bims-camemi 2018-10-07 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2018‒10‒07
ten papers selected by
Christian Frezza,

Deletion of the mitochondrial complex-IV co-factor heme A:farnesyltransferase causes focal segmental glomerulosclerosis and interferon response.
Nurr1 exacerbates cerebral ischemia-reperfusion injury via modulating YAP-INF2-mitochondrial fission pathways.
Celastrol ameliorates cisplatin nephrotoxicity by inhibiting NF-κB and improving mitochondrial function.
The mitochondrial phosphatase PPTC7 orchestrates mitochondrial metabolism regulating coenzyme Q10 biosynthesis.
A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily.
Modulation of the de novo purine nucleotide pathway as a therapeutic strategy in mitochondrial myopathy.
Mitochondrial damage and iron metabolic dysregulation in hepatitis C virus infection.
Trans-omic Analysis Reveals Selective Responses to Induced and Basal Insulin across Signaling, Transcriptional, and Metabolic Networks.
Role of Mcl-1 in regulation of cell death in human induced pluripotent stem cell-derived cardiomyocytes in vitro.
TIGAR inclusion pathology is specific for Lewy body diseases.

Am J Pathol. 2018 Sep 27. pii: S0002-9440(18)30225-6. [Epub ahead of print]

Deletion of the mitochondrial complex-IV co-factor heme A:farnesyltransferase causes focal segmental glomerulosclerosis and interferon response.

Jea-Hyun Baek, Ivan G Gomez, Yukihiro Wada, Allie Roach, Don Mahad, Jeremy S Duffield.

Mutations in mitochondrial DNA as well as nuclear-encoded mitochondrial proteins have been reported to cause tubulointerstitial kidney diseases and focal segmental glomerulosclerosis (FSGS). Recently, genes and pathways affecting mitochondrial turnover and permeability have been implicated in adult-onset FSGS. Furthermore, dysfunctioning mitochondria may be capable of engaging intracellular innate immune sensing pathways. To determine the impact of mitochondrial dysfunction in FSGS and secondary innate immune responses, we generated Cre/loxP transgenic mice to create loss-of-function deletion mutation of the Complex IV assembly co-factor heme A:farnesyltransferase (COX10) restricted to cells of the developing nephrons. These mice develop severe, early onset FSGS with innate immune activation and die prematurely with kidney failure. Mutant kidneys showed loss of glomerular and tubular epithelial function, epithelial apoptosis and, in addition, a marked interferon response. In vitro modeling of Cox10 deletion in primary kidney epithelium compromises oxygen consumption, ATP generation, and induces oxidative stress. In addition, loss of Cox10 triggers a selective interferon response, which may be caused by the leak of mitochondrial DNA into the cytosol activating the intracellular DNA sensor, STING. This new animal model provides a mechanism to study mitochondrial dysfunction in vivo and demonstrates a direct link between mitochondrial dysfunction and intracellular innate immune response.

DOI: https://doi.org/10.1016/j.ajpath.2018.08.018
Int J Biochem Cell Biol. 2018 Sep 26. pii: S1357-2725(18)30207-3. [Epub ahead of print]104 149-160

Nurr1 exacerbates cerebral ischemia-reperfusion injury via modulating YAP-INF2-mitochondrial fission pathways.

Zhanwei Zhang, Jianbai Yu.

  Nurr1, a nuclear transcription factor, has been linked to ischemia-reperfusion injury (IRI) in heart and kidney via modulating mitochondrial homeostasis. However, its role in cerebral ischemia-reperfusion has not been defined. In the present study, we found that cerebral IRI significantly increased the expression of Nurr1 and genetic ablation of Nurr1 attenuated the infarction area and reduced the neuron apoptosis under brain IRI burden. Functional studies have demonstrated that Nurr1 induced neuron death via activating mitochondrial fission. Aberrant mitochondrial fission promoted mitochondrial membrane potential reduction, evoked cellular oxidative stress and activated caspase-9-dependent mitochondrial apoptotic pathway. Interestingly, Nurr1 deletion alleviated fission-mediated mitochondrial damage, sustaining mitochondrial homeostasis and favoring neuron survival. Further, we found that Nurr1 deletion modulated mitochondrial fission via preventing INF2 upregulation in a manner dependent on YAP pathways. Either pharmacological blockade of YAP pathway or overexpression of INF2 abrogated the inhibitory effect of Nurr1 deletion on mitochondrial fission, leading to neuron death via mitochondrial apoptosis. Altogether, our results report that the pathogenesis of cerebral ischemia-reperfusion injury is associated with Nurr1 upregulation followed by augmented mitochondrial fission via an abnormal YAP-INF2 pathways.

Keywords:  Cerebral IR injury; Mitochondrial fission; Nurr1; YAP-INF2 axis

DOI:  https://doi.org/10.1016/j.biocel.2018.09.014
EBioMedicine. 2018 Sep 26. pii: S2352-3964(18)30388-8. [Epub ahead of print]

Celastrol ameliorates cisplatin nephrotoxicity by inhibiting NF-κB and improving mitochondrial function.

Xiaowen Yu, Xia Meng, Man Xu, Xuejuan Zhang, Yue Zhang, Guixia Ding, Songming Huang, Aihua Zhang, Zhanjun Jia.

  BACKGROUND: Celastrol is an active ingredient of Chinese medicine Tripterygium wilfordii which is clinically used to treat the immune diseases. Currently, celastrol is documented as a potent agent for treating cancer and inflammatory disorders. This study was to investigate the effect of celastrol on cisplatin nephrotoxicity and the underlying mechanism.METHODS: Male C57BL/6 mice were treated with cisplatin (20 mg/kg) with or without celastrol treatment (1 and 2 mg/kg/day). In vitro, human proximal tubule epithelial cell line (HK-2) and mouse renal tubule epithelial cells (RTECs) were treated with cisplatin (5 μg/mL) with or without celastrol administration. Then renal injury and cell damage were evaluated.
FINDINGS: In vivo, after celastrol treatment, cisplatin-induced kidney injury was significantly ameliorated as shown by the improvement of renal function (BUN, serum creatinine, and cystatin C), kidney morphology (PAS staining) and oxidative stress (MDA) and the suppression of renal tubular injury markers of KIM-1 and NGAL. Meanwhile, the renal apoptosis and inflammation induced by cisplatin were also strikingly attenuated in celastrol-treated mice. In vitro, celastrol treatment markedly inhibited cisplatin-induced renal tubular cell apoptosis, suppressed NF-κB activation, and improved mitochondrial function evidenced by the restored mtDNA copy number, mitochondrial membrane potential, and OXPHOS activity in cisplatin-treated renal tubular epithelial cells.
INTERPRETATION: This work suggested that celastrol could protect against cisplatin-induced acute kidney injury possibly through suppressing NF-κB and improving mitochondrial function. FUND: The National Natural Science Foundation of China, National Key Research and Development Program, and Natural Science Foundation of Jiangsu Province.

Keywords:  AKI; Celastrol; Cisplatin; Mitochondrial Dysfunction; NF-κB

DOI:  https://doi.org/10.1016/j.ebiom.2018.09.031
Biochim Biophys Acta Bioenerg. 2018 Sep 26. pii: S0005-2728(18)30230-5. [Epub ahead of print]1859(11): 1235-1248

The mitochondrial phosphatase PPTC7 orchestrates mitochondrial metabolism regulating coenzyme Q10 biosynthesis.

Isabel González-Mariscal, Alejandro Martin-Montalvo, Luis Vazquez-Fonseca, Teresa Pomares-Viciana, Ana Sánchez-Cuesta, Daniel José Fernández-Ayala, Placido Navas, Carlos Santos-Ocana.

  Coenzyme Q10 (CoQ10) is a redox molecule critical for the proper function of energy metabolism and antioxidant defenses. Despite its essential role in cellular metabolism, the regulation of CoQ10 biosynthesis in humans remains mostly unknown. Herein, we determined that PPTC7 is a regulatory protein of CoQ10 biosynthesis required for human cell survival. We demonstrated by in vitro approaches that PPTC7 is a bona fide protein phosphatase that dephosphorylates the human COQ7. Expression modulation experiments determined that human PPTC7 dictates cellular CoQ10 content. Using two different approaches (PPTC7 over-expression and caloric restriction), we demonstrated that PPTC7 facilitates and improves the human cell adaptation to respiratory conditions. Moreover, we determined that the physiological role of PPTC7 takes place in the adaptation to starvation and pro-oxidant conditions, facilitating the induction of mitochondrial metabolism while preventing the accumulation of ROS. Here we unveil the first post-translational mechanism regulating CoQ10 biosynthesis in humans and propose targeting the induction of PPTC7 activity/expression for the treatment of CoQ10-related mitochondrial diseases.

Keywords:  Bioenergetics; Coenzyme Q(10); Lipid synthesis; Mitochondria; Phosphatase

DOI:  https://doi.org/10.1016/j.bbabio.2018.09.369
Cell Syst. 2018 Sep 14. pii: S2405-4712(18)30357-0. [Epub ahead of print]

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily.

Cancer Genome Atlas Research Network

  We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily.

Keywords:  DNA methylation; Pan-Cancer; TCGA; TGF-β; TGF-β pathway; The Cancer Genome Atlas; cancer; microRNA; mutation hotspot; transcription

DOI:  https://doi.org/10.1016/j.cels.2018.08.010
Pharmacol Res. 2018 Sep 26. pii: S1043-6618(18)30339-6. [Epub ahead of print]

Modulation of the de novo purine nucleotide pathway as a therapeutic strategy in mitochondrial myopathy.

Sammy Kimoloi.

  Mitochondrial myopathy (MM) is characterised by muscle weakness, exercise intolerance and various histopathological changes. Recently, a subset of MM has also been associated with aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) in skeletal muscle. This aberrant mTORC1 activation promotes increased de novo nucleotide synthesis, which contributes to abnormal expansion and imbalance of skeletal muscle deoxyribonucleoside triphosphates (dNTP) pools. However, the exact mechanism via which mTORC1-stimulated de novo nucleotide biosynthesis ultimately disturbs muscle dNTP pools remains unclear. In this article, it is proposed that mTORC1-stimulated de novo nucleotide synthesis in skeletal muscle cells with respiratory chain dysfunction promotes an asymmetric increase of purine nucleotides, probably due to NAD+ deficiency. This in turn could disrupt purine nucleotide-dependent allosteric feedback regulatory mechanisms, ultimately leading dNTP pools aberration. Pharmacological down-modulation of aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase (ATIC) activity is also proposed as a potential therapeutic strategy in MM exhibiting mTORC1-driven abnormal metabolic reprogramming, including aberrant dNTPs pools.

Keywords:  ATIC; NAD+ deficiency; deoxyribonucleoside triphosphates; mTORC1; mitochondrial myopathy

DOI:  https://doi.org/10.1016/j.phrs.2018.09.027
Free Radic Biol Med. 2018 Sep 27. pii: S0891-5849(18)31729-5. [Epub ahead of print]

Mitochondrial damage and iron metabolic dysregulation in hepatitis C virus infection.

Keisuke Hino, Sohij Nishina, Kyo Sasaki, Yuichi Hara.

  Hepatitis C virus (HCV) infection often leads to chronic hepatitis that can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Although HCV infection is expected to decrease due to the high rate of HCV eradication via the rapid dissemination and use of directly acting antivirals, HCV infection remains a leading cause of HCC. Although the mechanisms underlying the HCC development are not fully understood, oxidative stress is present to a greater degree in HCV infection than in other inflammatory liver diseases and has been proposed as a major mechanism of liver injury in patients with chronic hepatitis C. Hepatocellular mitochondrial alterations and iron accumulation are well-known characteristics in patients with chronic hepatitis C and are closely related to oxidative stress, since the mitochondria are the main site of reactive oxygen species generation, and iron produces hydroxy radicals via the Fenton reaction. In addition, phlebotomy is an iron reduction approach that aims to lower serum transaminase levels in patients with chronic hepatitis C. Here, we review and discuss the mechanisms by which HCV induces mitochondrial damage and iron accumulation in the liver and offer new insights concerning how mitochondrial damage and iron accumulation are linked to the development of HCC.

Keywords:  hepatitis C virus; hepatocellular carcinoma; hepcidin; iron; mitochondria; mitophagy; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1016/j.freeradbiomed.2018.09.044
iScience. 2018 Sep 28. pii: S2589-0042(18)30110-X. [Epub ahead of print]7 212-229

Trans-omic Analysis Reveals Selective Responses to Induced and Basal Insulin across Signaling, Transcriptional, and Metabolic Networks.

Kentaro Kawata, Atsushi Hatano, Katsuyuki Yugi, Hiroyuki Kubota, Takanori Sano, Masashi Fujii, Yoko Tomizawa, Toshiya Kokaji, Kaori Y Tanaka, Shinsuke Uda, Yutaka Suzuki, Masaki Matsumoto, Keiichi I Nakayama, Kaori Saitoh, Keiko Kato, Ayano Ueno, Maki Ohishi, Akiyoshi Hirayama, Tomoyoshi Soga, Shinya Kuroda.

  The concentrations of insulin selectively regulate multiple cellular functions. To understand how insulin concentrations are interpreted by cells, we constructed a trans-omic network of insulin action in FAO hepatoma cells using transcriptomic data, western blotting analysis of signaling proteins, and metabolomic data. By integrating sensitivity into the trans-omic network, we identified the selective trans-omic networks stimulated by high and low doses of insulin, denoted as induced and basal insulin signals, respectively. The induced insulin signal was selectively transmitted through the pathway involving Erk to an increase in the expression of immediate-early and upregulated genes, whereas the basal insulin signal was selectively transmitted through a pathway involving Akt and an increase of Foxo phosphorylation and a reduction of downregulated gene expression. We validated the selective trans-omic network in vivo by analysis of the insulin-clamped rat liver. This integrated analysis enabled molecular insight into how liver cells interpret physiological insulin signals to regulate cellular functions.

Keywords:  Metabolomics; Omics; Systems Biology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2018.07.022
Toxicol Appl Pharmacol. 2018 Sep 27. pii: S0041-008X(18)30447-2. [Epub ahead of print]

Role of Mcl-1 in regulation of cell death in human induced pluripotent stem cell-derived cardiomyocytes in vitro.

Liang Guo, Sandy Eldridge, Michael Furniss, Jodie Mussio, Myrtle Davis.

  Targeting the anti-apoptotic protein Mcl-1 holds a promise to improve therapy of multiple types of Mcl-1 dependent cancers but raises concerns of on-target cardiotoxicity due to the presence and reported role of Mcl-1 in heart. Herein, we investigated the importance of Mcl-1 in the survival and contractile function of human pluripotent stem cell-derived cardiomyocytes in culture. Effective knockdown of Mcl-1 with siRNAs reproducibly resulted in early (measured at Day 3) marginal alterations in caspase 3/7 activity, LDH leakage, ATP content and cellular impedance. After 14 days of Mcl-1 knockdown, loss of mitochondrial membrane potential, deteriorating effects on mitochondrial ultrastructure, and alterations in beat rate and amplitude were revealed. Inhibition of Bcl-xL by siRNA-mediated knockdown or selective inhibitors did not cause any overt cellular responses except for a minimal increase in caspase 3/7 activity; however, loss of Mcl-1 concomitant with down-regulated Bcl-xL activated apoptosis and caused extensive cell death as reflected by an 80% loss in cell index, activation of caspase-3 with associated PARP cleavage, and a decrease in beat amplitude and mitochondrial membrane potential after 3 days of Mcl-1/Bcl-xL knockdown., Together, these findings suggest that Mcl-1 and Bcl-xL provide duplicate safeguard measures in maintaining structural and functional integrity of cardiomyocytes. Hence, BH3-mimetic drugs targeting Mcl-1 may be well tolerated in the presence of intact Bcl-xL.

Keywords:  Apoptosis; Bcl-xL; Cardio-oncology; Mcl-1; Mitochondria; hiPSC-cardiomyocyte

DOI:  https://doi.org/10.1016/j.taap.2018.09.041
Brain Res. 2018 Sep 26. pii: S0006-8993(18)30497-9. [Epub ahead of print]

TIGAR inclusion pathology is specific for Lewy body diseases.

Karla L Robles López, Julie E Simpson, Lisa C Watson, Heather Mortiboys, Guillaume M Hautbergue, Oliver Bandmann, J Robin Highley.

  BACKGROUND: We previously reported up-regulation of tigarb (the zebrafish orthologue? of human TIGAR, TP53 -Induced Glycolysis and Apoptosis Regulator) in a zebrafish pink1-/- model of Parkinson's disease (PD). Genetic inactivation of tigarb led to the rescue of dopaminergic neurons and mitochondrial function in pink-/- zebrafish. The aim of this study was to determine the relevance of TIGAR for human PD, investigate its disease specificity and identify relevant upstream and downstream mechanisms.MATERIALS AND METHODS: TIGAR Immunohistochemistry using a range of antibodies was undertaken for detailed assessment of TIGAR in formalin-fixed, paraffin-embedded tissue from post mortem brains of PD patients and other neurodegenerative disorders (n=10 controls, 10 PD cases, 10 dementia with Lewy bodies, 5 motor neurone disease (MND), 3 multiple system atrophy (MSA) and complemented by immunohistochemistry for p53, hexokinase I (HK-I) and hexokinase II (HK-II; n=4 control, 4 PD, and 4 dementia with Lewy bodies).
RESULTS: TIGAR was detected in Lewy bodies and Lewy neurites in the substantia nigra of sporadic PD and Dementia with Lewy bodies (DLB) patients. Staining of adjacent sections confirmed the presence of TIGAR alongside alpha-synuclein in these LB and Neurites. In contrast, TIGAR-positive aggregates were not seen in cortical Lewy bodies. TIGAR protein was also absent in both TDP-43-positive inclusions in MND and glial cytoplasmic inclusions in MSA. Subsequent investigation of the TIGAR-upstream regulator p53 and the downstream targets HK-I and HK-II in PD brains suggested a possible mild increase in HK-I.
CONCLUSIONS: TIGAR protein, is present in SN Lewy bodies of both sporadic PD and DLB. The absence of TIGAR protein in the pathological inclusions of MND or MSA suggests disease specificity and further raises the possibility that TIGAR may be involved in PD pathogenesis.

Keywords:  Alpha-synuclein; Dementia with Lewy bodies; Lewy body; Parkinson’s disease; Substantia nigra; TIGAR

DOI:  https://doi.org/10.1016/j.brainres.2018.09.032