bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒08‒14
thirteen papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Mitochondrial double-stranded RNAs govern the stress response in chondrocytes to promote osteoarthritis development.
  2. IGF-1 receptor regulates upward firing rate homeostasis via the mitochondrial calcium uniporter.
  3. Lipid droplets promote efficient mitophagy.
  4. Calcium, mitochondria and the initiation of acute pancreatitis.
  5. OPA1 regulation of mitochondrial dynamics in skeletal and cardiac muscle.
  6. Oligomeric CHMP7 mediates three-way ER junctions and ER-mitochondria interactions.
  7. Stressed to death: Mitochondrial stress responses connect respiration and apoptosis in cancer.
  8. Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice.
  9. Endoplasmic Reticulum Architecture and Inter-Organelle Communication in Metabolic Health and Disease.
  10. The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene affecting SIRT3 functions.
  11. High-content screening of mitochondrial polarization in neural cells derived from human pluripotent stem cells.
  12. Come on mtDNA, light my fire.
  13. Clonal hematopoiesis, inflammation, and cardiovascular disorders: a mitochondrial connection.
  1. Cell Rep. 2022 Aug 09. pii: S2211-1247(22)00991-3. [Epub ahead of print]40(6): 111178
    Mitochondrial double-stranded RNAs govern the stress response in chondrocytes to promote osteoarthritis development.
    Sujin Kim, Keonyong Lee, Yong Seok Choi, Jayoung Ku, Hyeonkyeong Kim, Raisa Kharbash, Jimin Yoon, Yong Seuk Lee, Jin-Hong Kim, Yun Jong Lee, Yoosik Kim.
      Protein kinase R (PKR) is an immune response protein that becomes activated by double-stranded RNAs (dsRNAs). PKR overactivation is associated with degenerative diseases with inflammation, including osteoarthritis (OA), but the dsRNA activator remains largely unknown. Here, we find that mitochondrial dsRNA (mt-dsRNA) expression and its cytosolic efflux are facilitated in chondrocytes under OA-eliciting conditions, leading to innate immune activation. Moreover, mt-dsRNAs are released to the extracellular space and activate Toll-like receptor 3 at the plasma membrane. Elevated levels of mt-dsRNAs in the synovial fluids and damaged cartilage of OA patients and in the cartilage of surgery-induced OA mice further support our data. Importantly, autophagy prevents PKR activation and protects chondrocytes from mitochondrial stress partly by removing cytosolic mtRNAs. Our study provides a comprehensive understanding of innate immune activation by mt-dsRNAs during stress responses that underlie the development of OA and suggests mt-dsRNAs as a potential target for chondroprotective intervention.
    Keywords:  CP: Molecular biology; autophagy; innate immune response; mitochondrial double-stranded RNA; osteoarthritis; protein kinase R
    DOI:  https://doi.org/10.1016/j.celrep.2022.111178
  2. Proc Natl Acad Sci U S A. 2022 Aug 16. 119(33): e2121040119
    IGF-1 receptor regulates upward firing rate homeostasis via the mitochondrial calcium uniporter.
    Maxim Katsenelson, Ilana Shapira, Eman Abbas, Kristina Jevdokimenko, Boaz Styr, Antonella Ruggiero, Saba Aïd, Eugenio F Fornasiero, Martin Holzenberger, Silvio O Rizzoli, Inna Slutsky.
      Regulation of firing rate homeostasis constitutes a fundamental property of central neural circuits. While intracellular Ca2+ has long been hypothesized to be a feedback control signal, the molecular machinery enabling a network-wide homeostatic response remains largely unknown. We show that deletion of insulin-like growth factor-1 receptor (IGF-1R) limits firing rate homeostasis in response to inactivity, without altering the distribution of baseline firing rates. The deficient firing rate homeostatic response was due to disruption of both postsynaptic and intrinsic plasticity. At the cellular level, we detected a fraction of IGF-1Rs in mitochondria, colocalized with the mitochondrial calcium uniporter complex (MCUc). IGF-1R deletion suppressed transcription of the MCUc members and burst-evoked mitochondrial Ca2+ (mitoCa2+) by weakening mitochondria-to-cytosol Ca2+ coupling. Overexpression of either mitochondria-targeted IGF-1R or MCUc in IGF-1R-deficient neurons was sufficient to rescue the deficits in burst-to-mitoCa2+ coupling and firing rate homeostasis. Our findings indicate that mitochondrial IGF-1R is a key regulator of the integrated homeostatic response by tuning the reliability of burst transfer by MCUc. Based on these results, we propose that MCUc acts as a homeostatic Ca2+ sensor. Faulty activation of MCUc may drive dysregulation of firing rate homeostasis in aging and in brain disorders associated with aberrant IGF-1R/MCUc signaling.
    Keywords:  IGF-1 receptor; MCU; firing rate homeostasis; homeostatic plasticity; mitochonria
    DOI:  https://doi.org/10.1073/pnas.2121040119
  3. Autophagy. 2022 Aug 08. 1-2
    Lipid droplets promote efficient mitophagy.
    Maeve Long, Thomas G McWilliams.
      Mitophagy neutralizes defective mitochondria via lysosomal elimination. Increased levels of mitophagy hallmark metabolic transitions and are induced by iron depletion, yet its metabolic basis has not been studied in-depth. How mitophagy integrates with different homeostatic mechanisms to support metabolic integrity is incompletely understood. We examined metabolic adaptations in cells treated with deferiprone (DFP), a therapeutic iron chelator known to induce PINK1-PRKN-independent mitophagy. We found that iron depletion profoundly rewired the cellular metabolome, remodeling lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurs upstream of mitochondrial turnover, with many LDs bordering mitochondria upon iron chelation. Surprisingly, DGAT1 inhibition restricts mitophagy in vitro by lysosomal dysfunction. Genetic depletion of mdy/DGAT1 in vivo impairs neuronal mitophagy and locomotor function in Drosophila, demonstrating the physiological relevance of our findings.
    Keywords:  DGAT1; iron; lipid droplet; metabolism; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2089956
  4. Pancreatology. 2022 Aug 03. pii: S1424-3903(22)00466-5. [Epub ahead of print]
    Calcium, mitochondria and the initiation of acute pancreatitis.
    Stephen J Pandol, Roberta A Gottlieb.
      Acute pancreatitis is characterized by necrosis of its parenchymal cells and influx and activation of inflammatory cells that further promote injury and necrosis. This review is intended to discuss the central role of disorders of calcium metabolism and mitochondrial dysfunction in the mechanism of pancreatitis development. The disorders are placed in context of calcium and mitochondria in physiologic function of the pancreas. Moreover, we discuss potential therapeutics for preventing pathologic calcium signals that injure mitochondria and interventions that promote the removal of injured mitochondria and regenerate new and heathy populations of mitochondria.
    Keywords:  Acute pancreatitis; Autophagy; Calcium; Inflammation; Mitochondria; Mitophagy; Necrosis
    DOI:  https://doi.org/10.1016/j.pan.2022.07.011
  5. Trends Endocrinol Metab. 2022 Aug 06. pii: S1043-2760(22)00134-5. [Epub ahead of print]
    OPA1 regulation of mitochondrial dynamics in skeletal and cardiac muscle.
    John Noone, Donal J O'Gorman, Helena C Kenny.
      The mitochondria are double-membrane organelles integral for energy metabolism. Mitochondrial dynamics is regulated by inner and outer mitochondrial membrane (IMM and OMM) proteins, which promote fission and fusion. Optic atrophy 1 (OPA1) regulates IMM fusion, prevents apoptosis, and is a key regulator of morphological change in skeletal and cardiac muscle physiology and pathophysiology. OPA1 fuses the inner membranes of adjacent mitochondria, allowing for an increase in oxidative phosphorylation (OXPHOS). Considering the importance of energy metabolism in whole-body physiology, OPA1 and its regulators have been proposed as novel targets for the treatment of skeletal muscle atrophy and heart failure. Here, we review the role and regulation of OPA1 in skeletal muscle and cardiac pathophysiology, epitomizing its critical role in the cell.
    Keywords:  exercise; heart; metabolism; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1016/j.tem.2022.07.003
  6. Cell Death Differ. 2022 Aug 12.
    Oligomeric CHMP7 mediates three-way ER junctions and ER-mitochondria interactions.
    Qingzhu Chu, Jingru Wang, Yuanjiao Du, Tiantian Zhou, Anbing Shi, Juan Xiong, Wei-Ke Ji, Lin Deng.
      In metazoans the endoplasmic reticulum (ER) undergoes extensive remodeling during the cell cycle. The endosomal sorting complexes required for transport (ESCRT) protein CHMP7 coordinates ESCRT-III dependent nuclear envelope reformation during mitotic exit. However, potential roles of ER-associated CHMP7 at non-mitotic stages remain unclear. Here we discovered a new role of CHMP7 in mediating three-way ER and ER-mitochondrial membrane contact sites (MCSs). We showed that CHMP7 localizes to multiple cellular membranes including the ER, mitochondrial-associated membranes (MAMs) and the outer mitochondrial membrane (OMM) via its N-terminal membrane-binding domain. CHMP7 undergoes dynamic assembly at three-way ER junctions and ER-mitochondrial MCSs through hydrophobic interactions among α helix-1 and α helix-2 of the C-terminal CHMP-like domain, which was required for tethering different organelles in vivo. Furthermore, CHMP7 mediates the formation of three-way ER junctions in parallel with Atlastins (ATLs). Importantly, CHMP7 also regulates ER-mitochondrial interactions and its depletion affects mitochondrial division independently of ESCRT complex. Taken together, our results suggest a direct role of CHMP7 in the formation of the ER contacts in interphase.
    DOI:  https://doi.org/10.1038/s41418-022-01048-2
  7. Mol Cell. 2022 Aug 09. pii: S1097-2765(22)00708-0. [Epub ahead of print]
    Stressed to death: Mitochondrial stress responses connect respiration and apoptosis in cancer.
    Jacob M Winter, Tarun Yadav, Jared Rutter.
      Mitochondrial energetics and respiration have emerged as important factors in how cancer cells respond to or evade apoptotic signals. The study of the functional connection between these two processes may provide insight into following questions old and new: how might we target respiration or downstream signaling pathways to amplify apoptotic stress in the context of cancer therapy? Why are respiration and apoptotic regulation housed in the same organelle? Here, we briefly review mitochondrial respiration and apoptosis and then focus on how the intersection of these two processes is regulated by cytoplasmic signaling pathways such as the integrated stress response.
    Keywords:  CRISPR; apoptosis; cancer; electron transport chain; integrated stress response; leukemia; mitochondria; oncology; oxidative phosphorylation; respiration; stress; venetoclax
    DOI:  https://doi.org/10.1016/j.molcel.2022.07.012
  8. Mol Metab. 2022 Aug 06. pii: S2212-8778(22)00129-6. [Epub ahead of print] 101560
    Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice.
    Patrick M Schaefer, Jessica Huang, Arrienne Butic, Caroline Perry, Tal Yardeni, Wendy Tan, Ryan Morrow, Joseph A Baur, Douglas C Wallace.
      OBJECTIVE: Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. Here we decipher the molecular underpinnings of ANT1-deficiency-mediated exercise intolerance.METHODS: This was achieved by correlating exercise physiology, mitochondrial function and metabolomics of mice deficient in ANT1 and comparing this to control mice.
    RESULTS: We demonstrate a peripheral limitation of skeletal muscle mitochondrial respiration and a reduced complex I respiration in ANT1-deficient mice. Upon exercise, this results in a lack of NAD+ leading to a substrate limitation and stalling of the TCA cycle and mitochondrial respiration, further limiting skeletal muscle mitochondrial respiration. Treatment of ANT1-deficient mice with nicotinamide riboside increased NAD+ levels in skeletal muscle and liver, which increased the exercise capacity and the mitochondrial respiration.
    CONCLUSION: Increasing NAD + levels with nicotinamide riboside can alleviate the exercise intolerance associated to ANT1-deficiency, indicating the therapeutic potential of NAD+-stimulating compounds in mitochondrial myopathies.
    Keywords:  Exercise; Mitochondrial disorder; NAD(+)/NADH; Nicotinamide riboside
    DOI:  https://doi.org/10.1016/j.molmet.2022.101560
  9. Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041261. [Epub ahead of print]
    Endoplasmic Reticulum Architecture and Inter-Organelle Communication in Metabolic Health and Disease.
    Ana Paula Arruda, Güneş Parlakgül.
      The endoplasmic reticulum (ER) is a key organelle involved in the regulation of lipid and glucose metabolism, proteostasis, Ca2+ signaling, and detoxification. The structural organization of the ER is very dynamic and complex, with distinct subdomains such as the nuclear envelope and the peripheral ER organized into ER sheets and tubules. ER also forms physical contact sites with all other cellular organelles and with the plasma membrane. Both form and function of the ER are highly adaptive, with a potent capacity to respond to transient changes in environmental cues such as nutritional fluctuations. However, under obesity-induced chronic stress, the ER fails to adapt, leading to ER dysfunction and the development of metabolic pathologies such as insulin resistance and fatty liver disease. Here, we discuss how the remodeling of ER structure and contact sites with other organelles results in diversification of metabolic function and how perturbations to this structural flexibility by chronic overnutrition contribute to ER dysfunction and metabolic pathologies in obesity.
    DOI:  https://doi.org/10.1101/cshperspect.a041261
  10. Metabolism. 2022 Aug 04. pii: S0026-0495(22)00153-6. [Epub ahead of print]135 155275
    The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene affecting SIRT3 functions.
    Zhiyao Fu, Hyunbae Kim, Paul T Morse, Mu-Jie Lu, Maik Hüttemann, Xiaolu A Cambronne, Kezhong Zhang, Ren Zhang.
      INTRODUCTION: Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism and energy production. NAD+-dependent deacetylase sirtuin 3 (SIRT3) regulates the acetylation levels of mitochondrial proteins that are involved in mitochondrial homeostasis. Fasting up-regulates hepatic SIRT3 activity, which requires mitochondrial NAD+. What is the mechanism, then, to transport more NAD+ into mitochondria to sustain enhanced SIRT3 activity during fasting?OBJECTIVE: SLC25A51 is a recently discovered mitochondrial NAD+ transporter. We tested the hypothesis that, during fasting, increased expression of SLC25A51 is needed for enhanced mitochondrial NAD+ uptake to sustain SIRT3 activity. Because the fasting-fed cycle and circadian rhythm are closely linked, we further tested the hypothesis that SLC25A51 is a circadian regulated gene.
    METHODS: We examined Slc25a51 expression in the liver of fasted mice, and examined its circadian rhythm in wild-type mice and those with liver-specific deletion of the clock gene BMAL1 (LKO). We suppressed Slc25a51 expression in hepatocytes and the mouse liver using shRNA-mediated knockdown, and then examined mitochondrial NAD+ levels, SIRT3 activities, and acetylation levels of SIRT3 target proteins (IDH2 and ACADL). We measured mitochondrial oxygen consumption rate using Seahorse analysis in hepatocytes with reduced Slc25a51 expression.
    RESULTS: We found that fasting induced the hepatic expression of Slc25a51, and its expression showed a circadian rhythm-like pattern that was disrupted in LKO mice. Reduced expression of Slc25a51 in hepatocytes decreased mitochondrial NAD+ levels and SIRT3 activity, reflected by increased acetylation of SIRT3 targets. Slc25a51 knockdown reduced the oxygen consumption rate in intact hepatocytes. Mice with reduced Slc25a51 expression in the liver manifested reduced hepatic mitochondrial NAD+ levels, hepatic steatosis and hypertriglyceridemia.
    CONCLUSIONS: Slc25a51 is a fasting-induced gene that is needed for hepatic SIRT3 functions.
    Keywords:  Mitochondria; NAD; SIRT3; SLC25A51
    DOI:  https://doi.org/10.1016/j.metabol.2022.155275
  11. STAR Protoc. 2022 Sep 16. 3(3): 101602
    High-content screening of mitochondrial polarization in neural cells derived from human pluripotent stem cells.
    Annika Zink, Undine Haferkamp, Annika Wittich, Mathias Beller, Ole Pless, Alessandro Prigione.
      We present a high-content screening (HCS) protocol for quantifying mitochondrial activity in live neural cells from human induced pluripotent stem cells (iPSCs). The assessment is based on mitochondrial membrane potential, which is influenced by the efficiency of mitochondrial bioenergetics. We describe how to perform the analysis using both an HCS platform and the open-source software CellProfiler. The protocol can identify the mitochondrial fitness of human neurons and may be used to carry out high-throughput compound screenings in patient-derived neural cells. For complete details on the use and execution of this protocol, please refer to Lorenz et al. (2017) and Zink et al. (2020).
    Keywords:  Cell Biology; Cell-based Assays; Metabolism; Microscopy; Neuroscience; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2022.101602
  12. Immunity. 2022 Aug 09. pii: S1074-7613(22)00345-4. [Epub ahead of print]55(8): 1331-1333
    Come on mtDNA, light my fire.
    Grace M E P Lawrence, Caroline L Holley, Kate Schroder.
      Oxidized mitochondrial DNA (ox-mtDNA) activates NLRP3 inflammasome signaling through an ill-defined mechanism. In this issue of Immunity, Xian et al. reveal FEN1 endonuclease cleaves ox-mtDNA into fragments that escape mitochondria, igniting NLRP3 and cGAS-STING signaling and inflammation.
    DOI:  https://doi.org/10.1016/j.immuni.2022.07.011
  13. Trends Immunol. 2022 Aug 06. pii: S1471-4906(22)00158-2. [Epub ahead of print]
    Clonal hematopoiesis, inflammation, and cardiovascular disorders: a mitochondrial connection.
    Francesco Pileri, Gioacchino Natoli.
      Mutations in two antagonistic regulators of DNA methylation, DNMT3A and TET2, are associated with clonal hematopoiesis and increased risk of cardiovascular disorders. Recently, Cobo et al. traced the mechanistic bases for such links to loss of mitochondrial integrity, cytoplasmic dispersion of mitochondrial DNA, and the subsequent activation of interferon-stimulated genes (ISGs) in macrophages.
    DOI:  https://doi.org/10.1016/j.it.2022.07.009
This page is being maintained by Thomas Krichel. It was last updated on 2022‒08‒15 at 14:13:01.