dependent autophagic membrane formation. Excessive mitochondrial fission by Drp1 enhanced the Rab9-dependent autophagosome recognition and engulfing of damaged mitochondria and eventually decreased cardiomyocyte viability. Therefore, these results demonstrated the connection between Rab9-dependent autophagosomes and mitochondrial fission in cardiac myocytes, which provides a potential therapeutic strategy for treating heart disease.
    Keywords:  Drp1; ERK; IGF-IIR; Mitophagy; Rab9
    DOI:  https://doi.org/10.1016/j.yjmcc.2018.08.006
  10. Mitochondrion. 2018 Aug 09. pii: S1567-7249(18)30105-3. [Epub ahead of print]
    Naviaux RK.
      Without healing, multicellular life on Earth would not exist. Without healing, one injury predisposes to another, leading to disability, chronic disease, accelerated aging, and death. Over 50% of adults and 30% of children and teens in the United States now live with a chronic illness. Advances in mass spectrometry and metabolomics have given scientists a new lens for studying health and disease. This study defines the healing cycle in metabolic terms and reframes the pathophysiology of chronic illness as the result of metabolic signaling abnormalities that block healing and cause the normal stages of the cell danger response (CDR) to persist abnormally. Once an injury occurs, active progress through the stages of healing is driven by sequential changes in cellular bioenergetics and the disposition of oxygen and carbon skeletons used for fuel, signaling, defense, repair, and recovery. >100 chronic illnesses can be organized into three persistent stages of the CDR. One hundred and two targetable chemosensory G-protein coupled and ionotropic receptors are presented that regulate the CDR and healing. Metabokines are signaling molecules derived from metabolism that regulate these receptors. Reframing the pathogenesis of chronic illness in this way, as a systems problem that maintains disease, rather than focusing on remote trigger(s) that caused the initial injury, permits new research to focus on novel signaling therapies to unblock the healing cycle, and restore health when other approaches have failed.
    Keywords:  Allostasis; Allostatic load, integrated stress response; Antipurinergic therapy; Cell danger response; Ecoalleles; Ecogenetics; Healing cycle; M0, M1 and M2 mitochondria; Metabokines; Metabolic addiction; Metabolic memory; Mitochondrial nexus; Purinergic signaling
    DOI:  https://doi.org/10.1016/j.mito.2018.08.001
  11. Exp Cell Res. 2018 Aug 08. pii: S0014-4827(18)30391-4. [Epub ahead of print]
    Gao Y, Zhao Y, Yuan A, Xu L, Huang X, Su Y, Gao L, Ji Q, Pu J, He B.
      Myocardial ischemia/reperfusion (MI/R) injury induces excessive cellular apoptosis and contributes significantly to final infarct size. We previously demonstrated that a nuclear receptor, Farnesoid X receptor (FXR), plays a crucial role in mediating myocardial apoptosis. The FXR functions are regulated by post translational modifications (PTM). However, whether the proapoptotic effect of FXR in MI/R injury is regulated by PTM remains unclear. Here, we aimed to study the effect of SUMOylation, a PTM involved in the pathogenesis of MI/R injury per se, on the proapoptotic effect of FXR in MI/R injury. We observed that FXR could be SUMOylated in heart tissues, and FXR SUMOylation levels were downregulated in ischemia reperfused myocardium. By overexpression of SUMOylation-defective FXR mutant, it was demonstrated that decreased SUMOylation augmented the detrimental effect of FXR, via activation of mitochondrial apoptosis pathway and autophagy dysfunction in MI/R injury. Further mechanistic studies suggested that decreased SUMOylation levels increased the transcription activity of FXR, and the subsequently upregulated FXR target gene SHP mediated the proapoptotic effects of FXR. Taken together, we provided the first evidence that the cardiac effects of FXR could be regulated by SUMOylation, and that manipulating FXR SUMOylation levels may hold therapeutic promise for constraining MI/R injury.
    Keywords:  Apoptosis; Farnesoid X receptor; Ischemia-reperfusion; Nuclear receptor
    DOI:  https://doi.org/10.1016/j.yexcr.2018.07.004
  12. Kidney Blood Press Res. 2018 Aug 10. 43(4): 1297-1309
    Hua H, Ge X, Wu M, Zhu C, Chen L, Yang G, Zhang Y, Huang S, Zhang A, Jia Z.
      BACKGROUND/AIMS: In clinic, excessive acetaminophen (APAP) can cause kidney damage with uncertain mechanisms. Recently, accumulating evidence demonstrated a pathogenic role of mitochondrial dysfunction in the kidney injury. Thus, in this study, rotenone, a mitochondrial complex I inhibitor, was applied to the mice with APAP-induced acute kidney injury to evaluate the effect of mitochondrial complex I inhibition on APAP nephrotoxicity.METHODS: After 3 days of rotenone pretreatment, mice were administered with APAP (300mg/kg) by intraperitoneal injection for 24 h. Then the kidney injury, inflammation, and oxidative stress were evaluated.
    RESULTS: APAP significantly enhanced the BUN, serum creatine, and cystatin C levels in line with a moderate alteration of renal morphology. Strikingly, rotenone treatment normalized BUN, serum creatinine, and cystatin C levels, as well as the kidney morphology. Meanwhile, APAP enhanced tubular injury markers of NGAL and KIM-1 by 347- and 5-fold at mRNA levels, respectively. By Western blotting, we confirmed a 15-fold increment of NGAL in APAP-exposed kidneys. Importantly, rotenone treatment largely normalized NGAL and KIM-1 levels and attenuated inflammatory response in APAP-treated mice. Similarly, rotenone treatment enhanced the expressions of SOD1-3 compared with APAP group in line with a significant suppression of kidney MDA content. Finally, we observed that inhibition of mitochondrial complex III failed to protect against APAP-induced nephrotoxicity.
    CONCLUSION: Mitochondrial complex I inhibitor rotenone protected kidneys against APAP-induced injury possibly via the inhibition of mitochondrial oxidative stress and inflammation.
    Keywords:  Acetaminophen; Inflammation; Kidney injury; Oxidative stress; Rotenone
    DOI:  https://doi.org/10.1159/000492589