bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–02–12
23 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial Transplantation in Mitochondrial Medicine: Current Challenges and Future Perspectives.
  2. Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis.
  3. Mitochondrial-Derived Vesicles-Link to Extracellular Vesicles and Implications in Cardiovascular Disease.
  4. The Journey of Mitochondrial Protein Import and the Roadmap to Follow.
  5. Effectiveness and safety of CGRP monoclonal antibodies in migraine related to mitochondrial diseases in patients with NARP and PEO syndromes.
  6. Mitochondrial Transfer into Human Oocytes Improved Embryo Quality and Clinical Outcomes in Recurrent Pregnancy Failure Cases.
  7. L-arginine homeostasis governs adult neural stem cell activation by modulating energy metabolism in vivo.
  8. The Crosstalk between Microbiome and Mitochondrial Homeostasis in Neurodegeneration.
  9. Mitochondria: Emerging Consequential in Sickle Cell Disease.
  10. The role of mitochondrial energy metabolism in neuroprotection and axonal regeneration after spinal cord injury.
  11. Cardiolipin metabolism regulates expression of muscle transcription factor MyoD1 and muscle development.
  12. The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.
  13. Oxidized mitochondrial DNA: a protective signal gone awry.
  14. Intravenous AAV9 administration results in safe and widespread distribution of transgene in the brain of mini-pig.
  15. Myo19 tethers mitochondria to endoplasmic reticulum-associated actin to promote mitochondrial fission.
  16. The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
  17. Mitochondrial calcium cycling in neuronal function and neurodegeneration.
  18. Leber's Hereditary Optic Neuropathy with Mitochondrial DNA Mutation G11778A: A Systematic Literature Review and Meta-Analysis.
  19. Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle.
  20. An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration.
  21. Targeting the mitochondrial Ca2+ uniporter complex in cardiovascular disease.
  22. How hot can mitochondria be? Incubation at temperatures above 43 °C induces the degradation of respiratory complexes and supercomplexes in intact cells and isolated mitochondria.
  23. Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.
  1. Int J Mol Sci. 2023 Jan 19. pii: 1969. [Epub ahead of print]24(3):
    Mitochondrial Transplantation in Mitochondrial Medicine: Current Challenges and Future Perspectives.
    Marco D'Amato, Francesca Morra, Ivano Di Meo, Valeria Tiranti.
      Mitochondrial diseases (MDs) are inherited genetic conditions characterized by pathogenic mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Current therapies are still far from being fully effective and from covering the broad spectrum of mutations in mtDNA. For example, unlike heteroplasmic conditions, MDs caused by homoplasmic mtDNA mutations do not yet benefit from advances in molecular approaches. An attractive method of providing dysfunctional cells and/or tissues with healthy mitochondria is mitochondrial transplantation. In this review, we discuss what is known about intercellular transfer of mitochondria and the methods used to transfer mitochondria both in vitro and in vivo, and we provide an outlook on future therapeutic applications. Overall, the transfer of healthy mitochondria containing wild-type mtDNA copies could induce a heteroplasmic shift even when homoplasmic mtDNA variants are present, with the aim of attenuating or preventing the progression of pathological clinical phenotypes. In summary, mitochondrial transplantation is a challenging but potentially ground-breaking option for the treatment of various mitochondrial pathologies, although several questions remain to be addressed before its application in mitochondrial medicine.
    Keywords:  mitochondria; mitochondrial diseases; mitochondrial dysfunction; mitochondrial medicine; mitochondrial transplantation
    DOI:  https://doi.org/10.3390/ijms24031969
  2. Cell Metab. 2023 Feb 07. pii: S1550-4131(23)00003-7. [Epub ahead of print]35(2): 345-360.e7
    Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis.
    Joonho Suh, Na-Kyung Kim, Wonn Shim, Seung-Hoon Lee, Hyo-Jeong Kim, Eunyoung Moon, Hiromi Sesaki, Jae Hyuck Jang, Jung-Eun Kim, Yun-Sil Lee.
      Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we demonstrate that mitochondria and mitochondrial-derived vesicles (MDVs) are secreted from mature osteoblasts to promote differentiation of osteoprogenitors. We show that osteogenic induction stimulates mitochondrial fragmentation, donut formation, and secretion of mitochondria through CD38/cADPR signaling. Enhancing mitochondrial fission and donut formation through Opa1 knockdown or Fis1 overexpression increases mitochondrial secretion and accelerates osteogenesis. We also show that mitochondrial fusion promoter M1, which induces Opa1 expression, impedes osteogenesis, whereas osteoblast-specific Opa1 deletion increases bone mass. We further demonstrate that secreted mitochondria and MDVs enhance bone regeneration in vivo. Our findings suggest that mitochondrial morphology in mature osteoblasts is adapted for extracellular secretion, and secreted mitochondria and MDVs are critical promoters of osteogenesis.
    Keywords:  FIS1; M1; OPA1; donut mitochondria; mitochondria; mitochondrial secretion; mitochondrial transplantation; mitochondrial-derived vesicles; osteoblasts; osteogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2023.01.003
  3. Int J Mol Sci. 2023 Jan 30. pii: 2637. [Epub ahead of print]24(3):
    Mitochondrial-Derived Vesicles-Link to Extracellular Vesicles and Implications in Cardiovascular Disease.
    Jonas Heyn, Marina Augusto Heuschkel, Claudia Goettsch.
      Mitochondria are dynamic organelles regulating metabolism, cell death, and energy production. Therefore, maintaining mitochondrial health is critical for cellular homeostasis. Mitophagy and mitochondrial reorganization via fission and fusion are established mechanisms for ensuring mitochondrial quality. In recent years, mitochondrial-derived vesicles (MDVs) have emerged as a novel cellular response. MDVs are shed from the mitochondrial surface and can be directed to lysosomes or peroxisomes for intracellular degradation. MDVs may contribute to cardiovascular disease (CVD) which is characterized by mitochondrial dysfunction. In addition, evidence suggests that mitochondrial content is present in extracellular vesicles (EVs). Herein, we provide an overview of the current knowledge on MDV formation and trafficking. Moreover, we review recent findings linking MDV and EV biogenesis and discuss their role in CVD. Finally, we discuss the role of vesicle-mediated mitochondrial transfer and its potential cardioprotective effects.
    Keywords:  cardiovascular disease; extracellular vesicles; mitochondria; mitochondrial transfer; mitochondrial-derived vesicles
    DOI:  https://doi.org/10.3390/ijms24032637
  4. Int J Mol Sci. 2023 Jan 27. pii: 2479. [Epub ahead of print]24(3):
    The Journey of Mitochondrial Protein Import and the Roadmap to Follow.
    Mary Oluwadamilola Haastrup, Kunwar Somesh Vikramdeo, Seema Singh, Ajay Pratap Singh, Santanu Dasgupta.
      Mitochondria are double membrane-bound organelles that play critical functions in cells including metabolism, energy production, regulation of intrinsic apoptosis, and maintenance of calcium homeostasis. Mitochondria are fascinatingly equipped with their own genome and machinery for transcribing and translating 13 essential proteins of the oxidative phosphorylation system (OXPHOS). The rest of the proteins (99%) that function in mitochondria in the various pathways described above are nuclear-transcribed and synthesized as precursors in the cytosol. These proteins are imported into the mitochondria by the unique mitochondrial protein import system that consists of seven machineries. Proper functioning of the mitochondrial protein import system is crucial for optimal mitochondrial deliverables, as well as mitochondrial and cellular homeostasis. Impaired mitochondrial protein import leads to proteotoxic stress in both mitochondria and cytosol, inducing mitochondrial unfolded protein response (UPRmt). Altered UPRmt is associated with the development of various disease conditions including neurodegenerative and cardiovascular diseases, as well as cancer. This review sheds light on the molecular mechanisms underlying the import of nuclear-encoded mitochondrial proteins, the consequences of defective mitochondrial protein import, and the pathological conditions that arise due to altered UPRmt.
    Keywords:  diseases; mitochondria; mitochondrial protein import machineries; mitochondrial unfolded protein response; proteins
    DOI:  https://doi.org/10.3390/ijms24032479
  5. Clin Neurol Neurosurg. 2023 Jan 27. pii: S0303-8467(23)00027-6. [Epub ahead of print]226 107611
    Effectiveness and safety of CGRP monoclonal antibodies in migraine related to mitochondrial diseases in patients with NARP and PEO syndromes.
    Marcello Silvestro, Ilaria Orologio, Francesca Trojsi, Alessandro Tessitore, Gioacchino Tedeschi, Antonio Russo.
      
    Keywords:  CGRP; Migraine; Mitochondrial disease; NARP; PEO
    DOI:  https://doi.org/10.1016/j.clineuro.2023.107611
  6. Int J Mol Sci. 2023 Feb 01. pii: 2738. [Epub ahead of print]24(3):
    Mitochondrial Transfer into Human Oocytes Improved Embryo Quality and Clinical Outcomes in Recurrent Pregnancy Failure Cases.
    Yoshiharu Morimoto, Udayanga Sanath Kankanam Gamage, Takayuki Yamochi, Noriatsu Saeki, Naoharu Morimoto, Masaya Yamanaka, Akiko Koike, Yuki Miyamoto, Kumiko Tanaka, Aisaku Fukuda, Shu Hashimoto, Ryuzo Yanagimachi.
      One of the most critical issues to be solved in reproductive medicine is the treatment of patients with multiple failures of assisted reproductive treatment caused by low-quality embryos. This study investigated whether mitochondrial transfer to human oocytes improves embryo quality and provides subsequent acceptable clinical results and normality to children born due to the use of this technology. We transferred autologous mitochondria extracted from oogonia stem cells to mature oocytes with sperm at the time of intracytoplasmic sperm injection in 52 patients with recurrent failures (average 5.3 times). We assessed embryo quality using the following three methods: good-quality embryo rates, transferable embryo rates, and a novel embryo-scoring system (embryo quality score; EQS) in 33 patients who meet the preset inclusion criteria for analysis. We also evaluated the clinical outcomes of the in vitro fertilization and development of children born using this technology and compared the mtDNA sequences of the children and their mothers. The good-quality embryo rates, transferable embryo rates, and EQS significantly increased after mitochondrial transfer and resulted in 13 babies born in normal conditions. The mtDNA sequences were almost identical to the respective maternal sequences at the 83 major sites examined. Mitochondrial transfer into human oocytes is an effective clinical option to enhance embryo quality in recurrent in vitro fertilization-failure cases.
    Keywords:  clinical outcome; cognitive development; embryo quality; mitochondrial transfer; mtDNA
    DOI:  https://doi.org/10.3390/ijms24032738
  7. EMBO J. 2023 Feb 06. e112647
    L-arginine homeostasis governs adult neural stem cell activation by modulating energy metabolism in vivo.
    Mingyue Xu, Ye Guo, Min Wang, Xing Luo, Xuning Shen, Zhimin Li, Lei Wang, Weixiang Guo.
      Neurogenesis in the developing and adult brain is intimately linked to remodeling of cellular metabolism. However, it is still unclear how distinct metabolic programs and energy sources govern neural stem cell (NSC) behavior and subsequent neuronal differentiation. Here, we found that adult mice lacking the mitochondrial urea metabolism enzyme, Arginase-II (Arg-II), exhibited NSC overactivation, thereby leading to accelerated NSC pool depletion and decreased hippocampal neurogenesis over time. Mechanistically, Arg-II deficiency resulted in elevated L-arginine levels and induction of a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) caused by impaired attachment of hexokinase-I to mitochondria. Notably, selective inhibition of OXPHOS ameliorated NSC overactivation and restored abnormal neurogenesis in Arg-II deficient mice. Therefore, Arg-II-mediated intracellular L-arginine homeostasis directly influences the metabolic fitness of neural stem cells that is essential to maintain neurogenesis with age.
    Keywords:  Adult neurogenesis; Arginase-II; Hexokinase; L-arginine; NSC pool
    DOI:  https://doi.org/10.15252/embj.2022112647
  8. Cells. 2023 Jan 28. pii: 429. [Epub ahead of print]12(3):
    The Crosstalk between Microbiome and Mitochondrial Homeostasis in Neurodegeneration.
    Fivos Borbolis, Eirini Mytilinaiou, Konstantinos Palikaras.
      Mitochondria are highly dynamic organelles that serve as the primary cellular energy-generating system. Apart from ATP production, they are essential for many biological processes, including calcium homeostasis, lipid biogenesis, ROS regulation and programmed cell death, which collectively render them invaluable for neuronal integrity and function. Emerging evidence indicates that mitochondrial dysfunction and altered mitochondrial dynamics are crucial hallmarks of a wide variety of neurodevelopmental and neurodegenerative conditions. At the same time, the gut microbiome has been implicated in the pathogenesis of several neurodegenerative disorders due to the bidirectional communication between the gut and the central nervous system, known as the gut-brain axis. Here we summarize new insights into the complex interplay between mitochondria, gut microbiota and neurodegeneration, and we refer to animal models that could elucidate the underlying mechanisms, as well as novel interventions to tackle age-related neurodegenerative conditions, based on this intricate network.
    Keywords:  Alzheimer’s disease; Amyotrophic Lateral Sclerosis; Huntington’s disease; ageing; gut–brain axis; microbiome; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.3390/cells12030429
  9. J Clin Med. 2023 Jan 18. pii: 765. [Epub ahead of print]12(3):
    Mitochondria: Emerging Consequential in Sickle Cell Disease.
    Mohammad S Akhter, Hassan A Hamali, Hina Rashid, Gasim Dobie, Aymen M Madkhali, Abdullah A Mobarki, Johannes Oldenburg, Arijit Biswas.
      Advanced mitochondrial multi-omics indicate a multi-facet involvement of mitochondria in the physiology of the cell, changing the perception of mitochondria from being just the energy-generating organelles to organelles that highly influence cell structure, function, signaling, and cell fate. This sets mitochondrial dysfunction in the centerstage of numerous acquired and genetic diseases. Sickle cell disease is also being increasingly associated with mitochondrial anomalies and the pathophysiology of sickle cell disease finds mitochondria at crucial intersections in the pathological cascade. Altered mitophagy, increased ROS, and mitochondrial DNA all contribute to the condition and its severity. Such mitochondrial aberrations lead to consequent mitochondrial retention in red blood cells in sickle cell diseases, increased oxidation in the cellular environment, inflammation, worsened vaso-occlusive crisis, etc. There are increasing studies indicating mitochondrial significance in sickle cell disease, consequently providing an opportunity to target it for improving the outcomes of treatment. Identification of the impaired mitochondrial attributes in sickle cell disease and their modulation by therapeutic interventions can impart a better management of the disease. This review aims to describe the mitochondria in the perspective of sicke cell disease so as to provide the reader an overview of the emerging mitochondrial stance in sickle cell disease.
    Keywords:  ROS; mitochondria; mitochondrial retention; mtDNA; sickle cell disease
    DOI:  https://doi.org/10.3390/jcm12030765
  10. Mitochondrion. 2023 Feb 04. pii: S1567-7249(23)00009-0. [Epub ahead of print]69 57-63
    The role of mitochondrial energy metabolism in neuroprotection and axonal regeneration after spinal cord injury.
    Li Cheng, Bin Cai, Dezhi Lu, Hong Zeng.
      Mitochondrial dysfunction occurs in the early stage of axonal degeneration after spinal cord injury and involves oxidative stress, energy deficiency, imbalance of mitochondrial dynamics, etc., which play a key role in axonal degeneration and regeneration under physiological and pathological conditions. Failure of axonal regeneration can lead to long-term structural and functional damage. Several recent studies have shown that improved mitochondrial energy metabolism provides conditions for axonal regeneration and central nervous system repair. Here, we describe the role of mitochondrial energy metabolism in neuroprotection and axonal regeneration after spinal cord injury and review recent advances in targeted mitochondrial therapy.
    Keywords:  Axon regeneration; Energy metabolism; Mitochondria; Mitochondrial dysfunction; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.mito.2023.01.009
  11. J Biol Chem. 2023 Feb 03. pii: S0021-9258(23)00110-2. [Epub ahead of print] 102978
    Cardiolipin metabolism regulates expression of muscle transcription factor MyoD1 and muscle development.
    Linh Vo, Michael W Schmidtke, Nevton T Da Rosa-Junior, Mindong Ren, Michael Schlame, Miriam L Greenberg.
      The mitochondrial phospholipid cardiolipin (CL) is critical for numerous essential biological processes, including mitochondrial dynamics and energy metabolism. Mutations in the CL remodeling enzyme TAFAZZIN cause Barth syndrome (BTHS), a life-threatening genetic disorder that results in severe physiological defects, including cardiomyopathy, skeletal myopathy, and neutropenia. To study the molecular mechanisms whereby CL deficiency leads to skeletal myopathy, we carried out transcriptomic analysis of the TAFAZZIN-knockout (TAZ-KO) mouse myoblast C2C12 cell line. Our data indicated that cardiac and muscle development pathways are highly decreased in TAZ-KO cells, consistent with a previous report of defective myogenesis in this cell line. Interestingly, the muscle transcription factor myoblast determination protein 1 (MyoD1) is significantly repressed in TAZ-KO cells and TAZ-KO mouse hearts. Exogenous expression of MyoD1 rescued the myogenesis defects previously observed in TAZ-KO cells. Our data suggest that MyoD1 repression is caused by up-regulation of the MyoD1 negative regulator, homeobox protein Mohawk (MKX), and decreased Wnt signaling. Our findings reveal, for the first time, that CL metabolism regulates muscle differentiation through MyoD1 and identify the mechanism whereby MyoD1 is repressed in CL-deficient cells.
    DOI:  https://doi.org/10.1016/j.jbc.2023.102978
  12. Mol Cells. 2023 Feb 09.
    The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.
    Min-Ji Kim, Hoyul Lee, Dipanjan Chanda, Themis Thoudam, Hyeon-Ji Kang, Robert A Harris, In-Kyu Lee.
      Pyruvate metabolism, a key pathway in glycolysis and oxidative phosphorylation, is crucial for energy homeostasis and mitochondrial quality control (MQC), including fusion/fission dynamics and mitophagy. Alterations in pyruvate flux and MQC are associated with reactive oxygen species accumulation and Ca2+ flux into the mitochondria, which can induce mitochondrial ultrastructural changes, mitochondrial dysfunction and metabolic dysregulation. Perturbations in MQC are emerging as a central mechanism for the pathogenesis of various metabolic diseases, such as neurodegenerative diseases, diabetes and insulin resistance-related diseases. Mitochondrial Ca2+ regulates the pyruvate dehydrogenase complex (PDC), which is central to pyruvate metabolism, by promoting its dephosphorylation. Increase of pyruvate dehydrogenase kinase (PDK) is associated with perturbation of mitochondria-associated membranes (MAMs) function and Ca2+ flux. Pyruvate metabolism also plays an important role in immune cell activation and function, dysregulation of which also leads to insulin resistance and inflammatory disease. Pyruvate metabolism affects macrophage polarization, mitochondrial dynamics and MAM formation, which are critical in determining macrophage function and immune response. MAMs and MQCs have also been intensively studied in macrophage and T cell immunity. Metabolic reprogramming connected with pyruvate metabolism, mitochondrial dynamics and MAM formation are important to macrophages polarization (M1/M2) and function. T cell differentiation is also directly linked to pyruvate metabolism, with inhibition of pyruvate oxidation by PDKs promoting proinflammatory T cell polarization. This article provides a brief review on the emerging role of pyruvate metabolism in MQC and MAM function, and how dysfunction in these processes leads to metabolic and inflammatory diseases.
    Keywords:  T cell; macrophage; mitochondria quality control; mitochondria-associated membranes; pyruvate dehydrogenase complex; pyruvate dehydrogenase kinase
    DOI:  https://doi.org/10.14348/molcells.2023.2128
  13. Trends Immunol. 2023 Feb 02. pii: S1471-4906(23)00017-0. [Epub ahead of print]
    Oxidized mitochondrial DNA: a protective signal gone awry.
    Hongxu Xian, Michael Karin.
      Despite the emergence of mitochondria as key regulators of innate immunity, the mechanisms underlying the generation and release of immunostimulatory alarmins by stressed mitochondria remains nebulous. We propose that the major mitochondrial alarmin in myeloid cells is oxidized mitochondrial DNA (Ox-mtDNA). Fragmented Ox-mtDNA enters the cytosol where it activates the NLRP3 inflammasome and generates IL-1β, IL-18, and cGAS-STING to induce type I interferons and interferon-stimulated genes. Inflammasome activation further enables the circulatory release of Ox-mtDNA by opening gasdermin D pores. We summarize new data showing that, in addition to being an autoimmune disease biomarker, Ox-mtDNA converts beneficial transient inflammation into long-lasting immunopathology. We discuss how Ox-mtDNA induces short- and long-term immune activation, and highlight its homeostatic and immunopathogenic functions.
    Keywords:  NLRP3 inflammasome; Ox-mtDNA; autoimmunity; cGAS–STING; cell-free DNA; immunopathology; inflammation; stressed mitochondria
    DOI:  https://doi.org/10.1016/j.it.2023.01.006
  14. Front Cell Dev Biol. 2022 ;10 1115348
    Intravenous AAV9 administration results in safe and widespread distribution of transgene in the brain of mini-pig.
    Yingqi Lin, Caijuan Li, Wei Wang, Jiawei Li, Chunhui Huang, Xiao Zheng, Zhaoming Liu, Xichen Song, Yizhi Chen, Jiale Gao, Jianhao Wu, Jiaxi Wu, Zhuchi Tu, Liangxue Lai, Xiao-Jiang Li, Shihua Li, Sen Yan.
      Animal models are important for understanding the pathogenesis of human diseases and for developing and testing new drugs. Pigs have been widely used in the research on the cardiovascular, skin barrier, gastrointestinal, and central nervous systems as well as organ transplantation. Recently, pigs also become an attractive large animal model for the study of neurodegenerative diseases because their brains are very similar to human brains in terms of mass, gully pattern, vascularization, and the proportions of the gray and white matters. Although adeno-associated virus type 9 (AAV9) has been widely used to deliver transgenes in the brain, its utilization in large animal models remains to be fully characterized. Here, we report that intravenous injection of AAV9-GFP can lead to widespread expression of transgene in various organs in the pig. Importantly, GFP was highly expressed in various brain regions, especially the striatum, cortex, cerebellum, hippocampus, without detectable inflammatory responses. These results suggest that intravenous AAV9 administration can be used to establish large animal models of neurodegenerative diseases caused by gene mutations and to treat these animal models as well.
    Keywords:  AAV9; CNS; large animal; neurodegeneration; pig
    DOI:  https://doi.org/10.3389/fcell.2022.1115348
  15. J Cell Sci. 2023 Feb 06. pii: jcs.260612. [Epub ahead of print]
    Myo19 tethers mitochondria to endoplasmic reticulum-associated actin to promote mitochondrial fission.
    Stephen M Coscia, Cameron P Thompson, Qing Tang, Elana E Baltrusaitis, Joseph A Rhodenhiser, Omar A Quintero-Carmona, E Michael Ostap, Melike Lakadamyali, Erika L F Holzbaur.
      Mitochondrial homeostasis requires a dynamic balance of fission and fusion. The actin cytoskeleton promotes fission; we find that the mitochondrially-localized myosin, Myosin 19 (Myo19), is integral to this process. Myo19 knock-down induces mitochondrial elongation, while Myo19 overexpression induces fragmentation. This mitochondrial fragmentation is blocked by a Myo19 mutation predicted to inhibit ATPase activity and strong actin binding but not by mutations predicted to affect the motor's working stroke that preserve ATPase activity. Super-resolution imaging indicates a dispersed localization of Myo19 on mitochondria, which we find to be dependent on metaxins. These observations suggest that Myo19 acts as a dynamic actin-binding tether that facilitates mitochondrial fragmentation. Myo19-driven fragmentation is blocked by depletion of either the endoplasmic reticulum (ER)-anchored formin INF2-CAAX or the mitochondrially-localized F-actin nucleator Spire1C, which together polymerize actin at sites of mito-ER contact for fission. These observations imply that Myo19 promotes fission by stabilizing mito-ER contacts; we used a split-luciferase system to demonstrate a reduction in these contacts following Myo19 depletion. Our data support a model in which Myo19 tethers mitochondria to ER-associated actin to promote mitochondrial fission.
    Keywords:  Actin; Endoplasmic reticulum; Fission; Mito-ER contacts; Mitochondria; Myosin
    DOI:  https://doi.org/10.1242/jcs.260612
  16. Nat Commun. 2023 Feb 06. 14(1): 638
    The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
    Rakesh Ganji, Joao A Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S Clemen, Conrad C Weihl, John G Purdy, Steve P Gygi, Malavika Raman.
      The intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-Mitochondria contact sites (ERMCS) is a platform for critical cellular processes, particularly lipid synthesis. How contacts are remodeled and the impact of altered contacts on lipid metabolism remains poorly understood. We show that the p97 AAA-ATPase and its adaptor ubiquitin-X domain adaptor 8 (UBXD8) regulate ERMCS. The p97-UBXD8 complex localizes to contacts and its loss increases contacts in a manner that is dependent on p97 catalytic activity. Quantitative proteomics and lipidomics of ERMCS demonstrates alterations in proteins regulating lipid metabolism and a significant change in membrane lipid saturation upon UBXD8 deletion. Loss of p97-UBXD8 increased membrane lipid saturation via SREBP1 and the lipid desaturase SCD1. Aberrant contacts can be rescued by unsaturated fatty acids or overexpression of SCD1. We find that the SREBP1-SCD1 pathway is negatively impacted in the brains of mice with p97 mutations that cause neurodegeneration. We propose that contacts are exquisitely sensitive to alterations to membrane lipid composition and saturation.
    DOI:  https://doi.org/10.1038/s41467-023-36298-2
  17. Front Cell Dev Biol. 2023 ;11 1094356
    Mitochondrial calcium cycling in neuronal function and neurodegeneration.
    Grant C Walters, Yuriy M Usachev.
      Mitochondria are essential for proper cellular function through their critical roles in ATP synthesis, reactive oxygen species production, calcium (Ca2+) buffering, and apoptotic signaling. In neurons, Ca2+ buffering is particularly important as it helps to shape Ca2+ signals and to regulate numerous Ca2+-dependent functions including neuronal excitability, synaptic transmission, gene expression, and neuronal toxicity. Over the past decade, identification of the mitochondrial Ca2+ uniporter (MCU) and other molecular components of mitochondrial Ca2+ transport has provided insight into the roles that mitochondrial Ca2+ regulation plays in neuronal function in health and disease. In this review, we discuss the many roles of mitochondrial Ca2+ uptake and release mechanisms in normal neuronal function and highlight new insights into the Ca2+-dependent mechanisms that drive mitochondrial dysfunction in neurologic diseases including epilepsy, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We also consider how targeting Ca2+ uptake and release mechanisms could facilitate the development of novel therapeutic strategies for neurological diseases.
    Keywords:  MCU; calcium; mitochondria; neurodegeneration; neuronal calcium homeostasis
    DOI:  https://doi.org/10.3389/fcell.2023.1094356
  18. Biomed Res Int. 2023 ;2023 1107866
    Leber's Hereditary Optic Neuropathy with Mitochondrial DNA Mutation G11778A: A Systematic Literature Review and Meta-Analysis.
    Jiajia Yuan, Jiaxun Zhao, Chong Ye, Long Pang, Xin Zhang, Alvin Luk, Yangyang Du, Kai Yoon Fan, Xiaowen Zhang, Bin Li, Changzheng Chen.
       Background: LHON is a progressive disease with early disease onset and male predominance, usually causing devastating visual loss to patients. These systematic review and meta-analysis are aimed at summarizing epidemiology, disease onset and progression, visual recovery, risk factors, and treatment options of Leber's hereditary optic neuropathy (LHON) with mitochondrial DNA mutation G11778A from current evidence.
    Methods: The PubMed database was examined from its inception date to November 2021. Data from included studies were pooled with either a fixed-effects model or a random-effects model, depending on the results of heterogeneity tests. Sensitivity analysis was conducted to test the robustness of results.
    Results: A total of 41 articles were included in the systematic review for qualitative analysis, and 34 articles were included for quantitative meta-analysis. The pooled estimate of proportion of G11778A mutation among the three primary mutations of mitochondrial DNA (G11778A, G3460A, and T14484C) for LHON was 73% (95% CI: 67% and 79%), and the LHON patients with G11778A mutation included the pooled male ratio estimate of 77% (76% and 79%), the pooled age estimate of 35.3 years (33.2 years and 37.3 years), the pooled onset age estimate of 22.1 years (19.7 years and 24.6 years), the pooled visual acuity estimate of 1.4 LogMAR (1.2 LogMAR and 1.6 LogMAR), and the pooled estimate of spontaneous visual recovery rate (in either 1 eye) of 20% (15% and 27%).
    Conclusions: The G11778A mutation is a prevalent mitochondrial DNA mutation accounting for over half of LHON cases with three primary mutations. Spontaneous visual recovery is rare, and no effective treatment is currently available.
    DOI:  https://doi.org/10.1155/2023/1107866
  19. Nat Commun. 2023 Feb 06. 14(1): 602
    Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle.
    Caterina Marchioretti, Giulia Zanetti, Marco Pirazzini, Gaia Gherardi, Leonardo Nogara, Roberta Andreotti, Paolo Martini, Lorenzo Marcucci, Marta Canato, Samir R Nath, Emanuela Zuccaro, Mathilde Chivet, Cristina Mammucari, Marco Pacifici, Anna Raffaello, Rosario Rizzuto, Andrea Mattarei, Maria A Desbats, Leonardo Salviati, Aram Megighian, Gianni Sorarù, Elena Pegoraro, Elisa Belluzzi, Assunta Pozzuoli, Carlo Biz, Pietro Ruggieri, Chiara Romualdi, Andrew P Lieberman, Gopal J Babu, Marco Sandri, Bert Blaauw, Manuela Basso, Maria Pennuto.
      Polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy (SBMA). Skeletal muscle is a primary site of toxicity; however, the current understanding of the early pathological processes that occur and how they unfold during disease progression remains limited. Using transgenic and knock-in mice and patient-derived muscle biopsies, we show that SBMA mice in the presymptomatic stage develop a respiratory defect matching defective expression of genes involved in excitation-contraction coupling (ECC), altered contraction dynamics, and increased fatigue. These processes are followed by stimulus-dependent accumulation of calcium into mitochondria and structural disorganization of the muscle triads. Deregulation of expression of ECC genes is concomitant with sexual maturity and androgen raise in the serum. Consistent with the androgen-dependent nature of these alterations, surgical castration and AR silencing alleviate the early and late pathological processes. These observations show that ECC deregulation and defective mitochondrial respiration are early but reversible events followed by altered muscle force, calcium dyshomeostasis, and dismantling of triad structure.
    DOI:  https://doi.org/10.1038/s41467-023-36185-w
  20. Nat Commun. 2023 Feb 04. 14(1): 619
    An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration.
    M Tanvir Rahman, M Kristian Koski, Joanna Panecka-Hofman, Werner Schmitz, Alexander J Kastaniotis, Rebecca C Wade, Rik K Wierenga, J Kalervo Hiltunen, Kaija J Autio.
      Mitochondrial fatty acid synthesis (mtFAS) is essential for respiratory function. MtFAS generates the octanoic acid precursor for lipoic acid synthesis, but the role of longer fatty acid products has remained unclear. The structurally well-characterized component of mtFAS, human 2E-enoyl-ACP reductase (MECR) rescues respiratory growth and lipoylation defects of a Saccharomyces cerevisiae Δetr1 strain lacking native mtFAS enoyl reductase. To address the role of longer products of mtFAS, we employed in silico molecular simulations to design a MECR variant with a shortened substrate binding cavity. Our in vitro and in vivo analyses indicate that the MECR G165Q variant allows synthesis of octanoyl groups but not long chain fatty acids, confirming the validity of our computational approach to engineer substrate length specificity. Furthermore, our data imply that restoring lipoylation in mtFAS deficient yeast strains is not sufficient to support respiration and that long chain acyl-ACPs generated by mtFAS are required for mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-023-36358-7
  21. Acta Physiol (Oxf). 2023 Feb 08. e13946
    Targeting the mitochondrial Ca2+ uniporter complex in cardiovascular disease.
    Omar Lozano, Patricio Marcos, Felipe de Jesús Salazar-Ramirez, Anay F Lázaro-Alfaro, Luis Sobrevia, Gerardo García-Rivas.
      Cardiovascular diseases (CVDs), the leading cause of death worldwide, share in common mitochondrial dysfunction, in specific a dysregulation of Ca2+ uptake dynamics through the mitochondrial Ca2+ uniporter (MCU) complex. In particular, Ca2+ uptake regulates the mitochondrial ATP production, mitochondrial dynamics, oxidative stress, and cell death. Therefore, modulating the activity of the MCU complex to regulate Ca2+ uptake, has been suggested as a potential therapeutic approach for the treatment of CVDs. Here, it is presented the role and implications of the MCU complex in CVDs are presented, followed by a review of the evidence for MCU complex modulation, genetically and pharmacologically. While most approaches have aimed within the MCU complex for the modulation of the Ca2+ pore channel, the MCU subunit, its intra- and extra- mitochondrial implications, including Ca2+ dynamics, oxidative stress, post-translational modifications, and its repercussions in the cardiac function, highlight that targeting the MCU complex has the translational potential for novel CVDs therapeutics.
    Keywords:  cardiovascular diseases; gene therapy; mitochondrial Ca2+ uniporter; mitochondrial Ca2+ uptake; pharmacological therapy
    DOI:  https://doi.org/10.1111/apha.13946
  22. Mitochondrion. 2023 Feb 08. pii: S1567-7249(23)00011-9. [Epub ahead of print]
    How hot can mitochondria be? Incubation at temperatures above 43 °C induces the degradation of respiratory complexes and supercomplexes in intact cells and isolated mitochondria.
    Raquel Moreno-Loshuertos, Joaquín Marco-Brualla, Patricia Meade, Ruth Soler-Agesta, José A Enriquez, Patricio Fernández-Silva.
      Mitochondrial function generates an important fraction of the heat that contributes to cellular and organismal temperature maintenance, but the actual values of this parameter reached in the organelles is a matter of debate. The studies addressing this issue have reported divergent results: from detecting in the organelles the same temperature as the cell average or the incubation temperature, to increasing differences of up to 10 degrees above the incubation value. Theoretical calculations based on physical laws exclude the possibility of relevant temperature gradients between mitochondria and their surroundings. These facts have given rise to a conundrum or paradox about hot mitochondria. We have examined by Blue-Native electrophoresis, both in intact cells and in isolated organelles, the stability of respiratory complexes and supercomplexes at different temperatures to obtain information about their tolerance to heat stress. We observe that, upon incubation at values above 43 °C and after relatively short periods, respiratory complexes, and especially complex I and its supercomplexes, are unstable even when the respiratory activity is inhibited. These results support the conclusion that high temperatures (> 43 °C) cause damage to mitochondrial structure and function and question the proposal that these organelles can physiologically work at close to 50 °C.
    Keywords:  hyperthermia; mitochondria; respiratory complex; stability; supercomplex; temperature
    DOI:  https://doi.org/10.1016/j.mito.2023.02.002
  23. Nature. 2023 Feb 08.
    Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.
    Joe Nassour, Lucia Gutierrez Aguiar, Adriana Correia, Tobias T Schmidt, Laura Mainz, Sara Przetocka, Candy Haggblom, Nimesha Tadepalle, April Williams, Maxim N Shokhirev, Semih C Akincilar, Vinay Tergaonkar, Gerald S Shadel, Jan Karlseder.
      Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations1,2. However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS-STING DNA-sensing pathway, but reaches full activation only when associated with telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adapter protein mitochondrial antiviral-signalling protein (MAVS). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA-ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study reveals a mechanism for telomere-mediated tumour suppression, whereby dysfunctional telomeres activate innate immune responses through mitochondrial TERRA-ZBP1 complexes to eliminate cells destined for neoplastic transformation.
    DOI:  https://doi.org/10.1038/s41586-023-05710-8
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