bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2020–08–30
twenty-one papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. An indispensable role for dynamin-related protein 1 (DRP1) in beige and brown adipogenesis.
  2. The dynamic landscape of transcription initiation in yeast mitochondria.
  3. Mitochondrial import, health and mtDNA copy number variability using type II and type V CRISPR effectors.
  4. Mitochondrial Regulation of the 26S Proteasome.
  5. Complete chemical structures of human mitochondrial tRNAs.
  6. Atomic structure of a mitochondrial complex I intermediate from vascular plants.
  7. Defining the ATPome reveals cross-optimization of metabolic pathways.
  8. Mitofusin 2 in Macrophages Links Mitochondrial ROS Production, Cytokine Release, Phagocytosis, Autophagy, and Bactericidal Activity.
  9. Cytosolic ME1 integrated with mitochondrial IDH2 supports tumor growth and metastasis.
  10. The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes.
  11. Mitochondria Are Fundamental for the Emergence of Metazoans: On Metabolism, Genomic Regulation, and the Birth of Complex Organisms.
  12. Mito-Omics and immune function: Applying novel mitochondrial omic techniques to the context of the aging immune system.
  13. Silibinin Promotes Cell Proliferation Through Facilitating G1/S Transitions by Activating Drp1-Mediated Mitochondrial Fission in Cells.
  14. Induction of UCP1 and thermogenesis by a small molecule via AKAP1/PKA modulation.
  15. Supramolecular Induction of Mitochondrial Aggregation and Fusion.
  16. Mitochondrial control of cellular protein homeostasis.
  17. Mito-oncology agent: fermented extract suppresses the Warburg effect, restores oxidative mitochondrial activity, and inhibits in vivo tumor growth.
  18. Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers.
  19. Mitophagy is induced by short ubiquitin chains on mitochondria.
  20. The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model.
  21. Conditional Deletion of PGC-1α Results in Energetic and Functional Defects in NK Cells.
  1. J Cell Sci. 2020 Aug 25. pii: jcs.247593. [Epub ahead of print]
    An indispensable role for dynamin-related protein 1 (DRP1) in beige and brown adipogenesis.
    Raja Gopal Reddy Mooli, Dhanunjay Mukhi, Zhonghe Chen, Nia Buckner, Sadeesh K Ramakrishnan.
      Emerging evidence indicates that proper mitochondrial dynamics is critical for adipocyte differentiation and functional thermogenic capacity. We found that mitochondrial fission protein dynamin-related protein 1 (DRP1) is highly expressed in brown adipose tissue compared to white adipose tissue and their levels increase during brown adipocyte differentiation. Our results reveal that the inhibition of DRP1 using Mdivi-1 mitigates beige adipocyte differentiation and differentiation-associated mitochondrial biogenesis. We found that DRP1 is essential for the induction of the early phase beige adipogenic transcriptional program. Intriguingly, inhibition of DRP1 is dispensable following the induction of beige adipogenesis and adipogenesis-associated mitochondrial biogenesis. Together, we demonstrate that DRP1 in the preadipocytes plays an essential role in beige and brown adipogenesis.
    Keywords:  Adipogenesis; Beige adipocytes; Brown adipocytes; DRP1; Mitochondrial biogenesis
    DOI:  https://doi.org/10.1242/jcs.247593
  2. Nat Commun. 2020 Aug 27. 11(1): 4281
    The dynamic landscape of transcription initiation in yeast mitochondria.
    Byeong-Kwon Sohn, Urmimala Basu, Seung-Won Lee, Hayoon Cho, Jiayu Shen, Aishwarya Deshpande, Laura C Johnson, Kalyan Das, Smita S Patel, Hajin Kim.
      Controlling efficiency and fidelity in the early stage of mitochondrial DNA transcription is crucial for regulating cellular energy metabolism. Conformational transitions of the transcription initiation complex must be central for such control, but how the conformational dynamics progress throughout transcription initiation remains unknown. Here, we use single-molecule fluorescence resonance energy transfer techniques to examine the conformational dynamics of the transcriptional system of yeast mitochondria with single-base resolution. We show that the yeast mitochondrial transcriptional complex dynamically transitions among closed, open, and scrunched states throughout the initiation stage. Then abruptly at position +8, the dynamic states of initiation make a sharp irreversible transition to an unbent conformation with associated promoter release. Remarkably, stalled initiation complexes remain in dynamic scrunching and unscrunching states without dissociating the RNA transcript, implying the existence of backtracking transitions with possible regulatory roles. The dynamic landscape of transcription initiation suggests a kinetically driven regulation of mitochondrial transcription.
    DOI:  https://doi.org/10.1038/s41467-020-17793-2
  3. J Cell Sci. 2020 Aug 25. pii: jcs.248468. [Epub ahead of print]
    Mitochondrial import, health and mtDNA copy number variability using type II and type V CRISPR effectors.
    Zuriñe Antón, Grace Mullally, Holly Ford, Marc W van der Kamp, Mark D Szczelkun, Jon D Lane.
      Current methodologies for targeting the mitochondrial genome for research and/or therapy development in mitochondrial diseases are restricted by practical limitations and technical inflexibility. A molecular toolbox for CRISPR-mediated mitochondrial genome editing is desirable, as this could enable targeting of mtDNA haplotypes using the precision and tuneability of CRISPR enzymes. "MitoCRISPR" systems described to date lack reproducibility and independent corroboration. We have explored the requirements for MitoCRISPR in human cells by CRISPR nuclease engineering, including the use of alternative mitochondrial protein targeting sequences and smaller paralogues, and the application of gRNA modifications for mitochondrial import. We demonstrate varied mitochondrial targeting efficiencies and effects on mitochondrial dynamics/function of different CRISPR nucleases, with Lachnospiraceae bacterium ND2006 (Lb) Cas12a being better targeted and tolerated than Cas9 variants. We also provide evidence of Cas9 gRNA association with mitochondria in HeLa cells and isolated yeast mitochondria, even in the absence of a targeting RNA aptamer. Our data link mitochondrial-targeted LbCas12a/crRNA with increased mtDNA copy number dependent upon DNA binding and cleavage activity. We discuss reproducibility issues and the future steps necessary for MitoCRISPR.
    Keywords:  Cas12a; Cas9; CrRNA; GRNA; Import; MitoCRISPR; Targeting
    DOI:  https://doi.org/10.1242/jcs.248468
  4. Cell Rep. 2020 Aug 25. pii: S2211-1247(20)31044-5. [Epub ahead of print]32(8): 108059
    Mitochondrial Regulation of the 26S Proteasome.
    Thomas Meul, Korbinian Berschneider, Sabine Schmitt, Christoph H Mayr, Laura F Mattner, Herbert B Schiller, Ayse S Yazgili, Xinyuan Wang, Christina Lukas, Camille Schlesser, Cornelia Prehn, Jerzy Adamski, Elisabeth Graf, Thomas Schwarzmayr, Fabiana Perocchi, Alexandra Kukat, Aleksandra Trifunovic, Laura Kremer, Holger Prokisch, Bastian Popper, Christine von Toerne, Stefanie M Hauck, Hans Zischka, Silke Meiners.
      The proteasome is the main proteolytic system for targeted protein degradation in the cell and is fine-tuned according to cellular needs. Here, we demonstrate that mitochondrial dysfunction and concomitant metabolic reprogramming of the tricarboxylic acid (TCA) cycle reduce the assembly and activity of the 26S proteasome. Both mitochondrial mutations in respiratory complex I and treatment with the anti-diabetic drug metformin impair 26S proteasome activity. Defective 26S assembly is reversible and can be overcome by supplementation of aspartate or pyruvate. This metabolic regulation of 26S activity involves specific regulation of proteasome assembly factors via the mTORC1 pathway. Of note, reducing 26S activity by metformin confers increased resistance toward the proteasome inhibitor bortezomib, which is reversible upon pyruvate supplementation. Our study uncovers unexpected consequences of defective mitochondrial metabolism for proteasomal protein degradation in the cell, which has important pathophysiological and therapeutic implications.
    Keywords:  26S proteasome; Rpn6; TCA; aspartate; metabolic reprogramming; metformin; mitochondria; proteasome assembly factors; proteasome inhibitor resistance; pyruvate; respiratory complex I
    DOI:  https://doi.org/10.1016/j.celrep.2020.108059
  5. Nat Commun. 2020 Aug 28. 11(1): 4269
    Complete chemical structures of human mitochondrial tRNAs.
    Takeo Suzuki, Yuka Yashiro, Ittoku Kikuchi, Yuma Ishigami, Hironori Saito, Ikuya Matsuzawa, Shunpei Okada, Mari Mito, Shintaro Iwasaki, Ding Ma, Xuewei Zhao, Kana Asano, Huan Lin, Yohei Kirino, Yuriko Sakaguchi, Tsutomu Suzuki.
      Mitochondria generate most cellular energy via oxidative phosphorylation. Twenty-two species of mitochondrial (mt-)tRNAs encoded in mtDNA translate essential subunits of the respiratory chain complexes. mt-tRNAs contain post-transcriptional modifications introduced by nuclear-encoded tRNA-modifying enzymes. They are required for deciphering genetic code accurately, as well as stabilizing tRNA. Loss of tRNA modifications frequently results in severe pathological consequences. Here, we perform a comprehensive analysis of post-transcriptional modifications of all human mt-tRNAs, including 14 previously-uncharacterized species. In total, we find 18 kinds of RNA modifications at 137 positions (8.7% in 1575 nucleobases) in 22 species of human mt-tRNAs. An up-to-date list of 34 genes responsible for mt-tRNA modifications are provided. We identify two genes required for queuosine (Q) formation in mt-tRNAs. Our results provide insight into the molecular mechanisms underlying the decoding system and could help to elucidate the molecular pathogenesis of human mitochondrial diseases caused by aberrant tRNA modifications.
    DOI:  https://doi.org/10.1038/s41467-020-18068-6
  6. Elife. 2020 Aug 25. pii: e56664. [Epub ahead of print]9
    Atomic structure of a mitochondrial complex I intermediate from vascular plants.
    Maria Maldonado, Abhilash Padavannil, Long Zhou, Fei Guo, James A Letts.
      Respiration, an essential metabolic process, provides cells with chemical energy. In eukaryotes, respiration occurs via the mitochondrial electron transport chain (mETC) composed of several large membrane-protein complexes. Complex I (CI) is the main entry point for electrons into the mETC. For plants, limited availability of mitochondrial material has curbed detailed biochemical and structural studies of their mETC. Here, we present the cryoEM structure of the known CI assembly intermediate CI* from Vigna radiata at 3.9 Å resolution. CI* contains CI's NADH-binding and CoQ-binding modules, the proximal-pumping module and the plant-specific γ-carbonic-anhydrase domain (γCA). Our structure reveals significant differences in core and accessory subunits of the plant complex compared to yeast, mammals and bacteria, as well as the details of the γCA domain subunit composition and membrane anchoring. The structure sheds light on differences in CI assembly across lineages and suggests potential physiological roles for CI* beyond assembly.
    Keywords:  Vigna radiata; assembly; biochemistry; chemical biology; complex I; electron microscopy; mitochondria; molecular biophysics; respiration; structural biology
    DOI:  https://doi.org/10.7554/eLife.56664
  7. Nat Commun. 2020 Aug 28. 11(1): 4319
    Defining the ATPome reveals cross-optimization of metabolic pathways.
    Neal K Bennett, Mai K Nguyen, Maxwell A Darch, Hiroki J Nakaoka, Derek Cousineau, Johanna Ten Hoeve, Thomas G Graeber, Markus Schuelke, Emin Maltepe, Martin Kampmann, Bryce A Mendelsohn, Jean L Nakamura, Ken Nakamura.
      Disrupted energy metabolism drives cell dysfunction and disease, but approaches to increase or preserve ATP are lacking. To generate a comprehensive metabolic map of genes and pathways that regulate cellular ATP-the ATPome-we conducted a genome-wide CRISPR interference/activation screen integrated with an ATP biosensor. We show that ATP level is modulated by distinct mechanisms that promote energy production or inhibit consumption. In our system HK2 is the greatest ATP consumer, indicating energy failure may not be a general deficiency in producing ATP, but rather failure to recoup the ATP cost of glycolysis and diversion of glucose metabolites to the pentose phosphate pathway. We identify systems-level reciprocal inhibition between the HIF1 pathway and mitochondria; glycolysis-promoting enzymes inhibit respiration even when there is no glycolytic ATP production, and vice versa. Consequently, suppressing alternative metabolism modes paradoxically increases energy levels under substrate restriction. This work reveals mechanisms of metabolic control, and identifies therapeutic targets to correct energy failure.
    DOI:  https://doi.org/10.1038/s41467-020-18084-6
  8. Cell Rep. 2020 Aug 25. pii: S2211-1247(20)31064-0. [Epub ahead of print]32(8): 108079
    Mitofusin 2 in Macrophages Links Mitochondrial ROS Production, Cytokine Release, Phagocytosis, Autophagy, and Bactericidal Activity.
    Juan Tur, Selma Pereira-Lopes, Tania Vico, Eros A Marín, Juan P Muñoz, Maribel Hernández-Alvarez, Pere-Joan Cardona, Antonio Zorzano, Jorge Lloberas, Antonio Celada.
      Mitofusin 2 (Mfn2) plays a major role in mitochondrial fusion and in the maintenance of mitochondria-endoplasmic reticulum contact sites. Given that macrophages play a major role in inflammation, we studied the contribution of Mfn2 to the activity of these cells. Pro-inflammatory stimuli such as lipopolysaccharide (LPS) induced Mfn2 expression. The use of the Mfn2 and Mfn1 myeloid-conditional knockout (KO) mouse models reveals that Mfn2 but not Mfn1 is required for the adaptation of mitochondrial respiration to stress conditions and for the production of reactive oxygen species (ROS) upon pro-inflammatory activation. Mfn2 deficiency specifically impairs the production of pro-inflammatory cytokines and nitric oxide. In addition, the lack of Mfn2 but not Mfn1 is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. Mfn2floxed;CreLysM mice fail to be protected from Listeria, Mycobacterium tuberculosis, or LPS endotoxemia. These results reveal an unexpected contribution of Mfn2 to ROS production and inflammation in macrophages.
    Keywords:  apoptotic bodies; inflammation; lipopolysaccharide (LPS); macrophages; mitochondria; mitofusin; phagocytosis; protein degradation; reactive oxygen species (ROS); septic shock
    DOI:  https://doi.org/10.1016/j.celrep.2020.108079
  9. Redox Biol. 2020 Aug 13. pii: S2213-2317(20)30890-9. [Epub ahead of print]36 101685
    Cytosolic ME1 integrated with mitochondrial IDH2 supports tumor growth and metastasis.
    Chang Shao, Wenjie Lu, Ye Du, Wenchao Yan, Qiuyu Bao, Yang Tian, Guangji Wang, Hui Ye, Haiping Hao.
      NADPH is a pivotal cofactor that maintains redox homeostasis and lipogenesis in cancer cells and interference with NADPH production is a promising approach for treating cancer. However, how normal and cancer cells differentially exploit NADPH-producing pathways is unclear, and selective approaches to targeting NADPH are lacking. Here, we show that the assayed cancer cell lines preferentially depend on ME1-mediated NADPH production. ME1 knockdown increases intracellular ROS levels and impairs lipogenesis in cancer cells, leading to retarded proliferation and increased anoikis, while sparing normal cells. Notably, ME1 interference ultimately resulted in adaptive upregulation of mitochondrial IDH2 dependent of AMPK-FoxO1 activation to replenish the NADPH pool and mitigate cytosolic ROS. Combining ME1 ablation and IDH2 inhibition drastically reduces intracellular NADPH and prevents resistance to ME1 interference, resulting in increased apoptosis and impeded tumor growth and metastasis. This study demonstrates that cytosolic ME1 integrated with mitochondrial IDH2 is essential for tumor growth and metastasis, thereby highlighting the blockade of metabolic compensation by disrupting mitochondrial-cytosol NADPH transport as a promising approach to selectively targeting NADPH in cancer cells that rely on NADPH-driven antioxidant systems.
    Keywords:  IDH2; ME1; Metabolic adaptability; NADPH; ROS; Reductive carboxylation
    DOI:  https://doi.org/10.1016/j.redox.2020.101685
  10. Life (Basel). 2020 Aug 26. pii: E164. [Epub ahead of print]10(9):
    The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes.
    James Chapman, Yi Shiau Ng, Thomas J Nicholls.
      Mitochondria are complex organelles that harbour their own genome. Mitochondrial DNA (mtDNA) exists in the form of a circular double-stranded DNA molecule that must be replicated, segregated and distributed around the mitochondrial network. Human cells typically possess between a few hundred and several thousand copies of the mitochondrial genome, located within the mitochondrial matrix in close association with the cristae ultrastructure. The organisation of mtDNA around the mitochondrial network requires mitochondria to be dynamic and undergo both fission and fusion events in coordination with the modulation of cristae architecture. The dysregulation of these processes has profound effects upon mtDNA replication, manifesting as a loss of mtDNA integrity and copy number, and upon the subsequent distribution of mtDNA around the mitochondrial network. Mutations within genes involved in mitochondrial dynamics or cristae modulation cause a wide range of neurological disorders frequently associated with defects in mtDNA maintenance. This review aims to provide an understanding of the biological mechanisms that link mitochondrial dynamics and mtDNA integrity, as well as examine the interplay that occurs between mtDNA, mitochondrial dynamics and cristae structure.
    Keywords:  cristae; mitochondria; mitochondrial diseas; mitochondrial fission; mitochondrial fusion; mtDNA
    DOI:  https://doi.org/10.3390/life10090164
  11. Annu Rev Genet. 2020 Aug 28.
    Mitochondria Are Fundamental for the Emergence of Metazoans: On Metabolism, Genomic Regulation, and the Birth of Complex Organisms.
    Hadar Medini, Tal Cohen, Dan Mishmar.
      Out of many intracellular bacteria, only the mitochondria and chloroplasts abandoned their independence billions of years ago and became endosymbionts within the host eukaryotic cell. Consequently, one cannot grow eukaryotic cells without their mitochondria, and the mitochondria cannot divide outside of the cell, thus reflecting interdependence. Here, we argue that such interdependence underlies the fundamental role of mitochondrial activities in the emergence of metazoans. Several lines of evidence support our hypothesis: (a) Differentiation and embryogenesis rely on mitochondrial function; (b) mitochondrial metabolites are primary precursors for epigenetic modifications (such as methyl and acetyl), which are critical for chromatin remodeling and gene expression, particularly during differentiation and embryogenesis; (c) mitonuclear coregulation adapted to accommodate both housekeeping and tissue-dependent metabolic needs. We discuss the evolution of the unique mitochondrial genetic system, mitochondrial metabolites, mitonuclear coregulation, and their critical roles in the emergence of metazoans and in human disorders. Expected final online publication date for the Annual Review of Genetics, Volume 54 is November 23, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-genet-021920-105545
  12. Transl Med Aging. 2020 Aug 21.
    Mito-Omics and immune function: Applying novel mitochondrial omic techniques to the context of the aging immune system.
    Affiliations Ana R Silverstein, Melanie Flores, Brendan Miller, Su-Jeong Kim, Kelvin Yen, Hemal H Mehta, Pinchas Cohen.
      Recent advancements in genomic, transcriptomic, proteomic, and metabolomic techniques have prompted fresh inquiry in the field of aging. Here, we outline the application of these techniques in the context of the mitochondrial genome and suggest their potential for use in exploring the biological mechanisms of the aging immune system.
    Keywords:  Genomics; Immune function; Mitochondria; Proteomics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.tma.2020.08.001
  13. Cell Transplant. 2020 Jan-Dec;29:29 963689720950213
    Silibinin Promotes Cell Proliferation Through Facilitating G1/S Transitions by Activating Drp1-Mediated Mitochondrial Fission in Cells.
    Yanting You, Liqian Chen, Yifen Wu, Ming Wang, Hanqi Lu, Xinghong Zhou, Huaxi Liu, Zixuan Fu, Qiuxing He, Jinying Ou, Xiuqiong Fu, Yanyan Liu, Hiuyee Kwan, Donghui Liang, Xiaoshan Zhao, Jiaojiao Dai.
      Heart, liver, and kidney, which are known as the essential organs for metabolism, possess the unique ability to regulate the proliferation function of the body against injury. Silibinin (SB), a natural polyphenolic flavonoid extracted from traditional herb Silybum marianum L., has been used to protect hepatocytes. Whether SB can regulate mitochondrial fission in normal cells and the underlying mechanisms remain unclear. Here, we showed that SB markedly promoted cell proliferation by facilitating G1/S transition via activating dynamin-related protein 1 (Drp1), which in turn mediated mitochondrial fission in these normal cells. SB dose-dependently increased the mitochondrial mass, mtDNA copy number, cellular adenosine triphosphate production, mitochondrial membrane potential, and reactive oxygen species in normal cells. Furthermore, SB dose-dependently increased the expression of Drp1. Blocking Drp1 abolished SB-induced mitochondrial fission. In conclusion, we demonstrate that SB promotes cell proliferation through facilitating G1/S transition by activating Drp1-mediated mitochondrial fission. This study suggests that SB is a potentially useful herbal derivative for the daily prevention of various diseases caused by impaired mitochondrial fission.
    Keywords:  G1/S cell cycle; dynamin-related protein 1; mitochondrial fission; silibinin
    DOI:  https://doi.org/10.1177/0963689720950213
  14. J Biol Chem. 2020 Aug 27. pii: jbc.RA120.013322. [Epub ahead of print]
    Induction of UCP1 and thermogenesis by a small molecule via AKAP1/PKA modulation.
    Laurent Vergnes, Jason Y Lin, Graeme R Davies, Christopher D Church, Karen Reue.
      Strategies to increase energy expenditure are an attractive approach to reduce excess fat storage and body weight to improve metabolic health. In mammals, uncoupling protein-1 (UCP1) in brown and beige adipocytes uncouples fatty acid oxidation from ATP generation in mitochondria and promotes energy dissipation as heat. We set out to identify small molecules that enhance UCP1 levels and activity using a high-throughput screen of nearly 12,000 compounds in mouse brown adipocytes. We identified a family of compounds that increase Ucp1 expression and mitochondrial activity (including uncoupled respiration) in mouse brown adipocytes and human brown and white adipocytes. The mechanism of action may be through compound binding to A kinase anchoring protein (AKAP) 1, modulating its localization to mitochondria and its interaction with protein kinase A (PKA), a known node in the β-adrenergic signaling pathway. In mice, the hit compound increased body temperature, UCP1 protein levels, and thermogenic gene expression. Some of the compound effects on mitochondrial function were UCP1- or AKAP1-independent, suggesting compound effects on multiple nodes of energy regulation. Overall, our results highlight a role for AKAP1 in thermogenesis, uncoupled respiration, and regulation energy balance.
    Keywords:  A-kinase anchoring protein (AKAP); adipocyte; mitochondrial metabolism; protein kinase A (PKA); uncoupling protein
    DOI:  https://doi.org/10.1074/jbc.RA120.013322
  15. J Am Chem Soc. 2020 Aug 26.
    Supramolecular Induction of Mitochondrial Aggregation and Fusion.
    Chen Sun, Ziyi Wang, Ludan Yue, Qiaoxian Huang, Qian Cheng, Ruibing Wang.
      Mitochondrial fission is often associated with the development of oxidative stress related diseases, as the fragmentation of mitochondria undermines their membranes, advances production of reactive oxygen species, and promotes apoptosis. Therefore, induction of mitochondrial aggregation and fusion could potentially reverse such medical conditions. Herein, a supramolecular strategy to induce mitochondrial aggregation and fusion is developed for the first time. A polyethylene glycol (PEG) system that was dually tagged with triphenylphosphonium (TPP) and adamantane (ADA), namely TPP-PEG-ADA, was designed to target mitochondria and functionalize their surfaces with ADA. Thereafter, the addition of cucurbit[7]uril (CB[7]) grafted hyaluronic acid (HA) induced supramolecular aggregation and fusion of mitochondria, via strong host-guest interactions between the CB[7] moiety of CB[7]-HA and ADA residing on the surface of mitochondria. As a proof-of-principle, chemically-stressed SH-SY5Y cells and zebrafish neurons were effectively protected via this supramolecular mitochondrial fusion strategy in vitro and in vivo, respectively. This study may open up new venues in not only fundamentally controlling mitochondrial dynamics, but also addressing the medical needs to treat diseases associated with mitochondrial fission and fragmentation.
    DOI:  https://doi.org/10.1021/jacs.0c06783
  16. Biochem J. 2020 Aug 28. 477(16): 3033-3054
    Mitochondrial control of cellular protein homeostasis.
    Karthik Mohanraj, Urszula Nowicka, Agnieszka Chacinska.
      Mitochondria are involved in several vital functions of the eukaryotic cell. The majority of mitochondrial proteins are coded by nuclear DNA. Constant import of proteins from the cytosol is a prerequisite for the efficient functioning of the organelle. The protein import into mitochondria is mediated by diverse import pathways and is continuously under watch by quality control systems. However, it is often challenged by both internal and external factors, such as oxidative stress or energy shortage. The impaired protein import and biogenesis leads to the accumulation of mitochondrial precursor proteins in the cytosol and activates several stress response pathways. These defense mechanisms engage a network of processes involving transcription, translation, and protein clearance to restore cellular protein homeostasis. In this review, we provide a comprehensive analysis of various factors and processes contributing to mitochondrial stress caused by protein biogenesis failure and summarize the recovery mechanisms employed by the cell.
    Keywords:  mitochondrial dysfunction; oxidative stress; protein import; protein misfolding; translation
    DOI:  https://doi.org/10.1042/BCJ20190654
  17. Sci Rep. 2020 Aug 25. 10(1): 14174
    Mito-oncology agent: fermented extract suppresses the Warburg effect, restores oxidative mitochondrial activity, and inhibits in vivo tumor growth.
    Gyula Bencze, Szilvia Bencze, Keith D Rivera, James D Watson, Laszlo Orfi, Nicholas K Tonks, Darryl J Pappin.
      Mitochondrial dysfunction and significant changes in metabolic pathways accompany cancer development and are responsible for maintaining the tumor microenvironment. Normal mitochondria can trigger intrinsic apoptosis by releasing cytochrome c into the cytosol. The survival of malignant cells highly depends on the suppression of this function. We validated that A250, a highly purified fraction of fermented wheat germ extract (FWGE), increases the carbon flux into the mitochondria, the expression of key elements of the Krebs cycle and oxidative phosphorylation (OXPHOS). The increased respiratory chain activity is related to the mitochondria's ability to release cytochrome c into the cytosol, which triggers the apoptotic cascade. The 68% tumor growth inhibitory effect observed in the murine melanoma study is related to this effect, as proteomic analysis validated similar changes in mitochondrial protein levels in the isolated tumor tissue samples. Blood count data indicated that this effect was not accompanied by general toxicity. This study is significant, as it shows that a highly concentrated form of FWGE is an effective agent that increases normal mitochondrial functionality. The lack of hepatotoxic and general toxic effects makes A250 an excellent candidate targeting mitochondria function in cancer therapy.
    DOI:  https://doi.org/10.1038/s41598-020-71118-3
  18. Int J Mol Sci. 2020 Aug 22. pii: E6052. [Epub ahead of print]21(17):
    Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers.
    Rosita Curcio, Paola Lunetti, Vincenzo Zara, Alessandra Ferramosca, Federica Marra, Giuseppe Fiermonte, Anna Rita Cappello, Francesco De Leonardis, Loredana Capobianco, Vincenza Dolce.
      Mitochondrial carriers are a family of structurally related proteins responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. The in silico analysis of the Drosophila melanogaster genome has highlighted the presence of 48 genes encoding putative mitochondrial carriers, but only 20 have been functionally characterized. Despite most Drosophila mitochondrial carrier genes having human homologs and sharing with them 50% or higher sequence identity, D. melanogaster genes display peculiar differences from their human counterparts: (1) in the fruit fly, many genes encode more transcript isoforms or are duplicated, resulting in the presence of numerous subfamilies in the genome; (2) the expression of the energy-producing genes in D. melanogaster is coordinated from a motif known as Nuclear Respiratory Gene (NRG), a palindromic 8-bp sequence; (3) fruit-fly duplicated genes encoding mitochondrial carriers show a testis-biased expression pattern, probably in order to keep a duplicate copy in the genome. Here, we review the main features, biological activities and role in the metabolism of the D. melanogaster mitochondrial carriers characterized to date, highlighting similarities and differences with their human counterparts. Such knowledge is very important for obtaining an integrated view of mitochondrial function in D. melanogaster metabolism.
    Keywords:  Drosophila melanogaster; SLC25; membrane transport; mitochondria; mitochondrial carrier; mitochondrial metabolism; mitochondrial transporter; proteoliposomes
    DOI:  https://doi.org/10.3390/ijms21176052
  19. J Cell Biol. 2020 Sep 07. pii: e202008031. [Epub ahead of print]219(9):
    Mitophagy is induced by short ubiquitin chains on mitochondria.
    Fumiyo Ikeda.
      Mitophagy has a critical role in maintaining cellular homeostasis by removing damaged mitochondria. In this issue, Yamano et al. (2020. J. Cell Biol. https://doi.org/10.1083/jcb.201912144) uncover that a novel complex of the autophagy adaptor optineurin and the membrane protein ATG9A specifically regulate ubiquitin-induced mitophagy.
    DOI:  https://doi.org/10.1083/jcb.202008031
  20. Dis Model Mech. 2020 Aug 28. pii: dmm.044925. [Epub ahead of print]
    The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model.
    Éva Saskői, Zoltán Hujber, Gábor Nyírő, István Likó, Barbara Mátyási, Gábor Petővári, Katalin Mészáros, Attila L Kovács, László Patthy, Shreyas Supekar, Hao Fan, Gergely Sváb, László Tretter, Arunabh Sarkar, Aamir Nazir, Anna Sebestyén, Attila Patócs, Anil Mehta, Krisztina Takács-Vellai.
      The conserved B-subunit of succinate dehydrogenase (SDH) participates in the TCA cycle and mitochondrial electron transport. The Arg230His mutation in SDHB causes heritable pheochromocytoma/paraganglioma (PPGL). In C. elegans, we generated an in vivo PPGL model (SDHB-1 Arg244His; equivalent to human Arg230His) which manifests delayed development, shortened lifespan, attenuated ATP production and reduced mitochondrial number. Although succinate is elevated in both missense and null sdhb-1(gk165) mutants, transcriptomic comparison suggests very different causal mechanisms that are supported by metabolic analysis where only Arg244His (not null) worms elevate lactate/pyruvate levels, pointing to a missense-induced, 'Warburg'-like aberrant glycolysis. In silico predictions of the SDHA-B dimer structure demonstrate that Arg230His modifies the catalytic cleft despite the latter's remoteness from the mutation site. We hypothesise that Arg230His SDHB mutation rewires metabolism, reminiscent of metabolic reprogramming in cancer. Our tractable model provides a novel tool to investigate the metastatic propensity of this familial cancer and our approach may illuminate wider SDH pathology.
    Keywords:  C. elegans; Cancer; Familial Paraganglioma Syndrome (FPS); Succinate dehydrogenase; TCA cycle; Warburg-like glycolysis
    DOI:  https://doi.org/10.1242/dmm.044925
  21. iScience. 2020 Aug 13. pii: S2589-0042(20)30646-5. [Epub ahead of print]23(9): 101454
    Conditional Deletion of PGC-1α Results in Energetic and Functional Defects in NK Cells.
    Zachary J Gerbec, Elaheh Hashemi, Arash Nanbakhsh, Sandra Holzhauer, Chao Yang, Ao Mei, Shirng-Wern Tsaih, Angela Lemke, Michael J Flister, Matthew J Riese, Monica S Thakar, Subramaniam Malarkannan.
      During an immune response, natural killer (NK) cells activate specific metabolic pathways to meet the increased energetic and biosynthetic demands associated with effector functions. Here, we found in vivo activation of NK cells during Listeria monocytogenes infection-augmented transcription of genes encoding mitochondria-associated proteins in a manner dependent on the transcriptional coactivator PGC-1α. Using an Ncr1Cre-based conditional knockout mouse, we found that PGC-1α was crucial for optimal NK cell effector functions and bioenergetics, as the deletion of PGC-1α was associated with decreased cytotoxic potential and cytokine production along with altered ADP/ATP ratios. Lack of PGC-1α also significantly impaired the ability of NK cells to control B16F10 tumor growth in vivo, and subsequent gene expression analysis showed that PGC-1α mediates transcription required to maintain mitochondrial activity within the tumor microenvironment. Together, these data suggest that PGC-1α-dependent transcription of specific target genes is required for optimal NK cell function during the response to infection or tumor growth.
    Keywords:  Biological Sciences; Cancer; Cellular Physiology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2020.101454
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