bims-camemi Biomed news
on Mitochondrial metabolism in cancer
Issue of 2018‒10‒21
nine papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit

  1. Free Radic Biol Med. 2018 Oct 10. pii: S0891-5849(18)30970-5. [Epub ahead of print]
    Morra EA, Rodrigues PL, Guedes de Jesus IC, Do Val Lima PR, Ávila RA, Zanardo TÉC, Nogueira BV, Bers DM, Guatimosim S, Stefanon I, Ribeiro Júnior RF.
      We previously demonstrated that the loss of female hormones induces cardiac and mitochondrial dysfunction in the female heart. Here, we show the impact of endurance training for twelve weeks, a nonpharmacological therapy against cardiovascular disease caused by ovariectomy and its contribution to cardiac contractility, mitochondrial quality control, bioenergetics and oxidative damage. We found that ovariectomy induced cardiac hypertrophy and dysfunction by decreasing SERCA2 and increasing phospholamban protein expression. Endurance training restored myocardial contractility, SERCA2 levels, increased calcium transient in ovariectomized rats but did not change phospholamban protein expression or cardiac hypertrophy. Additionally, ovariectomy decreased the amount of intermyofibrillar mitochondria and induced mitochondrial fragmentation that were accompanied by decreased levels of mitofusin 1, PGC-1α, NRF-1, total AMPK-α and mitochondrial Tfam. Endurance training prevented all these features except for mitofusin 1. Ovariectomy reduced O2 consumption, elevated O2.- release and increased Ca2+-induced mitochondrial permeability transition pore opening in both mitochondrial subpopulations. Ovariectomy also increased NOX-4 protein expression in the heart, reduced mitochondrial Mn-SOD, catalase protein expression and increased protein carbonylation in both mitochondrial subpopulations, which were prevented by endurance training. Taken together, our findings show that endurance training prevented cardiac contractile dysfunction and mitochondrial quality control in ovariectomized rats.
    Keywords:  bioenergetics; cardiac dysfunction; endurance training; female hormone deprivation; intermyofibrillar and subsarcolemmal mitochondria; mitochondrial quality control
  2. Neurosci Lett. 2018 Oct 11. pii: S0304-3940(18)30696-7. [Epub ahead of print]
    Shishido T, Nagano Y, Araki M, Kurashige T, Obayashi H, Nakamura T, Takahashi T, Matsumoto M, Maruyama H.
      Synphilin-1, a cytoplasmic protein, interacts with α-synuclein which is one of the main constituents of Lewy bodies and plays an important role in the pathology of Parkinson's disease (PD), in neurons. This interaction indicates that synphilin-1 may also play a central role in PD. However, the biological functions of synphilin-1 are not fully understood, and whether synphilin-1 is neurotoxic or neuroprotective remains controversial. This study examined the function of synphilin-1 in a PD model in vitro. We used an inhibitor of mitochondrial complex I, 1-methyl-4-phenylpyridinium (MPP+). We established human neuroblastoma SH-SY5Y cell lines that stably expressed human synphilin-1. We found that overexpression of synphilin-1 increased SH-SY5Y cell viability after MPP+ treatment. We further found that synphilin-1 significantly suppressed apoptotic changes in nuclei, including nuclear condensation and fragmentation, after MPP+ treatment. We showed that synphilin-1 significantly decreased MPP+-induced cleaved caspase-3 and cleaved poly-ADP-ribose polymerase levels by using western blotting. Production of reactive oxygen species (ROS) induced by MPP+ was significantly reduced in cells expressing synphilin-1 compared to those expressing empty vector. Synphilin-1 inhibited MPP+-induced cytochrome c release from mitochondria into the cytosol. These data suggested that synphilin-1 may function to protect against dopaminergic cell death by preserving mitochondrial function and inhibiting early steps in the intrinsic apoptotic pathway. Taken together, our results indicated that synphilin-1 may play neuroprotective roles in PD pathogenesis by inhibiting ROS production and apoptosis.
    Keywords:  MPP(+); Parkinson’s disease; apoptosis; dopaminergic neurodegeneration; synphilin-1
  3. Free Radic Biol Med. 2018 Oct 11. pii: S0891-5849(18)31744-1. [Epub ahead of print]
    Ramírez-Camacho I, Correa F, El Hafidi M, Silva-Palacios A, Ostolga-Chavarría M, Esparza-Perusquía M, Olvera-Sánchez S, Flores-Herrera O, Zazueta C.
      Electron leakage from dysfunctional respiratory chain and consequent superoxide formation leads to mitochondrial and cell injury during ischemia and reperfusion (IR). In this work we evaluate if the supramolecular assembly of the respiratory complexes into supercomplexes (SCs) is associated with preserved energy efficiency and diminished oxidative stress in post-ischemic hearts treated with the antioxidant N-acetylcysteine (NAC) and the cardioprotective maneuver of Postconditioning (PostC). Hemodynamic variables, infarct size, oxidative stress markers, oxygen consumption and the activity/stability of SCs were compared between groups. We found that mitochondrial oxygen consumption and the activity of respiratory complexes are preserved in mitochondria from reperfused hearts treated with both NAC and PostC. Both treatments contribute to recover the activity of individual complexes. NAC reduced oxidative stress and maintained SCs assemblies containing Complex I, Complex III, Complex IV and the adapter protein SCAFI more effectively than PostC. On the other hand, the activities of CI, CIII and CIV associated to SCs assemblies were preserved by this maneuver, suggesting that the activation of other cardioprotective mechanisms besides oxidative stress contention might participate in maintaining the activity of the mitochondrial respiratory complexes in such superstructures. We conclude that both the monomeric and the SCs assembly of the respiratory chain contribute to the in vivo functionality of the mitochondria. However, although the ROS-induced damage and the consequent increased production of ROS affect the assembly of SCs, other levels of regulation as those induced by PostC, might participate in maintaining the activity of the respiratory complexes in such superstructures.
    Keywords:  Mitochondrial respiratory chain; N-acetylcysteine; Postconditioning; Reactive oxygen species; Supercomplexes
  4. Am J Pathol. 2018 Oct 10. pii: S0002-9440(18)30278-5. [Epub ahead of print]
    Covarrubias AE, Lecarpentier E, Lo A, Salahuddin S, Gray KJ, Karumanchi SA, Zsengellér ZK.
      Although the etiology of preeclampsia, a pregnancy complication with significant maternal and neonatal morbidity, has not been fully characterized, placental ischemia due to impaired spiral artery remodeling and abnormal secretion of anti-angiogenic factors are thought to be important in the pathogenesis of the disease. Placental ischemia could impair trophoblast mitochondrial function and energy production leading to the release of reactive oxygen species (ROS). ROS has been shown to stabilize hypoxia inducible factor (HIF-1α), which in turn may induce transcription of anti-angiogenic factors, soluble fms-like tyrosine kinase 1 (sFLT1) and soluble endoglin in trophoblasts. Here, we tested whether the angiogenic imbalance and oxidative stress in the preeclamptic placenta may be prevented by improving mitochondrial function. First, to evaluate the cause-effect relationship between mitochondrial function and sFLT1 production, a human trophoblast primary cell culture model was established in which hypoxia induced mitochondrial ROS production and concurrent sFLT1 increase. Second, treatment with AP39 - a novel mitochondria-targeted hydrogen sulfide donor - prevented ROS production, reduced HIF-1α protein levels, and diminished sFLT1 production. Finally AP39, a modulator of mitochondrial bioenergetics enhanced cytochrome C oxidase activity, reversed oxidative stress and anti-angiogenic response in hypoxic trophoblasts. These results suggest that placental hypoxia induces ROS production, HIF-1α stabilization, and sFLT1 up-regulation; these pathophysiological alterations can be attenuated by mitochondrial-targeted anti-oxidants.
  5. Free Radic Biol Med. 2018 Oct 11. pii: S0891-5849(18)31281-4. [Epub ahead of print]
    Thorwald MA, Godoy-Lugo JA, Rodriguez GJ, Rodriguez MA, Jamal M, Kinoshita H, Nakano D, Nishiyama A, Forman HJ, Ortiz RM.
      Diabetic hearts are susceptible to damage from inappropriate activation of the renin angiotensin system (RAS) and hyperglycemic events both of which contribute to increased oxidant production. Inappropriately elevated oxidants impair mitochondrial enzyme function, further contributing to metabolic derangement. Nuclear factor erythriod-2-related factor 2 (Nrf2) induces antioxidant genes including those for glutathione (GSH) synthesis following translocation to the nucleus. We hypothesized that an acute elevation in plasma glucose facilitates Nrf2 nuclear translocation and subsequent expression of Nrf2-associated genes. We used four groups (n = 6-8/group) of 25-week-old rats: 1) LETO (lean strain-control), 2) type II diabetic OLETF, 3) OLETF + angiotensin receptor blocker (ARB; 10mg olmesartan/kg/d x 8 wks), and 4) ARBM (4 weeks on ARB, 4 weeks off) to study the effects of acutely elevated glucose on cardiac mitochondrial function and Nrf2 activity in the diabetic heart. Animals were gavaged with a glucose bolus (2g/kg) and groups were dissected at T0, T180, and T360 minutes. LETO GSH levels remained stable, while levels increased 125% in OLETF by T360. ARB treatment had no effect over the measurement period. Glutathione cysteine ligase regulatory (GCLM) subunit protein expression increased 78% in OLETF compared to LETO at T180, while ARB treatment lowered expression by 30% despite the elevations in GSH levels. Complex I activity was lowered 32% in OLETF compared to LETO at T0, while ARB treatment had no effect. These data suggest that ARB treatment improves Nrf2-related gene expression. However, GSH levels increase in diabetic hearts independent of AT1 signaling and mitochondrial function showed no improvement with AT1 antagonism suggesting ARB treatment isn't as beneficial once type II diabetes has manifested.
    Keywords:  AT1; Diabetes; Hyperglycemia; Mitochondrial Dysfunction; Nrf2
  6. Semin Cancer Biol. 2018 Oct 11. pii: S1044-579X(18)30049-X. [Epub ahead of print]
    Ahmed N, Escalona R, Leung D, Chan E, Kannourakis G.
      Cancer stem cells (CSCs) are a sub-population of tumour cells, which are responsible to drive tumour growth, metastasis and therapy resistance. It has recently been proposed that enhanced glucose metabolism and immune evasion by tumour cells are linked, and are modulated by the changing tumour microenvironment (TME) that creates a competition for nutrient consumption between tumour and different sub-types of cells attracted to the TME. To facilitate efficient nutrient distribution, oncogene-induced inflammatory milieu in the tumours facilitate adaptive metabolic changes in the surrounding non-malignant cells to secrete metabolites that are used as alternative nutrient sources by the tumours to sustain its increasing energy needs for growth and anabolic functions. This scenario also affects CSCs residing at the primary or metastatic niches. This review summarises recent advances in our understanding of the metabolic phenotypes of cancer cells and CSCs and how these processes are affected by the TME. We also discuss how the evolving TME modulates tumour cells and CSCs in cancer progression. Using previously described proteomic and genomic platforms, ovarian cancer cell lines and a mouse xenograft model we highlight the existence of metabolic and immune regulatory signatures in chemoresistant ovarian CSCs, and discuss how these processes may affect recurrence in ovarian tumours. We propose that progress in cancer control and eradication may depend not only on the elimination of highly chemoresistant CSCs, but also in designing novel strategies which would intervene with the tumour-promoting TME factors.
    Keywords:  ascites; cancer stem cells; cancer-associated fibroblasts; chemoresistance; endothelial cells; immune cells; ovarian carcinoma; tumour cells
  7. Placenta. 2018 Oct;pii: S0143-4004(18)30646-5. [Epub ahead of print]70 34-40
    Cai H, Chen L, Zhang M, Xiang W, Su P.
      INTRODUCTION: Miscarriage is a common complication during pregnancy. Mitofusin-2 (MFN2) deficiency in trophoblastic cells is reported to be an important cause for early miscarriage. MFN2 can regulate mitochondrial autophagy, although the mechanisms remain unknown. This study aims to investigate the roles of MFN2 and autophagy in early unexplained miscarriage.METHODS: Immunohistochemistry and western blotting were used to detect the MFN2 expression in villous tissues from women who had early unexplained miscarriage. Western blotting was used to detect the expression of autophagy-related proteins (ATG5, BECLIN1, and LC3), MMP-2, MMP-9, and integrin β1. Immunofluorescence was used to detect the expression of autophagosome after transfection with GFP-LC3. We used JC-1 to measure the mitochondrial membrane potential and transmission electron microscopy (TEM) to observe the ultrastructure of mitochondria. The levels of β-hCG and progesterone in the trophoblast were determined by the chemiluminescence method.
    RESULTS: Immunofluorescence analysis demonstrated that MFN2 in the villous tissues of women with early unexplained miscarriage was significantly lower than that of women in the normal pregnancy group. Increased levels of LC3, ATG5, and BECLIN1 were observed by western blotting. After transfection with MFN2-siRNA, the level of MFN2 decreased, whereas LC3, ATG5, and BECLIN1 levels increased significantly in the trophoblasts. More autophagosomes and significant impairment of mitochondrial function were observed by TEM. The levels of β-hCG, progesterone, MMP-2, MMP-9, and integrin β1 were significantly reduced in the MFN2-siRNA group.
    CONCLUSION: Low expression of MFN2 leads to mitochondrial dysfunction, increased level of autophagy, and trophoblast cell dysfunction, which could be accounted for early unexplained miscarriage.
    Keywords:  Autophagy; Early unexplained miscarriage; Mitochondria; Mitofusin-2; Trophoblast
  8. Metabolism. 2018 Oct 11. pii: S0026-0495(18)30211-7. [Epub ahead of print]
    Blanchard PG, Moreira RJ, de Castro É, Caron A, Côté M, Andrade ML, Oliveira TE, Ortiz-Silva M, Peixoto AS, Dias FA, Gélinas Y, Guerra-Sá R, Deshaies Y, Festuccia WT.
      OBJECTIVE: We investigated whether PPARγ modulates adipose tissue BCAA metabolism, and whether this mediates the attenuation of obesity-associated insulin resistance induced by pharmacological PPARγ activation.METHODS: Mice with adipocyte deletion of one or two PPARγ copies fed a chow diet and rats fed either chow, or high fat (HF) or HF supplemented with BCAA (HF/BCAA) diets treated with rosiglitazone (30 or 15 mg/kg/day, 14 days) were evaluated for glucose and BCAA homeostasis.
    RESULTS: Adipocyte deletion of one PPARγ copy increased mice serum BCAA and reduced inguinal white (iWAT) and brown (BAT) adipose tissues BCAA incorporation into triacylglycerol, as well as mRNA levels of branched-chain aminotransferase (BCAT)2 and branched-chain α-ketoacid dehydrogenase (BCKDH) complex subunits. Adipocyte deletion of two PPARγ copies induced lipodystrophy, severe glucose intolerance and markedly increased serum BCAA. Rosiglitazone abolished the increase in serum BCAA induced by adipocyte PPARγ deletion. In rats, HF increased serum BCAA, such levels being further increased by BCAA supplementation. Rosiglitazone, independently of diet, lowered serum BCAA and upregulated iWAT and BAT BCAT and BCKDH activities. This was associated with a reduction in mTORC1-dependent inhibitory serine phosphorylation of IRS1 in skeletal muscle and whole-body insulin resistance evaluated by HOMA-IR.
    CONCLUSIONS: PPARγ, through the regulation of both BAT and iWAT BCAA catabolism in lipoeutrophic mice and muscle insulin responsiveness and proteolysis in lipodystrophic mice, is a major determinant of circulating BCAA levels. PPARγ agonism, therefore, may improve whole-body and muscle insulin sensitivity by reducing blood BCAA, alleviating mTORC1-mediated inhibitory IRS1 phosphorylation.
  9. Biochim Biophys Acta Mol Basis Dis. 2018 Oct 10. pii: S0925-4439(18)30376-4. [Epub ahead of print]
    Zhu H, Wang Z, Dong Z, Wang C, Cao Q, Fan F, Zhao J, Liu X, Yuan M, Sun X, Peng X, Zou Y, Zhou J, Ge J, Zhou X, Zhang Y.
      Previous evidence has indicated a beneficial role for aldehyde dehydrogenase 2 (ALDH2) in suppressing atherosclerotic plaque progression and instability. However, the underlying mechanism remains somewhat elusive. This study was designed to examine the effect of ALDH2 deficiency on cholesterol diet-induced atherosclerotic plaque progression and plaque vulnerability in atherosclerosis-prone ApoE knockout (ApoE-/-) mice with a focus on foam cell formation in macrophages and senescence of vascular smooth muscle cells (VSMCs). Serum lipid profile, plaque progression, and plaque vulnerability were examined in ApoE-/- and ALDH2/ApoE double knockout (ALDH2-/-ApoE-/-) mice after high-cholesterol diet intake for 8 weeks. ALDH2 deficiency increased the serum levels of triglycerides while it decreased levels of total cholesterol and high-density lipoprotein cholesterol. Unexpectedly, ALDH2 deficiency reduced the plaque area by 58.9% and 37.5% in aorta and aortic sinus, respectively. Plaque instability was aggravated by ALDH2 deficiency although with the increased necrotic core size, decreased collagen content, thinner fibrous cap area, decreased VSMC content, and increased macrophage content. In atherosclerotic lesions, ALDH2 protein was located in both macrophages and VSMCs. Further results revealed downregulated ALDH2 expression in aorta of aged ApoE-/- mice compared with young mice. However, in vitro study suggested that ALDH2 upregulated bone marrow-derived macrophages (BMDMs) with an opposite effect in VSMCs following 80 μg/ml oxidized low-density lipoprotein (oxLDL) treatment. Interestingly, ALDH2 deficiency displayed little effect in oxLDL-induced foam cell formation from BMDMs, while ALDH2 knockdown by siRNA and ALDH2 overexpression by lentivirus infection promoted and retarded oxLDL-induced VSMC senescence, respectively. Mechanistically, ALDH2 mitigated oxLDL-induced overproduction of mitochondrial reactive oxygen species (mROS) and activation of downstream p53/p21/p16 pathway. Clearance of mROS by mitoTEMPO significantly reversed the promotive effect of ALDH2 knockdown on VSMC senescence. Taken together, our data revealed that ALDH2 deficiency suppressed atherosclerotic plaque area while facilitating plaque instability possibly through accelerating ROS-mediated VSMC senescence. This article is part of a Special Issue entitled: Genetic and epigenetic regulation of aging and longevity edited by Jun Ren & Megan Yingmei Zhang.
    Keywords:  ALDH2; Atherosclerosis; Macrophage; Mitochondrial ROS; Senescence; VSMC