bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2021–10–03
25 papers selected by
Marco Tigano, Thomas Jefferson University
  1. Targeting the mitochondrial unfolded protein response in cancer: opportunities and challenges.
  2. The modified mitochondrial outer membrane carrier MTCH2 links mitochondrial fusion to lipogenesis.
  3. Activation of mitochondrial unfolded protein response protects against multiple exogenous stressors.
  4. Yap-Hippo Signaling Activates Mitochondrial Protection and Sustains Breast Cancer Viability under Hypoxic Stress.
  5. Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.
  6. Paraptosis triggers mitochondrial pathway-mediated apoptosis in Alzheimer's disease.
  7. Preprint Highlight: ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA- dependent STING signaling.
  8. Live-Cell Probe for In Situ Single-Cell Monitoring of Mitochondrial DNA Methylation.
  9. Mitochondrial Dysfunction in Diseases, Longevity, and Treatment Resistance: Tuning Mitochondria Function as a Therapeutic Strategy.
  10. CRISPR-Cas9 correction of OPA1 c.1334G>A: p.R445H restores mitochondrial homeostasis in dominant optic atrophy patient-derived iPSCs.
  11. MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence.
  12. RTG Signaling Sustains Mitochondrial Respiratory Capacity in HOG1-Dependent Osmoadaptation.
  13. TASK-1 regulates mitochondrial function under hypoxia.
  14. MFN2 Stabilization: A Bridge for Endoplasmic Reticulum Stress Sensitivity in Melanoma.
  15. Extracellular vesicles and immunogenic stress in cancer.
  16. HIF1α stabilization in hypoxia is not oxidant-initiated.
  17. NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner.
  18. Structural basis and regulation of the reductive stress response.
  19. Bortezomib induces anti-multiple myeloma immune response mediated by cGAS/STING pathway activation.
  20. Simulated microgravity triggers DNA damage and mitochondria-mediated apoptosis through ROS generation in human promyelocytic leukemic cells.
  21. TBK1 has a new Akt.
  22. Activated PI3Kδ signals compromise plasma cell survival via limiting autophagy and increasing ER stress.
  23. Metabolism as a driver of immunity.
  24. Effect of the Non-Immunosuppressive MPT Pore Inhibitor Alisporivir on the Functioning of Heart Mitochondria in Dystrophin-Deficient mdx Mice.
  25. Mitochondrial Membrane Disrupting Molecules for Selective Killing of Senescent Cells.
  1. Trends Cancer. 2021 Sep 24. pii: S2405-8033(21)00176-X. [Epub ahead of print]
    Targeting the mitochondrial unfolded protein response in cancer: opportunities and challenges.
    Joseph R Inigo, Rahul Kumar, Dhyan Chandra.
      Increasing evidence indicates that a mitochondria-specific stress response referred to as the 'mitochondrial unfolded protein response' (UPRmt) is activated to maintain mitochondrial integrity and support tumor growth. In this forum article, we discuss the recent advances and current challenges in therapeutically targeting UPRmt in cancer.
    Keywords:  cancer; mitochondrial chaperonins; mitochondrial proteases; mitochondrial proteostasis; mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1016/j.trecan.2021.08.008
  2. J Cell Biol. 2021 Nov 01. pii: e202103122. [Epub ahead of print]220(11):
    The modified mitochondrial outer membrane carrier MTCH2 links mitochondrial fusion to lipogenesis.
    Katherine Labbé, Shona Mookerjee, Maxence Le Vasseur, Eddy Gibbs, Chad Lerner, Jodi Nunnari.
      Mitochondrial function is integrated with cellular status through the regulation of opposing mitochondrial fusion and division events. Here we uncover a link between mitochondrial dynamics and lipid metabolism by examining the cellular role of mitochondrial carrier homologue 2 (MTCH2). MTCH2 is a modified outer mitochondrial membrane carrier protein implicated in intrinsic cell death and in the in vivo regulation of fatty acid metabolism. Our data indicate that MTCH2 is a selective effector of starvation-induced mitochondrial hyperfusion, a cytoprotective response to nutrient deprivation. We find that MTCH2 stimulates mitochondrial fusion in a manner dependent on the bioactive lipogenesis intermediate lysophosphatidic acid. We propose that MTCH2 monitors flux through the lipogenesis pathway and transmits this information to the mitochondrial fusion machinery to promote mitochondrial elongation, enhanced energy production, and cellular survival under homeostatic and starvation conditions. These findings will help resolve the roles of MTCH2 and mitochondria in tissue-specific lipid metabolism in animals.
    DOI:  https://doi.org/10.1083/jcb.202103122
  3. Life Sci Alliance. 2021 Dec;pii: e202101182. [Epub ahead of print]4(12):
    Activation of mitochondrial unfolded protein response protects against multiple exogenous stressors.
    Sonja K Soo, Annika Traa, Paige D Rudich, Meeta Mistry, Jeremy M Van Raamsdonk.
      The mitochondrial unfolded protein response (mitoUPR) is an evolutionarily conserved pathway that responds to mitochondria insults through transcriptional changes, mediated by the transcription factor ATFS-1/ATF-5, which acts to restore mitochondrial homeostasis. In this work, we characterized the role of ATFS-1 in responding to organismal stress. We found that activation of ATFS-1 is sufficient to cause up-regulation of genes involved in multiple stress response pathways including the DAF-16-mediated stress response pathway, the cytosolic unfolded protein response, the endoplasmic reticulum unfolded protein response, the SKN-1-mediated oxidative stress response pathway, the HIF-1-mediated hypoxia response pathway, the p38-mediated innate immune response pathway, and antioxidant genes. Constitutive activation of ATFS-1 increases resistance to multiple acute exogenous stressors, whereas disruption of atfs-1 decreases stress resistance. Although ATFS-1-dependent genes are up-regulated in multiple long-lived mutants, constitutive activation of ATFS-1 decreases lifespan in wild-type animals. Overall, our work demonstrates that ATFS-1 serves a vital role in organismal survival of acute stressors through its ability to activate multiple stress response pathways but that chronic ATFS-1 activation is detrimental for longevity.
    DOI:  https://doi.org/10.26508/lsa.202101182
  4. J Oncol. 2021 ;2021 5212721
    Yap-Hippo Signaling Activates Mitochondrial Protection and Sustains Breast Cancer Viability under Hypoxic Stress.
    Chen Shi, Siyuan Zhang, Changkuo Guo, Jian Tie.
      Yes-associated protein (Yap) is a transcriptional regulator that upregulates oncogenes and downregulates tumor repressor genes. In this study, we analyzed protein expression, RNA transcription, and signaling pathways to determine the function and mechanism of Yap in breast cancer survival during hypoxic stress. Yap transcription was drastically upregulated by hypoxia in a time-dependent manner. siRNA-mediated Yap knockdown attenuated breast cancer viability and impaired cell proliferation under hypoxic conditions. Yap knockdown induced mitochondrial stress, including mitochondrial membrane potential reduction, mitochondrial oxidative stress, and ATP exhaustion after exposure to hypoxia. It also repressed mitochondrial protective systems, including mitophagy and mitochondrial fusion upon exposure to hypoxia. Finally, our data showed that Yap knockdown suppresses MCF-7 cell migration by inhibiting F-actin transcription and promoting lamellipodium degradation under hypoxic stress. Taken together, Yap maintenance of mitochondrial function and activation of F-actin/lamellipodium signaling is required for breast cancer survival, migration, and proliferation under hypoxic stress.
    DOI:  https://doi.org/10.1155/2021/5212721
  5. PLoS Genet. 2021 Sep 27. 17(9): e1009822
    Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.
    Roberta Filograna, Seungmin Lee, Katarina Tiklova, Mara Mennuni, Viktor Jonsson, Markus Ringnér, Linda Gillberg, Elena Sopova, Oleg Shupliakov, Camilla Koolmeister, Lars Olson, Thomas Perlmann, Nils-Göran Larsson.
      Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson's disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells.
    DOI:  https://doi.org/10.1371/journal.pgen.1009822
  6. Exp Ther Med. 2021 Nov;22(5): 1280
    Paraptosis triggers mitochondrial pathway-mediated apoptosis in Alzheimer's disease.
    Dong-Pei Jia, Song Wang, Bao-Chao Zhang, Fang Fang.
      [This retracts the article DOI: 10.3892/etm.2015.2531.].
    DOI:  https://doi.org/10.3892/etm.2021.10715
  7. Mol Biol Cell. 2021 Oct 01. 32(20): 1110
    Preprint Highlight: ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA- dependent STING signaling.
    Luis Bonet-Ponce.
      Loss-of-function mutations in VPS13C cause familial Parkinson's disease (PD) and increase the risk to develop the sporadic form of the disease. However, the underlying disease mechanisms remain unclear. It has been previously established that VPS13C tethers lysosomes with the endoplasmic reticulum (ER) and promotes lipid interchange between both organelles. This study provides a cellular role of VPS13C, specifically regulating the cGAS/STING pathway and contributing to the innate immune response. The authors generate VPS13C knockout HeLa cells and use confocal microscopy and biochemical approaches to show loss of VPS13C leads to altered lysosome lipid composition and mitochondrial DNA leakage. Understanding how VPS13C preserves cellular homeostasis is an exciting discovery for scientists working on neurodegeneration and for cell biologists interested in lysosome-to-mitochondria cross-talk.
    DOI:  https://doi.org/10.1091/mbc.E21-10-0125p
  8. ACS Sens. 2021 Sep 29.
    Live-Cell Probe for In Situ Single-Cell Monitoring of Mitochondrial DNA Methylation.
    Han Zhao, Donghan Ma, Junkai Xie, Oscar Sanchez, Fang Huang, Chongli Yuan.
      Mitochondria, as the center of energy production, play an important role in cell homeostasis by regulating the cellular metabolism and mediating the cellular response to stress. Epigenetic changes such as DNA and histone methylation have been increasingly recognized to play a significant role in homeostasis and stress response. The cross-talking between the metabolome and the epigenome has attracted significant attention in recent years but with a major focus on how metabolism contributes to epigenomic changes. Few studies have focused on how epigenetic modifications may alter the mitochondrial composition and activity. In this work, we designed a novel probe targeting methylated CpGs of mitochondrial DNA (mtDNA). We demonstrated the capability of our probe to reveal the spatial distribution of methylated mtDNA and capture the mtDNA methylation changes at a single-cell level. We were also able to track single-cell mtDNA and nDNA methylation simultaneously and discovered the unsynchronized dynamics of the nucleus and mitochondria. Our tool offers a unique opportunity to understand the epigenetic regulation of mtDNA and its dynamic response to the microenvironment and cellular changes.
    Keywords:  DNA CpG methylation; epigenetics; live-cell probe; mitochondria; super-resolution microscopy
    DOI:  https://doi.org/10.1021/acssensors.1c00731
  9. Genes (Basel). 2021 Aug 29. pii: 1348. [Epub ahead of print]12(9):
    Mitochondrial Dysfunction in Diseases, Longevity, and Treatment Resistance: Tuning Mitochondria Function as a Therapeutic Strategy.
    Kazuo Tomita, Yoshikazu Kuwahara, Kento Igarashi, Mehryar Habibi Roudkenar, Amaneh Mohammadi Roushandeh, Akihiro Kurimasa, Tomoaki Sato.
      Mitochondria are very important intracellular organelles because they have various functions. They produce ATP, are involved in cell signaling and cell death, and are a major source of reactive oxygen species (ROS). Mitochondria have their own DNA (mtDNA) and mutation of mtDNA or change the mtDNA copy numbers leads to disease, cancer chemo/radioresistance and aging including longevity. In this review, we discuss the mtDNA mutation, mitochondrial disease, longevity, and importance of mitochondrial dysfunction in cancer first. In the later part, we particularly focus on the role in cancer resistance and the mitochondrial condition such as mtDNA copy number, mitochondrial membrane potential, ROS levels, and ATP production. We suggest a therapeutic strategy employing mitochondrial transplantation (mtTP) for treatment-resistant cancer.
    Keywords:  cancer radioresistance; clinically relevant radioresistant (CRR) cells; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.3390/genes12091348
  10. Mol Ther Nucleic Acids. 2021 Dec 03. 26 432-443
    CRISPR-Cas9 correction of OPA1 c.1334G>A: p.R445H restores mitochondrial homeostasis in dominant optic atrophy patient-derived iPSCs.
    Paul E Sladen, Pedro R L Perdigão, Grace Salsbury, Tatiana Novoselova, Jacqueline van der Spuy, J Paul Chapple, Patrick Yu-Wai-Man, Michael E Cheetham.
      Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy in the United Kingdom. DOA has an insidious onset in early childhood, typically presenting with bilateral, central visual loss caused by the preferential loss of retinal ganglion cells. 60%-70% of genetically confirmed DOA cases are associated with variants in OPA1, a ubiquitously expressed GTPase that regulates mitochondrial homeostasis through coordination of inner membrane fusion, maintenance of cristae structure, and regulation of bioenergetic output. Whether genetic correction of OPA1 pathogenic variants can alleviate disease-associated phenotypes remains unknown. Here, we demonstrate generation of patient-derived OPA1 c.1334G>A: p.R445H mutant induced pluripotent stem cells (iPSCs), followed by correction of OPA1 through CRISPR-Cas9-guided homology-directed repair (HDR) and evaluate the effect of OPA1 correction on mitochondrial homeostasis. CRISPR-Cas9 gene editing demonstrated an efficient method of OPA1 correction, with successful gene correction in 57% of isolated iPSCs. Correction of OPA1 restored mitochondrial homeostasis, re-establishing the mitochondrial network and basal respiration and ATP production levels. In addition, correction of OPA1 re-established the levels of wild-type (WT) mitochondrial DNA (mtDNA) and reduced susceptibility to apoptotic stimuli. These data demonstrate that nuclear gene correction can restore mitochondrial homeostasis and improve mtDNA integrity in DOA patient-derived cells carrying an OPA1 variant.
    Keywords:  CRISPR; OPA1; apoptosis; bioenergetics; gene correction; gene editing; iPSC; mitochondria; optic atrophy; retinal ganglion cell
    DOI:  https://doi.org/10.1016/j.omtn.2021.08.015
  11. Front Physiol. 2021 ;12 734976
    MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence.
    Chiara Giordani, Andrea Silvestrini, Angelica Giuliani, Fabiola Olivieri, Maria Rita Rippo.
      Mitochondria are essential organelles that generate most of the chemical energy to power the cell through ATP production, thus regulating cell homeostasis. Although mitochondria have their own independent genome, most of the mitochondrial proteins are encoded by nuclear genes. An extensive bidirectional communication network between mitochondria and the nucleus has been discovered, thus making them semi-autonomous organelles. The nucleus-to-mitochondria signaling pathway, called Anterograde Signaling Pathway can be deduced, since the majority of mitochondrial proteins are encoded in the nucleus, less is known about the opposite pathway, the so-called mitochondria-to-nucleus retrograde signaling pathway. Several studies have demonstrated that non-coding RNAs are essential "messengers" of this communication between the nucleus and the mitochondria and that they might have a central role in the coordination of important mitochondrial biological processes. In particular, the finding of numerous miRNAs in mitochondria, also known as mitomiRs, enabled insights into their role in mitochondrial gene transcription. MitomiRs could act as important mediators of this complex crosstalk between the nucleus and the mitochondria. Mitochondrial homeostasis is critical for the physiological processes of the cell. Disruption at any stage in their metabolism, dynamics and bioenergetics could lead to the production of considerable amounts of reactive oxygen species and increased mitochondrial permeability, which are among the hallmarks of cellular senescence. Extensive changes in mitomiR expression and distribution have been demonstrated in senescent cells, those could possibly lead to an alteration in mitochondrial homeostasis. Here, we discuss the emerging putative roles of mitomiRs in the bidirectional communication pathways between mitochondria and the nucleus, with a focus on the senescence-associated mitomiRs.
    Keywords:  microRNA; mitochondria; mitomiRs; mitonuclear communication; senescence
    DOI:  https://doi.org/10.3389/fphys.2021.734976
  12. Microorganisms. 2021 Sep 06. pii: 1894. [Epub ahead of print]9(9):
    RTG Signaling Sustains Mitochondrial Respiratory Capacity in HOG1-Dependent Osmoadaptation.
    Nicoletta Guaragnella, Gennaro Agrimi, Pasquale Scarcia, Clelia Suriano, Isabella Pisano, Antonella Bobba, Cristina Mazzoni, Luigi Palmieri, Sergio Giannattasio.
      Mitochondrial RTG-dependent retrograde signaling, whose regulators have been characterized in Saccharomyces cerevisiae, plays a recognized role under various environmental stresses. Of special significance, the activity of the transcriptional complex Rtg1/3 has been shown to be modulated by Hog1, the master regulator of the high osmolarity glycerol pathway, in response to osmotic stress. The present work focuses on the role of RTG signaling in salt-induced osmotic stress and its interaction with HOG1. Wild-type and mutant cells, lacking HOG1 and/or RTG genes, are compared with respect to cell growth features, retrograde signaling activation and mitochondrial function in the presence and in the absence of high osmostress. We show that RTG2, the main upstream regulator of the RTG pathway, contributes to osmoadaptation in an HOG1-dependent manner and that, with RTG3, it is notably involved in a late phase of growth. Our data demonstrate that impairment of RTG signaling causes a decrease in mitochondrial respiratory capacity exclusively under osmostress. Overall, these results suggest that HOG1 and the RTG pathway may interact sequentially in the stress signaling cascade and that the RTG pathway may play a role in inter-organellar metabolic communication for osmoadaptation.
    Keywords:  HOG1; RTG signaling; metabolism; mitochondria; osmoadaptation; respiratory capacity; stress response
    DOI:  https://doi.org/10.3390/microorganisms9091894
  13. Biochem Biophys Res Commun. 2021 Sep 21. pii: S0006-291X(21)01326-7. [Epub ahead of print]578 163-169
    TASK-1 regulates mitochondrial function under hypoxia.
    Yang Yu, Harrison He, Chen Kang, Keli Hu.
      TASK-1, TWIK-related acid-sensitive potassium channel 1, is a member of the two-pore- domain potassium channel family. It is constitutively active at resting potentials and strongly expressed in the heart. However, little is known about the role of TASK-1 channels in hypoxia. A cellular model of hypoxia and reoxygenation from rat heart-derived H9c2 cells or TASK-1 deficient HEK293T cells was employed to explore the role of TASK-1 channels in cytoprotection against hypoxia. The cell viability assay revealed that TASK-1 expression increased the number of viable cells subjected to 2 h of hypoxia followed by 2 h of reoxygenation (H/R). To dissect the protective role of TASK-1 on mitochondrial function, mitochondrial membrane potential (MMP) was assessed by tetramethylrhodamine fluorescence. It was demonstrated that MMP was significantly decreased by H/R, but it was maintained by TASK-1 expression or pretreatment with cyclosporin A, an inhibitor of mitochondrial permeability transition pore (mPTP). The effect of cyclosporin A on MMP was not further altered by TASK-1 expression. Moreover, TASK-1 expression significantly blocked cytochrome c release induced by H/R. While a small fraction of endogenous TASK-1 was found to colocalize with the mitochondrial marker MitoTracker in H9c2 cells, H/R did not alter the extent of colocalization of TASK-1 with MitoTracker. The total TASK-1 protein level was not significantly affected by H/R. In summary, we provided the evidence that TASK-1 channels confer cytoprotection against hypoxia-reoxygenation injury, possibly by their capacity of maintaining the mitochondrial membrane potential via inhibiting MPTP opening.
    Keywords:  Cytochrome c; Hypoxia; Mitochondria; Mitochondrial membrane potential; TASK-1
    DOI:  https://doi.org/10.1016/j.bbrc.2021.09.032
  14. J Invest Dermatol. 2021 Sep 23. pii: S0022-202X(21)01224-0. [Epub ahead of print]
    MFN2 Stabilization: A Bridge for Endoplasmic Reticulum Stress Sensitivity in Melanoma.
    Charles H Adelmann, Inbal Rachmin, David E Fisher.
      In a new article in the Journal of Investigative Dermatology, Wang et al. (2021) report that mitochondrial quality control modulates responses to endoplasmic reticulum (ER) stress in melanoma. They implicate a linear pathway of XBP1, MARCH5, and MFN2 that act together to regulate mitochondrial fission and mitophagy and ultimately mediate melanoma cell sensitivity to ER stress. This work informs therapeutic combinations and biomarker strategies for targeting melanoma organellar homeostasis as well as for life‒death decisions.
    DOI:  https://doi.org/10.1016/j.jid.2021.05.003
  15. Cell Death Dis. 2021 Oct 01. 12(10): 894
    Extracellular vesicles and immunogenic stress in cancer.
    Qi Wu, Hanpu Zhang, Si Sun, Lijun Wang, Shengrong Sun.
      Tumor progression requires bidirectional cell-to-cell communication within a complex tumor microenvironment (TME). Extracellular vesicles (EVs) as carriers have the capacity to shuttle regulatory molecules, including nucleic acids, proteins, and lipids, between cancer cells and multiple stromal cells, inducing remarkable phenotypic alterations in the TME. Recently proposed the concept "immunogenic stress", which means in some stressed microenvironment, cancer cells can release EVs containing specific immunoregulatory mediators, depending on the initiating stress-associated pathway, thereby provoking the changes of immune status in the TME. Considerable evidence has revealed that the intracellular mechanisms underlying the response to diverse stresses are mainly autophagy, endoplasmic reticulum (ER) stress reactions and the DNA damage response (DDR). In addition, the activation of immunogenic stress responses endows hosts with immune surveillance capacity; in contrast, several cargoes in EVs under immunogenic stress trigger a passive immune response by mediating the function of immune cells. This review discusses the current understanding of the immunogenic stress pathways in cancer and describes the interrelation between EVs and immunogenic stress to propose potential treatment strategies and biomarkers.
    DOI:  https://doi.org/10.1038/s41419-021-04171-z
  16. Elife. 2021 Oct 01. pii: e72873. [Epub ahead of print]10
    HIF1α stabilization in hypoxia is not oxidant-initiated.
    Amit Kumar, Manisha Vaish, Saravanan S Karuppagounder, Irina Gazaryan, John W Cave, Anatoly A Starkov, Elizabeth T Anderson, Sheng Zhang, John T Pinto, Austin M Rountree, Wang Wang, Ian R Sweet, Rajiv R Ratan.
      Hypoxic adaptation mediated by HIF transcription factors requires mitochondria, which have been implicated in regulating HIF1α stability in hypoxia by distinct models that involve consuming oxygen or alternatively converting oxygen into the second messenger peroxide. Here, we use a ratiometric, peroxide reporter, HyPer to evaluate the role of peroxide in regulating HIF1α stability. We show that antioxidant enzymes are neither homeostatically induced nor are peroxide levels increased in hypoxia. Additionally, forced expression of diverse antioxidant enzymes, all of which diminish peroxide, had disparate effects on HIF1α protein stability. Moreover, decrease in lipid peroxides by glutathione peroxidase-4 or superoxide by mitochondrial SOD, failed to influence HIF1α protein stability. These data show that mitochondrial, cytosolic or lipid ROS were not necessary for HIF1α stability, and favor a model where mitochondria contribute to hypoxic adaptation as oxygen consumers.
    Keywords:  cell biology; neuroscience
    DOI:  https://doi.org/10.7554/eLife.72873
  17. Cell Death Discov. 2021 Oct 01. 7(1): 269
    NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner.
    Can Huang, Patricia Santofimia-Castaño, Xi Liu, Yi Xia, Ling Peng, Célia Gotorbe, Jose Luis Neira, Daolin Tang, Jacques Pouyssegur, Juan Iovanna.
      Ferroptosis is an iron-dependent cell death characterized by the accumulation of hydroperoxided phospholipids. Here, we report that the NUPR1 inhibitor ZZW-115 induces ROS accumulation followed by a ferroptotic cell death, which could be prevented by ferrostatin-1 (Fer-1) and ROS-scavenging agents. The ferroptotic activity can be improved by inhibiting antioxidant factors in pancreatic ductal adenocarcinoma (PDAC)- and hepatocellular carcinoma (HCC)-derived cells. In addition, ZZW-115-treatment increases the accumulation of hydroperoxided lipids in these cells. We also found that a loss of activity and strong deregulation of key enzymes involved in the GSH- and GPX-dependent antioxidant systems upon ZZW-115 treatment. These results have been validated in xenografts induced with PDAC- and HCC-derived cells in nude mice during the treatment with ZZW-115. More importantly, we demonstrate that ZZW-115-induced mitochondrial morphological changes, compatible with the ferroptotic process, as well as mitochondrial network disorganization and strong mitochondrial metabolic dysfunction, which are rescued by both Fer-1 and N-acetylcysteine (NAC). Of note, the expression of TFAM, a key regulator of mitochondrial biogenesis, is downregulated by ZZW-115. Forced expression of TFAM is able to rescue morphological and functional mitochondrial alterations, ROS production, and cell death induced by ZZW-115 or genetic inhibition of NUPR1. Altogether, these results demonstrate that the mitochondrial cell death mediated by NUPR1 inhibitor ZZW-115 is fully rescued by Fer-1 but also via TFAM complementation. In conclusion, TFAM could be considered as an antagonist of the ferroptotic cell death.
    DOI:  https://doi.org/10.1038/s41420-021-00662-2
  18. Cell. 2021 Sep 21. pii: S0092-8674(21)01049-7. [Epub ahead of print]
    Structural basis and regulation of the reductive stress response.
    Andrew G Manford, Elijah L Mena, Karen Y Shih, Christine L Gee, Rachael McMinimy, Brenda Martínez-González, Rumi Sherriff, Brandon Lew, Madeline Zoltek, Fernando Rodríguez-Pérez, Makda Woldesenbet, John Kuriyan, Michael Rape.
      Although oxidative phosphorylation is best known for producing ATP, it also yields reactive oxygen species (ROS) as invariant byproducts. Depletion of ROS below their physiological levels, a phenomenon known as reductive stress, impedes cellular signaling and has been linked to cancer, diabetes, and cardiomyopathy. Cells alleviate reductive stress by ubiquitylating and degrading the mitochondrial gatekeeper FNIP1, yet it is unknown how the responsible E3 ligase CUL2FEM1B can bind its target based on redox state and how this is adjusted to changing cellular environments. Here, we show that CUL2FEM1B relies on zinc as a molecular glue to selectively recruit reduced FNIP1 during reductive stress. FNIP1 ubiquitylation is gated by pseudosubstrate inhibitors of the BEX family, which prevent premature FNIP1 degradation to protect cells from unwarranted ROS accumulation. FEM1B gain-of-function mutation and BEX deletion elicit similar developmental syndromes, showing that the zinc-dependent reductive stress response must be tightly regulated to maintain cellular and organismal homeostasis.
    Keywords:  BEX2; BEX3; CUL2; FEM1B; mitochondria; oxidative phosphorylation; reactive oxygen species; reductive stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.cell.2021.09.002
  19. Blood Cancer Discov. 2021 Sep;2(5): 468-483
    Bortezomib induces anti-multiple myeloma immune response mediated by cGAS/STING pathway activation.
    Annamaria Gulla, Eugenio Morelli, Mehmet K Samur, Cirino Botta, Teru Hideshima, Giada Bianchi, Mariateresa Fulciniti, Stefano Malvestiti, Rao H Prabhala, Srikanth Talluri, Kenneth Wen, Yu-Tzu Tai, Paul G Richardson, Dharminder Chauhan, Tomasz Sewastianik, Ruben D Carrasco, Nikhil C Munshi, Kenneth C Anderson.
      Proteasome inhibitor bortezomib induces apoptosis in multiple myeloma (MM) cells, and has transformed patient outcome. Using in vitro as well as in vivo immunodeficient and immunocompetent murine MM models, we here show that bortezomib also triggers immunogenic cell death (ICD) characterized by exposure of calreticulin on dying MM cells, phagocytosis of tumor cells by dendritic cells, and induction of MM specific immunity. We identify a bortezomib-triggered specific ICD-gene signature associated with better outcome in two independent MM patient cohorts. Importantly, bortezomib stimulates MM cells immunogenicity via activation of cGAS/STING pathway and production of type-I interferons; and STING agonists significantly potentiate bortezomib-induced ICD. Our studies therefore delineate mechanisms whereby bortezomib exerts immunotherapeutic activity, and provide the framework for clinical trials of STING agonists with bortezomib to induce potent tumor-specific immunity and improve patient outcome in MM.
    Keywords:  STING; bortezomib; immunogenic cell death (ICD); immunotherapy; multiple myeloma
    DOI:  https://doi.org/10.1158/2643-3230.bcd-21-0047
  20. Mitochondrion. 2021 Sep 24. pii: S1567-7249(21)00132-X. [Epub ahead of print]
    Simulated microgravity triggers DNA damage and mitochondria-mediated apoptosis through ROS generation in human promyelocytic leukemic cells.
    Ragini Singh, Mohit Rajput, Rana P Singh.
      The weightlessness or microgravity, a physical factor in space, may adversely affect the health of the space travellers or astronauts. The knowledge about the effect of microgravity on human cancer cells is very limited and poorly understood. Here, we employed rotary cell culture system (RCCS) to induce simulated microgravity (SMG) and examined its effects on human promyelocytic leukemic HL-60 cells. These cells were grown in normal gravity condition (1g) for control purpose. The 72 h exposure of cells to SMG decreased cell proliferation and viability which were accompanied by the reduced expression of PCNA and phosphorylated ERK1/2 and AKT proteins. SMG increased the DNA damage as well as the expression of DNA damage sensing proteins including ATM, ATR, Chk1, Chk2 and γH2A.X. The expression of AP1, XRCC1 and APEX1 regulating BER, XPC regulating NER and MLH1 and PMS2 regulating MMR were downregulated. However, SMG increased the expression of Ku70/80, DNA-PK and Rad51, regulating NHEJ and HR. SMG induced apoptosis and increased the levels of cleaved-poly-(ADP-ribose) polymerase and cleaved-caspase-3. An increase in Bax/Bcl-2 ratio and dissipation of mitochondrial membrane potential were also observed. SMG enhanced reactive oxygen species (ROS) formation which led to the enhanced DNA damage and apoptotic cell death. Overall, SMG induced ROS, DNA damage and differential expression of DNA repair genes, and altered the overall DNA repair capacity which may activate ATM/ATR-Chk1/2 and Ku70/80 and DNA-PK-mediated apoptotic cell death.
    Keywords:  Apoptosis; Cancer; DNA damage; DNA repair; Microgravity; Mitochondria; ROS
    DOI:  https://doi.org/10.1016/j.mito.2021.09.006
  21. J Biol Chem. 2021 Sep 23. pii: S0021-9258(21)01047-4. [Epub ahead of print] 101244
    TBK1 has a new Akt.
    Leslie M Shaw.
      TANK-binding kinase 1 (TBK1) is a non-canonical IκB kinase that plays an essential role in the innate immune response to foreign pathogens. Recent studies have highlighted additional roles for TBK1 in the regulation of metabolism, although the mechanisms of this regulation have not been well characterized. In a recent issue, Tooley et al demonstrated that TBK1-dependent activation of downstream kinase Akt is mediated via mTOR complex 2 (mTORC2). This novel action of TBK1 reveals a key role for this kinase in the regulation of cellular metabolism and growth by diverse environmental inputs.
    Keywords:  AKT; TBK1; mTORC2
    DOI:  https://doi.org/10.1016/j.jbc.2021.101244
  22. J Exp Med. 2021 Dec 06. pii: e20211035. [Epub ahead of print]218(12):
    Activated PI3Kδ signals compromise plasma cell survival via limiting autophagy and increasing ER stress.
    Fahd Al Qureshah, Sara Sagadiev, Christopher D Thouvenel, Shuozhi Liu, Zhaolin Hua, Baidong Hou, Mridu Acharya, Richard G James, David J Rawlings.
      While phosphatidylinositide 3-kinase delta (PI3Kδ) plays a critical role in humoral immunity, the requirement for PI3Kδ signaling in plasma cells remains poorly understood. Here, we used a conditional mouse model of activated PI3Kδ syndrome (APDS), to interrogate the function of PI3Kδ in plasma cell biology. Mice expressing a PIK3CD gain-of-function mutation (aPIK3CD) in B cells generated increased numbers of memory B cells and mounted an enhanced secondary response but exhibited a rapid decay of antibody levels over time. Consistent with these findings, aPIK3CD expression markedly impaired plasma cell generation, and expression of aPIK3CD intrinsically in plasma cells was sufficient to diminish humoral responses. Mechanistically, aPIK3CD disrupted ER proteostasis and autophagy, which led to increased plasma cell death. Notably, this defect was driven primarily by elevated mTORC1 signaling and modulated by treatment with PI3Kδ-specific inhibitors. Our findings establish an essential role for PI3Kδ in plasma cell homeostasis and suggest that modulating PI3Kδ activity may be useful for promoting and/or thwarting specific immune responses.
    DOI:  https://doi.org/10.1084/jem.20211035
  23. Nat Rev Immunol. 2021 Oct;21(10): 618-619
    Metabolism as a driver of immunity.
    Erika L Pearce.
      
    DOI:  https://doi.org/10.1038/s41577-021-00601-3
  24. Biomedicines. 2021 Sep 16. pii: 1232. [Epub ahead of print]9(9):
    Effect of the Non-Immunosuppressive MPT Pore Inhibitor Alisporivir on the Functioning of Heart Mitochondria in Dystrophin-Deficient mdx Mice.
    Mikhail V Dubinin, Vlada S Starinets, Eugeny Yu Talanov, Irina B Mikheeva, Natalia V Belosludtseva, Dmitriy A Serov, Kirill S Tenkov, Evgeniya V Belosludtseva, Konstantin N Belosludtsev.
      Supporting mitochondrial function is one of the therapeutic strategies that improve the functioning of skeletal muscle in Duchenne muscular dystrophy (DMD). In this work, we studied the effect of a non-immunosuppressive inhibitor of mitochondrial permeability transition pore (MPTP) alisporivir (5 mg/kg/day), reducing the intensity of the necrotic process and inflammation in skeletal muscles on the cardiac phenotype of dystrophin-deficient mdx mice. We found that the heart mitochondria of mdx mice show an increase in the intensity of oxidative phosphorylation and an increase in the resistance of organelles to the MPT pore opening. Alisporivir had no significant effect on the hyperfunctionalization of the heart mitochondria of mdx mice, and the state of the heart mitochondria of wild-type animals did not affect the dynamics of organelles but significantly suppressed mitochondrial biogenesis and reduced the amount of mtDNA in the heart muscle. Moreover, alisporivir suppressed mitochondrial biogenesis in the heart of wild-type mice. Alisporivir treatment resulted in a decrease in heart weight in mdx mice, which was associated with a significant modification of the transmission of excitation in the heart. The latter was also noted in the case of WT mice treated with alisporivir. The paper discusses the prospects for using alisporivir to correct the function of heart mitochondria in DMD.
    Keywords:  Duchenne muscular dystrophy; alisporivir; heart; mitochondria; mitochondrial permeability transition
    DOI:  https://doi.org/10.3390/biomedicines9091232
  25. Chembiochem. 2021 Sep 27.
    Mitochondrial Membrane Disrupting Molecules for Selective Killing of Senescent Cells.
    Batakrishna Jana, Sangpil Kim, Jae-Byoung Chae, Hyewon Chung, Chaekyu Kim, Ja-Hyoung Ryu.
      Cellular senescence, a stable form of cell cycle arrest, facilitates protection from tumorigenesis and aids in tissue repair as they accumulate in the body at an early age. However, long-term retention of senescent cells causes inflammation, aging of the tissue, and progression of deadly diseases such as obesity, diabetes, and atherosclerosis. Various attempts have been made to achieve selective elimination of senescent cells from the body, yet little has been explored in designing the mitochondria-targeted senolytic agent. Many characteristics of senescence are associated with mitochondria. Here we have designed a library of alkyl-monoquaternary ammonium-triphenyl phosphine (TPP) and alkyl-diquaternary ammo-nium-TPP of varying alkyl chain lengths, which target the mitochondria; we also studied their senolytic properties. It was observed that the alkyl-diquaternary ammonium-TPP with the longest chain length induces apoptosis to senescent cells selectively via an increase of reactive oxygen species (ROS) and mitochondrial membrane disruption. This study demonstrated that mitochondria could be a potential target for designing new small molecules as senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging.
    Keywords:  alkyl-quaternary ammonium-TPP * mitochondria * membrane disruption * senescence * Macula retina mouse model
    DOI:  https://doi.org/10.1002/cbic.202100412
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