bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2021‒01‒24
fourteen papers selected by
Avinash N. Mukkala
University of Toronto
  1. Nrf2 is activated by disruption of mitochondrial thiol homeostasis but not by enhanced mitochondrial superoxide production.
  2. Visualizing, quantifying, and manipulating mitochondrial DNA in vivo.
  3. Multitasking guardian of mitochondrial quality: Parkin function and Parkinson's disease.
  4. PGC-1α protects from myocardial ischaemia-reperfusion injury by regulating mitonuclear communication.
  5. A Calcium Guard in the Outer Membrane: Is VDAC a Regulated Gatekeeper of Mitochondrial Calcium Uptake?
  6. Remote Ischemic Preconditioning Attenuates Hepatic Ischemia/Reperfusion Injury after Hemorrhagic Shock by Increasing Autophagy.
  7. Single nucleotide polymorphisms in interleukin-6 attenuates hepatocytes injury in hypoxia/re-oxygenation via STAT3 signal pathway mediated autophagy.
  8. Autophagy restricts mitochondrial DNA damage-induced release of ENDOG (endonuclease G) to regulate genome stability.
  9. Structure, mechanism, and regulation of mitochondrial DNA transcription initiation.
  10. UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import in Caenorhabditis elegans.
  11. BNIP3-dependent mitophagy promotes cytosolic localization of LC3B and metabolic homeostasis in the liver.
  12. The ubiquitin E3 ligase TRIM21 promotes hepatocarcinogenesis by suppressing the p62-Keap1-Nrf2 antioxidant pathway.
  13. Intricate role of mitochondrial calcium signalling in mitochondrial quality control for regulation of cancer cell fate.
  14. Neural cell-derived plasma exosome protein abnormalities implicate mitochondrial impairment in first episodes of psychosis.
  1. J Biol Chem. 2020 Dec 13. pii: S0021-9258(20)00163-5. [Epub ahead of print]296 100169
    Nrf2 is activated by disruption of mitochondrial thiol homeostasis but not by enhanced mitochondrial superoxide production.
    Filip Cvetko, Stuart T Caldwell, Maureen Higgins, Takafumi Suzuki, Masayuki Yamamoto, Hiran A Prag, Richard C Hartley, Albena T Dinkova-Kostova, Michael P Murphy.
      The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of genes involved in antioxidant defenses to modulate fundamental cellular processes such as mitochondrial function and GSH metabolism. Previous reports proposed that mitochondrial reactive oxygen species production and disruption of the GSH pool activate the Nrf2 pathway, suggesting that Nrf2 senses mitochondrial redox signals and/or oxidative damage and signals to the nucleus to respond appropriately. However, until now, it has not been possible to disentangle the overlapping effects of mitochondrial superoxide/hydrogen peroxide production as a redox signal from changes to mitochondrial thiol homeostasis on Nrf2. Recently, we developed mitochondria-targeted reagents that can independently induce mitochondrial superoxide and hydrogen peroxide production mitoParaquat (MitoPQ) or selectively disrupt mitochondrial thiol homeostasis MitoChlorodinitrobenzoic acid (MitoCDNB). Using these reagents, here we have determined how enhanced generation of mitochondrial superoxide and hydrogen peroxide or disruption of mitochondrial thiol homeostasis affects activation of the Nrf2 system in cells, which was assessed by the Nrf2 protein level, nuclear translocation, and expression of its target genes. We found that selective disruption of the mitochondrial GSH pool and inhibition of its thioredoxin system by MitoCDNB led to Nrf2 activation, whereas using MitoPQ to enhance the production of mitochondrial superoxide and hydrogen peroxide alone did not. We further showed that Nrf2 activation by MitoCDNB requires cysteine sensors of Kelch-like ECH-associated protein 1 (Keap1). These findings provide important information on how disruption to mitochondrial redox homeostasis is sensed in the cytoplasm and signaled to the nucleus.
    Keywords:  MitoCDNB; MitoPQ; Nrf2; energy metabolism; reactive oxygen species (ROS); redox signaling; thiol oxidation
    DOI:  https://doi.org/10.1074/jbc.RA120.016551
  2. J Biol Chem. 2020 Dec 18. pii: S0021-9258(17)50642-0. [Epub ahead of print]295(51): 17588-17601
    Visualizing, quantifying, and manipulating mitochondrial DNA in vivo.
    David L Prole, Patrick F Chinnery, Nick S Jones.
      Mitochondrial DNA (mtDNA) encodes proteins and RNAs that support the functions of mitochondria and thereby numerous physiological processes. Mutations of mtDNA can cause mitochondrial diseases and are implicated in aging. The mtDNA within cells is organized into nucleoids within the mitochondrial matrix, but how mtDNA nucleoids are formed and regulated within cells remains incompletely resolved. Visualization of mtDNA within cells is a powerful means by which mechanistic insight can be gained. Manipulation of the amount and sequence of mtDNA within cells is important experimentally and for developing therapeutic interventions to treat mitochondrial disease. This review details recent developments and opportunities for improvements in the experimental tools and techniques that can be used to visualize, quantify, and manipulate the properties of mtDNA within cells.
    Keywords:  aging; gene editing; microscopy; mitochondria; mitochondrial DNA (mtDNA); mitochondrial disease; mitophagy
    DOI:  https://doi.org/10.1074/jbc.REV120.015101
  3. Transl Neurodegener. 2021 01 20. 10(1): 5
    Multitasking guardian of mitochondrial quality: Parkin function and Parkinson's disease.
    Iryna Kamienieva, Jerzy Duszyński, Joanna Szczepanowska.
      The familial form of Parkinson's disease (PD) is linked to mutations in specific genes. The mutations in parkin are one of the most common causes of early-onset PD. Mitochondrial dysfunction is an emerging active player in the pathology of neurodegenerative diseases, because mitochondria are highly dynamic structures integrated with many cellular functions. Herein, we overview and discuss the role of the parkin protein product, Parkin E3 ubiquitin ligase, in the cellular processes related to mitochondrial function, and how parkin mutations can result in pathology in vitro and in vivo.
    Keywords:  Mitochondria; Mitophagy; PINK1; Parkin; Parkin mutations; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s40035-020-00229-8
  4. J Cell Mol Med. 2021 Jan 19.
    PGC-1α protects from myocardial ischaemia-reperfusion injury by regulating mitonuclear communication.
    Yan-Qing Li, Yan Jiao, Ya-Nan Liu, Jia-Ying Fu, Lian-Kun Sun, Jing Su.
      The recovery of blood supply after a period of myocardial ischaemia does not restore the heart function and instead results in a serious dysfunction called myocardial ischaemia-reperfusion injury (IRI), which involves several complex pathophysiological processes. Mitochondria have a wide range of functions in maintaining the cellular energy supply, cell signalling and programmed cell death. When mitochondrial function is insufficient or disordered, it may have adverse effects on myocardial ischaemia-reperfusion and therefore mitochondrial dysfunction caused by oxidative stress a core molecular mechanism of IRI. Peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) is an important antioxidant molecule found in mitochondria. However, its role in IRI has not yet been systematically summarized. In this review, we speculate the role of PGC-1α as a key regulator of mitonuclear communication, which may interacts with nuclear factor, erythroid 2 like -1 and -2 (NRF-1/2) to inhibit mitochondrial oxidative stress, promote the clearance of damaged mitochondria, enhance mitochondrial biogenesis, and reduce the burden of IRI.
    Keywords:  mitochondria; myocardial ischaemia-reperfusion injury (IRI); nuclear factor, erythroid 2 like 1/2 (NRF-1/2); nucleus; oxidative stress; peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α)
    DOI:  https://doi.org/10.1111/jcmm.16236
  5. Int J Mol Sci. 2021 Jan 19. pii: E946. [Epub ahead of print]22(2):
    A Calcium Guard in the Outer Membrane: Is VDAC a Regulated Gatekeeper of Mitochondrial Calcium Uptake?
    Paulina Sander, Thomas Gudermann, Johann Schredelseker.
      Already in the early 1960s, researchers noted the potential of mitochondria to take up large amounts of Ca2+. However, the physiological role and the molecular identity of the mitochondrial Ca2+ uptake mechanisms remained elusive for a long time. The identification of the individual components of the mitochondrial calcium uniporter complex (MCUC) in the inner mitochondrial membrane in 2011 started a new era of research on mitochondrial Ca2+ uptake. Today, many studies investigate mitochondrial Ca2+ uptake with a strong focus on function, regulation, and localization of the MCUC. However, on its way into mitochondria Ca2+ has to pass two membranes, and the first barrier before even reaching the MCUC is the outer mitochondrial membrane (OMM). The common opinion is that the OMM is freely permeable to Ca2+. This idea is supported by the presence of a high density of voltage-dependent anion channels (VDACs) in the OMM, forming large Ca2+ permeable pores. However, several reports challenge this idea and describe VDAC as a regulated Ca2+ channel. In line with this idea is the notion that its Ca2+ selectivity depends on the open state of the channel, and its gating behavior can be modified by interaction with partner proteins, metabolites, or small synthetic molecules. Furthermore, mitochondrial Ca2+ uptake is controlled by the localization of VDAC through scaffolding proteins, which anchor VDAC to ER/SR calcium release channels. This review will discuss the possibility that VDAC serves as a physiological regulator of mitochondrial Ca2+ uptake in the OMM.
    Keywords:  MCU; VDAC; mitochondrial calcium uptake
    DOI:  https://doi.org/10.3390/ijms22020946
  6. Int J Med Sci. 2021 ;18(4): 873-882
    Remote Ischemic Preconditioning Attenuates Hepatic Ischemia/Reperfusion Injury after Hemorrhagic Shock by Increasing Autophagy.
    Hao Zhou, Lin Li, Hao Sun, Hua Li, Yuxuan Wu, Xiaomin Zhang, Jinsong Zhang.
      Fluid resuscitation after hemorrhagic shock is a model of systemic ischemia/reperfusion injury (SI/RI), and the liver is one of the main target organs. Ischemic preconditioning (IPC) can reduce hepatic ischemia-reperfusion injury (I/RI) via autophagy. However, whether remote ischemic preconditioning (RIPC) can alleviate the liver injury that is secondary to hemorrhagic shock and the role of autophagy in this process remain unclear. Thus, we constructed a hemorrhagic shock model in rats with or without RIPC to monitor mean arterial pressure (MAP) and investigate liver secondary injury levels via serum aminotransferase, ultrasound, HE staining and TUNEL fluorescence staining. We also detected levels of serum inflammatory factors including tumor necrosis factor-alpha (TNF-α) and interleukin 1β (IL-1β) by enzyme-linked immunosorbent assay (ELLSA), observed autophagosomes by Transmission electron microscopy (TEM), and analyzed LC3, Beclin-1, p62 protein expression levels by immunohistochemical (IHC) and western blot (WB). We found that RIPC increased blood pressure adaptability, decreased lactate (Lac) and aminotransferase levels, and delayed the decrease in liver density. Levels of inflammatory factors TNF-α, IL-1β and apoptosis were attenuated, autophagosomes was increased in the RIPC group compared with controls. IHC and WB both revealed increased LC3 and Beclin-1 but decreased p62 protein expression levels in the RIPC group. Together, our data suggest that RIPC-activated autophagy could play a protective role against secondary liver injury following hemorrhagic shock.
    Keywords:  Remote ischemic preconditioning; autophagy.; hemorrhagic shock; hepatic; ischemia-reperfusion injury
    DOI:  https://doi.org/10.7150/ijms.51268
  7. Mol Biol Rep. 2021 Jan 23.
    Single nucleotide polymorphisms in interleukin-6 attenuates hepatocytes injury in hypoxia/re-oxygenation via STAT3 signal pathway mediated autophagy.
    Hongwei Tang, Hongbo Fang, Wenzhi Guo, Shengli Cao, Danfeng Guo, Huapeng Zhang, Jie Gao, Shuijun Zhang.
      Ischemia-reperfusion injury (IRI) is inevitable during liver surgery, and it is an important factor affecting the prognosis of patients. IL-6 rs1800796 single nucleotide polymorphisms (SNPs) can promote synthesis and secretion of IL-6 and protect hepatocytes from IRI. In this study, we investigated the mechanisms by which IL-6 alleviates hepatic IRI. We transfected lentivirus which carries IL-6 rs1800796 to L02 cells and constructed the cell line (L02-IL6) with a high expression of IL-6. The biological function of IL-6 SNPs was explored through a cell model of hypoxia-reoxygenation (H/R). Cell viability was evaluated by CCK8 and Real-Time Cell Analysis (RTCA), and found that the viability of the L02-IL6 cells was higher than that of the control group (P < 0.01). Flow cytometry assay showed that the rate of apoptosis was significantly decreased in L02-IL6 cells. Furthermore, in comparison with the control group, the level of cleaved-caspase3, which is an important marker of apoptosis, was dramatically decreased. These differences showed that the sequence variants at rs1800796 of the IL-6 gene could improve the resistance against H/R. Moreover, the levels of autophagy-related proteins, such as LC3 and Beclin-1, were upregulated in L02-IL6 group on H/R injury, which means IL-6 could alleviate apoptosis via activating the autophagy pathway. And we also found that the STAT3 signal pathway was activated. Next, we investigated whether the exogenous treatment with IL-6 affect hepatocytes and thus play a protective role. We pre-treated the L02 cells with recombinant human IL-6 for 12 h and then made H/R treatment. We found the treatment with 100 ng/ml IL-6 alleviated the damage of L02 cells and inhibited the apoptosis. And the further study revealed the pre-treatment with IL-6 activated the STAT3 signaling pathway in the L02 cells and then caused the activation of autophagy and apoptosis inhibition. IL-6 might play a critical role in alleviating hepatic IRI, through its modulation of the STAT3 signaling pathway, and activation of autophagy. Recombinant human IL-6 might be a potential therapeutic target in hepatic IRI.
    Keywords:  Autophagy; IL-6; Ischemia/reperfusion injury; STAT3 signaling pathway
    DOI:  https://doi.org/10.1007/s11033-020-06090-2
  8. Autophagy. 2021 Jan 19. 1-17
    Autophagy restricts mitochondrial DNA damage-induced release of ENDOG (endonuclease G) to regulate genome stability.
    Tung Chao, Hsueh-Tzu Shih, Shih-Chin Hsu, Pei-Jer Chen, Yu-Shan Fan, Yung-Ming Jeng, Zhao-Qing Shen, Ting-Fen Tsai, Zee-Fen Chang.
      Genotoxic insult causes nuclear and mitochondrial DNA damages with macroautophagy/autophagy induction. The role of mitochondrial DNA (mtDNA) damage in the requirement of autophagy for nuclear DNA (nDNA) stability is unclear. Using site-specific DNA damage approaches, we show that specific nDNA damage alone does not require autophagy for repair unless in the presence of mtDNA damage. We provide evidence that after IR exposure-induced mtDNA and nDNA damages, autophagy suppression causes non-apoptotic mitochondrial permeability, by which mitochondrial ENDOG (endonuclease G) is released and translocated to nuclei to sustain nDNA damage in a TET (tet methylcytosine dioxygenase)-dependent manner. Furthermore, blocking lysosome function is sufficient to increase the amount of mtDNA leakage to the cytosol, accompanied by ENDOG-free mitochondrial puncta formation with concurrent ENDOG nuclear accumulation. We proposed that autophagy eliminates the mitochondria specified by mtDNA damage-driven mitochondrial permeability to prevent ENDOG-mediated genome instability. Finally, we showed that HBx, a hepatitis B viral protein capable of suppressing autophagy, also causes mitochondrial permeability-dependent ENDOG mis-localization in nuclei and is linked to hepatitis B virus (HBV)-mediated hepatocellular carcinoma development. Abbreviations: 3-MA: 3-methyladenine; 5-hmC: 5-hydroxymethylcytosine; ACTB: actin beta; ATG5: autophagy related 5; ATM: ATM serine/threonine kinase; DFFB/CAD: DNA fragmentation factor subunit beta; cmtDNA: cytosolic mitochondrial DNA; ConA: concanamycin A; CQ: chloroquine; CsA: cyclosporin A; Dox: doxycycline; DSB: double-strand break; ENDOG: endonuclease G; GFP: green fluorescent protein; Gy: gray; H2AX: H2A.X variant histone; HBV: hepatitis B virus; HBx: hepatitis B virus X protein; HCC: hepatocellular carcinoma; I-PpoI: intron-encoded endonuclease; IR: ionizing radiation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOMP: mitochondrial outer membrane permeability; mPTP: mitochondrial permeability transition pore; mtDNA: mitochondrial DNA; nDNA: nuclear DNA; 4-OHT: 4-hydroxytamoxifen; rDNA: ribosomal DNA; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TET: tet methylcytosine dioxygenase; TFAM: transcription factor A, mitochondrial; TOMM20: translocase of outer mitochondrial membrane 20; VDAC: voltage dependent anion channel.
    Keywords:  Autophagy; TET; endonuclease G; genome instability; mitochondrial DNA; mitochondrial permeability
    DOI:  https://doi.org/10.1080/15548627.2021.1874209
  9. J Biol Chem. 2020 Dec 25. pii: S0021-9258(17)50708-5. [Epub ahead of print]295(52): 18406-18425
    Structure, mechanism, and regulation of mitochondrial DNA transcription initiation.
    Urmimala Basu, Alicia M Bostwick, Kalyan Das, Kristin E Dittenhafer-Reed, Smita S Patel.
      Mitochondria are specialized compartments that produce requisite ATP to fuel cellular functions and serve as centers of metabolite processing, cellular signaling, and apoptosis. To accomplish these roles, mitochondria rely on the genetic information in their small genome (mitochondrial DNA) and the nucleus. A growing appreciation for mitochondria's role in a myriad of human diseases, including inherited genetic disorders, degenerative diseases, inflammation, and cancer, has fueled the study of biochemical mechanisms that control mitochondrial function. The mitochondrial transcriptional machinery is different from nuclear machinery. The in vitro re-constituted transcriptional complexes of Saccharomyces cerevisiae (yeast) and humans, aided with high-resolution structures and biochemical characterizations, have provided a deeper understanding of the mechanism and regulation of mitochondrial DNA transcription. In this review, we will discuss recent advances in the structure and mechanism of mitochondrial transcription initiation. We will follow up with recent discoveries and formative findings regarding the regulatory events that control mitochondrial DNA transcription, focusing on those involved in cross-talk between the mitochondria and nucleus.
    Keywords:  DNA transcription; RNA polymerase; enzyme mechanism; enzyme structure; human mitochondrial RNA polymerase; mitochondria; mitochondrial DNA (mtDNA); mitochondrial DNA transcription; mitochondrial gene regulation; structure-function; transcription; transcription initiation factors; transcription regulation; yeast mitochondrial RNA polymerase
    DOI:  https://doi.org/10.1074/jbc.REV120.011202
  10. Nat Commun. 2021 01 20. 12(1): 479
    UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import in Caenorhabditis elegans.
    Tomer Shpilka, YunGuang Du, Qiyuan Yang, Andrew Melber, Nandhitha Uma Naresh, Joshua Lavelle, Sookyung Kim, Pengpeng Liu, Hilla Weidberg, Rui Li, Jun Yu, Lihua Julie Zhu, Lara Strittmatter, Cole M Haynes.
      As organisms develop, individual cells generate mitochondria to fulfill physiological requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS). Here, using the model organism Caenorhabditis elegans we demonstrate that ATFS-1 mediates an adaptable mitochondrial network expansion program that is active throughout normal development. Mitochondrial network expansion requires the relatively inefficient MTS in ATFS-1, which allows the transcription factor to be responsive to parameters that impact protein import capacity of the mitochondrial network. Increasing the strength of the ATFS-1 MTS impairs UPRmt activity by increasing accumulation within mitochondria. Manipulations of TORC1 activity increase or decrease ATFS-1 activity in a manner that correlates with protein synthesis. Lastly, expression of mitochondrial-targeted GFP is sufficient to expand the muscle cell mitochondrial network in an ATFS-1-dependent manner. We propose that mitochondrial network expansion during development is an emergent property of the synthesis of highly expressed mitochondrial proteins that exclude ATFS-1 from mitochondrial import, causing UPRmt activation.
    DOI:  https://doi.org/10.1038/s41467-020-20784-y
  11. Autophagy. 2021 Jan 17.
    BNIP3-dependent mitophagy promotes cytosolic localization of LC3B and metabolic homeostasis in the liver.
    Maya Z Springer, Logan P Poole, Lauren E Drake, Althea Bock-Hughes, Michelle L Boland, Alexandra G Smith, John Hart, Aparajita H Chourasia, Ivan Liu, Grazyna Bozek, Kay F Macleod.
      Mitophagy formed the basis of the original description of autophagy by Christian de Duve when he demonstrated that GCG (glucagon) induced macroautophagic/autophagic turnover of mitochondria in the liver. However, the molecular basis of liver-specific activation of mitophagy by GCG, or its significance for metabolic stress responses in the liver is not understood. Here we show that BNIP3 is required for GCG-induced mitophagy in the liver through interaction with processed LC3B; an interaction that is also necessary to localize LC3B out of the nucleus to cytosolic mitophagosomes in response to nutrient deprivation. Loss of BNIP3-dependent mitophagy caused excess mitochondria to accumulate in the liver, disrupting metabolic zonation within the liver parenchyma, with expansion of zone 1 metabolism at the expense of zone 3 metabolism. These results identify BNIP3 as a regulator of metabolic homeostasis in the liver through its effect on mitophagy and mitochondrial mass distribution.
    Keywords:  BNIP3; LC3B; glucagon; hepatocyte; liver zonation; mitophagy; nutrient deprivation
    DOI:  https://doi.org/10.1080/15548627.2021.1877469
  12. Cell Mol Gastroenterol Hepatol. 2021 Jan 19. pii: S2352-345X(21)00013-8. [Epub ahead of print]
    The ubiquitin E3 ligase TRIM21 promotes hepatocarcinogenesis by suppressing the p62-Keap1-Nrf2 antioxidant pathway.
    Fang Wang, Ye Zhang, Jianliang Shen, Bin Yang, Weiwei Dai, Junrong Yan, Sara Maimouni, Heineken Q Daguplo, Sara Coppola, Yingtang Gao, Yijun Wang, Zhi Du, Kesong Peng, Hui Liu, Qin Zhang, Fei Tang, Peng Wang, Shenglan Gao, Yongbo Wang, Wen-Xing Ding, Grace Guo, Fengmei Wang, Wei-Xing Zong.
      BACKGROUND AND AIMS: TRIM21 is a ubiquitin E3 ligase that is implicated in numerous biological processes including immune response, cell metabolism, redox homeostasis, and cancer development. We recently reported that TRIM21 can negatively regulate the p62-Keap1-Nrf2 antioxidant pathway by ubiquitylating p62 and prevents its oligomerization and protein sequestration function. As redox homeostasis plays a pivotal role in many cancers including liver cancer, we sought to determine the role of TRIM21 in hepatocarcinogenesis.METHODS: We examined the correlation between TRIM21 expression and the disease using publicly available data sets and 49 cases of HCC clinical samples. We used TRIM21 genetic knockout mice to determine how TRIM21 ablation impact HCC induced by the carcinogen DEN plus phenobarbital (PB). We explored the mechanism that loss of TRIM21 protects cells from DEN-induced oxidative damage and cell death.
    RESULTS: There is a positive correlation between TRIM21 expression and HCC. Consistently, TRIM21-knockout mice are resistant to DEN-induced hepatocarcinogenesis. This is accompanied by decreased cell death and tissue damage upon DEN treatment, hence reduced hepatic tissue repair response and compensatory proliferation. Cells deficient in TRIM21 display enhanced p62 sequestration of Keap1 and are protected from DEN-induced ROS induction and cell death. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient mutant TRIM21 impedes the protection from DEN-induced oxidative damage and cell death in TRIM21-deficient cells.
    CONCLUSIONS: Increased TRIM21 expression is associated with human HCC. Genetic ablation of TRIM21 leads to protection against oxidative hepatic damage and decreased hepatocarcinogenesis, suggesting TRIM21 as a preventive and therapeutic target.
    Keywords:  Nrf2; TRIM21; diethylnitrosamine; hepatocellular carcinoma; p62
    DOI:  https://doi.org/10.1016/j.jcmgh.2021.01.007
  13. Mitochondrion. 2021 Jan 18. pii: S1567-7249(21)00002-7. [Epub ahead of print]
    Intricate role of mitochondrial calcium signalling in mitochondrial quality control for regulation of cancer cell fate.
    Srimanta Patra, Kewal K Mahapatra, Prakash P Praharaj, Debasna P Panigrahi, Chandra S Bhol, Soumya R Mishra, Bishnu P Behera, Amruta Singh, Mrutyunjay Jena, Sujit K Bhutia.
      Mitochondrial quality control is crucial for sustaining cellular maintenance. Mitochondrial Ca2+ play an important role in the maintenance of mitochondrial quality control through regulation of mitochondrial dynamics, mitophagy and mitochondrial biogenesis for preserving cellular homeostasis. The regulation of this dynamic interlink between these mitochondrial networks and mitochondrial Ca2+ appears indispensable for the adaptation of cells under external stimuli. Moreover, dysregulation of mitochondrial Ca2+ divulges impaired mitochondrial control that results in several pathological conditions such as cancer. Hence this review untangles the interplay between mitochondrial Ca2+ and quality control that govern mitochondrial health and mitochondrial coordinates in the development of cancer.
    Keywords:  Cancer; Mitochondrial Ca(2+); Mitochondrial biogenesis; Mitochondrial quality control; Mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2021.01.002
  14. FASEB J. 2021 Feb;35(2): e21339
    Neural cell-derived plasma exosome protein abnormalities implicate mitochondrial impairment in first episodes of psychosis.
    Edward J Goetzl, Vinod H Srihari, Sinan Guloksuz, Maria Ferrara, Cenk Tek, George R Heninger.
      Neuroprotective and other functional proteins of mitochondria were quantified in extracts of plasma neural-derived exosomes from ten first-episode psychosis (FP) patients and ten matched psychiatrically normal controls (ctls). Astrocyte-derived extracellular vesicles (ADEVs) and neuron-derived extracellular vesicles (NDEVs) were immunoabsorbed separately from physically precipitated plasma total EVs. Extracted mitochondrial ATP synthase was specifically immunofixed to plastic wells for quantification of catalytic activity based on conversion of NADH to NAD+ . Other extracted mitochondrial functional proteins were quantified by ELISAs. All protein levels were normalized with EV content of the CD81 exosome marker. FP patient ADEV level but not NDEV level of mitochondrial ATP synthase activity was significantly lower than that of ctls. FP patient ADEV and NDEV levels of the functionally critical mitochondrial proteins mitofusin 2 and cyclophilin D, but not of transcription factor A of mitochondria, and of the mitochondrial short open-reading frame neuroprotective and metabolic regulatory peptides humanin and MOTS-c were significantly lower than those of ctls. In contrast, FP patient NDEV, but not ADEV, level of the mitochondrial-tethering protein syntaphilin, but not of myosin VI, was significantly higher than that of ctls. The distinctively different neural levels of some mitochondrial proteins in FP patients than ctls now should be correlated with diverse clinical characteristics. Drugs that increase depressed levels of proteins and mimetics of deficient short open-reading frame peptides may be of therapeutic value in early phases of schizophrenia.
    Keywords:  ATP synthase; MOTS-c; cyclophilin D; humanin; mitofusin 2; schizophrenia
    DOI:  https://doi.org/10.1096/fj.202002519R
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