bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023‒01‒15
twenty papers selected by
Catalina Vasilescu
Helmholz Munich
  1. Translation initiation of leaderless and polycistronic transcripts in mammalian mitochondria.
  2. Nuclear modifier YARS2 allele correction restored retinal ganglion cells-specific deficiencies in Leber's hereditary optic neuropathy.
  3. Monitoring Mitochondrial Protein Import Using Mitochondrial Targeting Sequence (MTS)-eGFP.
  4. Mitochondrial signalling and homeostasis: from cell biology to neurological disease.
  5. Total and reduced/oxidized forms of coenzyme Q10 in fibroblasts of patients with mitochondrial disease.
  6. OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases.
  7. Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation.
  8. The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4.
  9. Cryo-EM structures of mitochondrial respiratory complex I from Drosophila melanogaster.
  10. Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study.
  11. Remarks on Mitochondrial Myopathies.
  12. Mitochondrial Ca2+ handling as a cell signaling hub: lessons from astrocyte function.
  13. DPC29 promotes post-initiation mitochondrial translation in Saccharomyces cerevisiae.
  14. A role for BCL2L13 and autophagy in germline purifying selection of mtDNA.
  15. Protocol for direct measurement of stability and activity of mitochondria electron transport chain complex II.
  16. Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction.
  17. Advances in Human Mitochondria-Based Therapies.
  18. Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization.
  19. Regulation of Mitochondrial Hydrogen Peroxide Availability by Protein S-glutathionylation.
  20. Microtubule-mitochondrial attachment facilitates cell division symmetry and mitochondrial partitioning in fission yeast.
  1. Nucleic Acids Res. 2023 Jan 11. pii: gkac1233. [Epub ahead of print]
    Translation initiation of leaderless and polycistronic transcripts in mammalian mitochondria.
    Cristina Remes, Anas Khawaja, Sarah F Pearce, Adam M Dinan, Shreekara Gopalakrishna, Miriam Cipullo, Vasileios Kyriakidis, Jingdian Zhang, Xaquin Castro Dopico, Olessya Yukhnovets, Ilian Atanassov, Andrew E Firth, Barry Cooperman, Joanna Rorbach.
      The synthesis of mitochondrial OXPHOS complexes is central to cellular metabolism, yet many molecular details of mitochondrial translation remain elusive. It has been commonly held view that translation initiation in human mitochondria proceeded in a manner similar to bacterial systems, with the mitoribosomal small subunit bound to the initiation factors, mtIF2 and mtIF3, along with initiator tRNA and an mRNA. However, unlike in bacteria, most human mitochondrial mRNAs lack 5' leader sequences that can mediate small subunit binding, raising the question of how leaderless mRNAs are recognized by mitoribosomes. By using novel in vitro mitochondrial translation initiation assays, alongside biochemical and genetic characterization of cellular knockouts of mitochondrial translation factors, we describe unique features of translation initiation in human mitochondria. We show that in vitro, leaderless mRNA transcripts can be loaded directly onto assembled 55S mitoribosomes, but not onto the mitoribosomal small subunit (28S), in a manner that requires initiator fMet-tRNAMet binding. In addition, we demonstrate that in human cells and in vitro, mtIF3 activity is not required for translation of leaderless mitochondrial transcripts but is essential for translation of ATP6 in the case of the bicistronic ATP8/ATP6 transcript. Furthermore, we show that mtIF2 is indispensable for mitochondrial protein synthesis. Our results demonstrate an important evolutionary divergence of the mitochondrial translation system and further our fundamental understanding of a process central to eukaryotic metabolism.
    DOI:  https://doi.org/10.1093/nar/gkac1233
  2. Hum Mol Genet. 2023 Jan 05. pii: ddad001. [Epub ahead of print]
    Nuclear modifier YARS2 allele correction restored retinal ganglion cells-specific deficiencies in Leber's hereditary optic neuropathy.
    Jia-Rong Chen, Chao Chen, Jie Chen, Yanchun Ji, Yanna Lian, Juanjuan Zhang, Jialing Yu, Xiang-Yao Li, Jia Qu, Min-Xin Guan.
      Leber's hereditary optic neuropathy (LHON) is a maternally transmitted eye disease due to the degeneration of retinal ganglion cells (RGC). Mitochondrial 11778G > A mutation is the most common LHON-associated mitochondrial DNA (mtDNA) mutation. Our recent studies demonstrated some LHON families manifested by synergic interaction between m.11778G > A mutation and YARS2 allele (c.572G > T, p.Gly191Val) encoding mitochondrial tyrosyl-tRNA synthetase. However, the RGC-specific effects of LHON-associated mtDNA mutations remains elusive and there is no highly effective therapy for LHON. Here, we generated patients-derived induced pluripotent stem cells (iPSCs) from fibroblasts derived from a Chinese LHON family (both m.11778G > A and c.572G > T mutations, only m.11778G > A mutation, and control subject). The c.572G > T mutation in iPSC lines from a syndromic individual was corrected by CRISPR/Cas9. Those iPSCs were differentiated into neural progenitor cells (NPCs) and subsequently induced RGC-like cells using a stepwise differentiation procedure. Those RGC-like cells derived from symptomatic individual harboring both m.11778G > A and c.572G > T mutations exhibited greater defects in neuronal differentiation, morphology including reduced area of soma, numbers of neurites, and shortened length of axons, electrophysiological properties than those in cells bearing only m.11778G > A mutation. Furthermore, these RGC-like cells revealed more drastic reductions in oxygen consumption rates, levels of mitochondrial ATP and increasing productions of reactive oxygen species than those in other cell models. These mitochondrial dysfunctions promoted the apoptotic process for RGC degenerations. Correction of YARS2 c.572G > T mutation rescued deficiencies of patient-derived RGC-like cells. These findings provide new insights into pathophysiology of LHON arising from RGC-specific mitochondrial dysfunctions and step toward therapeutic intervention for this disease.
    DOI:  https://doi.org/10.1093/hmg/ddad001
  3. Bio Protoc. 2022 Dec 20. pii: e4578. [Epub ahead of print]12(24):
    Monitoring Mitochondrial Protein Import Using Mitochondrial Targeting Sequence (MTS)-eGFP.
    Jonas B Michaelis, Süleyman Bozkurt, Jasmin A Schäfer, Christian Münch.
      Mitochondria are cellular organelles essential for the function and survival of eukaryotic cells. Nearly all mitochondrial proteins are nuclear-encoded and require mitochondrial import upon their synthesis in the cytosol. Various approaches have been described to study mitochondrial protein import, such as monitoring the entry of radiolabeled proteins into purified mitochondria or quantifying newly synthesized proteins within mitochondria by proteomics. Here, we provide a detailed protocol for a commonly used and straightforward assay that quantitatively examines mitochondrial protein import by monitoring the co-localization of mitochondrially targeted enhanced green fluorescent protein (eGFP) with the mitochondrial fluorescence dye MitoTracker TM Deep Red FM by live cell imaging. We describe the preparation and use of a stable mammalian cell line inducibly expressing a mitochondrial targeting sequence (MTS)-eGFP, followed by quantitative image analysis using an open-source ImageJ-based plugin. This inducible expression system avoids the need for transient transfection while enabling titration of MTS-eGFP expression and thereby avoiding protein folding stress. Overall, the assay provides a simple and robust approach to assess mitochondrial import capacity of cells in various disease-related settings. This protocol was validated in: Mol Cell (2021), DOI: 10.1016/j.molcel.2021.11.004 Graphical abstract.
    Keywords:   Live cell imaging ; Microscopy ; Mitochondria ; Mitochondrial protein import ; Protein translocation
    DOI:  https://doi.org/10.21769/BioProtoc.4578
  4. Trends Neurosci. 2023 Jan 10. pii: S0166-2236(22)00239-9. [Epub ahead of print]
    Mitochondrial signalling and homeostasis: from cell biology to neurological disease.
    Jack J Collier, Monika Oláhová, Thomas G McWilliams, Robert W Taylor.
      Efforts to understand how mitochondrial dysfunction contributes to neurodegeneration have primarily focussed on the role of mitochondria in neuronal energy metabolism. However, progress in understanding the etiological nature of emerging mitochondrial functions has yielded new ideas about the mitochondrial basis of neurological disease. Studies aimed at deciphering how mitochondria signal through interorganellar contacts, vesicular trafficking, and metabolic transmission have revealed that mitochondrial regulation of immunometabolism, cell death, organelle dynamics, and neuroimmune interplay are critical determinants of neural health. Moreover, the homeostatic mechanisms that exist to protect mitochondrial health through turnover via nanoscale proteostasis and lysosomal degradation have become integrated within mitochondrial signalling pathways to support metabolic plasticity and stress responses in the nervous system. This review highlights how these distinct mitochondrial pathways converge to influence neurological health and contribute to disease pathology.
    Keywords:  immunity; inflammation; metabolism; mitochondrial-derived vesicles; mitochondria–lysosome axis; quality control
    DOI:  https://doi.org/10.1016/j.tins.2022.12.001
  5. Mol Genet Metab Rep. 2023 Mar;34 100951
    Total and reduced/oxidized forms of coenzyme Q10 in fibroblasts of patients with mitochondrial disease.
    Chika Watanabe, Hitoshi Osaka, Miyuki Watanabe, Akihiko Miyauchi, Eriko F Jimbo, Takeshi Tokuyama, Hideki Uosaki, Yoshihito Kishita, Yasushi Okazaki, Takanori Onuki, Tomohiro Ebihara, Kenichi Aizawa, Kei Murayama, Akira Ohtake, Takanori Yamagata.
      Coenzyme Q10 (CoQ10) is involved in ATP production through electron transfer in the mitochondrial respiratory chain complex. CoQ10 receives electrons from respiratory chain complex I and II to become the reduced form, and then transfers electrons at complex III to become the oxidized form. The redox state of CoQ10 has been reported to be a marker of the mitochondrial metabolic state, but to our knowledge, no reports have focused on the individual quantification of reduced and oxidized CoQ10 or the ratio of reduced to total CoQ10 (reduced/total CoQ10) in patients with mitochondrial diseases. We measured reduced and oxidized CoQ10 in skin fibroblasts from 24 mitochondrial disease patients, including 5 primary CoQ10 deficiency patients and 10 respiratory chain complex deficiency patients, and determined the reduced/total CoQ10 ratio. In primary CoQ10 deficiency patients, total CoQ10 levels were significantly decreased, however, the reduced/total CoQ10 ratio was not changed. On the other hand, in mitochondrial disease patients other than primary CoQ10 deficiency patients, total CoQ10 levels did not decrease. However, the reduced/total CoQ10 ratio in patients with respiratory chain complex IV and V deficiency was higher in comparison to those with respiratory chain complex I deficiency. Measurement of CoQ10 in fibroblasts proved useful for the diagnosis of primary CoQ10 deficiency. In addition, the reduced/total CoQ10 ratio may reflect the metabolic status of mitochondrial disease.
    Keywords:  Coenzyme Q10; Forward electron transport; Mitochondrial disease; Primary coenzyme Q10 deficiency; Reduced/total CoQ10; Reverse electron transport
    DOI:  https://doi.org/10.1016/j.ymgmr.2022.100951
  6. Commun Biol. 2023 Jan 12. 6(1): 22
    OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases.
    Gabriel Sturm, Kalpita R Karan, Anna S Monzel, Balaji Santhanam, Tanja Taivassalo, Céline Bris, Sarah A Ware, Marissa Cross, Atif Towheed, Albert Higgins-Chen, Meagan J McManus, Andres Cardenas, Jue Lin, Elissa S Epel, Shamima Rahman, John Vissing, Bruno Grassi, Morgan Levine, Steve Horvath, Ronald G Haller, Guy Lenaers, Douglas C Wallace, Marie-Pierre St-Onge, Saeed Tavazoie, Vincent Procaccio, Brett A Kaufman, Erin L Seifert, Michio Hirano, Martin Picard.
      Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present with fatigue and multi-system disorders, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. By integrating data from 17 cohorts of patients with mitochondrial diseases (n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism. We examine this phenomenon longitudinally in patient-derived fibroblasts from multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular energy expenditure. This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines including GDF15. In parallel, OxPhos defects accelerate telomere erosion and epigenetic aging per cell division, consistent with evidence that excess energy expenditure accelerates biological aging. To explore potential mechanisms for these effects, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations. Taken together, these findings highlight the need to understand how OxPhos defects influence the energetic cost of living, and the link between hypermetabolism and aging in cells and patients with mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s42003-022-04303-x
  7. Nat Commun. 2023 Jan 06. 14(1): 108
    Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation.
    Andrea Irazoki, Isabel Gordaliza-Alaguero, Emma Frank, Nikolaos Nikiforos Giakoumakis, Jordi Seco, Manuel Palacín, Anna Gumà, Lykke Sylow, David Sebastián, Antonio Zorzano.
      Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA recognition by intracellular DNA sensors. However, the involvement of mitochondrial dynamics in mitigating such processes and their impact on muscle fitness remain unaddressed. Here we report that opposite mitochondrial morphologies induce distinct inflammatory signatures, caused by differential activation of DNA sensors TLR9 or cGAS. In the context of mitochondrial fragmentation, we demonstrate that mitochondria-endosome contacts mediated by the endosomal protein Rab5C are required in TLR9 activation in cells. Skeletal muscle mitochondrial fragmentation promotes TLR9-dependent inflammation, muscle atrophy, reduced physical performance and enhanced IL6 response to exercise, which improved upon chronic anti-inflammatory treatment. Taken together, our data demonstrate that mitochondrial dynamics is key in preventing sterile inflammatory responses, which precede the development of muscle atrophy and impaired physical performance. Thus, we propose the targeting of mitochondrial dynamics as an approach to treating disorders characterized by chronic inflammation and mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-022-35732-1
  8. Diabetes Metab J. 2023 Jan 12.
    The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4.
    Min-Ji Kim, Ibotombi Singh Sinam, Zerwa Siddique, Jae-Han Jeon, In-Kyu Lee.
      Sarcopenia, defined as a progressive loss of muscle mass and function, is typified by mitochondrial dysfunction and loss of mitochondrial resilience. Sarcopenia is associated not only with aging, but also with various metabolic diseases characterized by mitochondrial dyshomeostasis. Pyruvate dehydrogenase kinases (PDKs) are mitochondrial enzymes that inhibit the pyruvate dehydrogenase complex, which controls pyruvate entry into the tricarboxylic acid cycle and the subsequent adenosine triphosphate production required for normal cellular activities. PDK4 is upregulated in mitochondrial dysfunction-related metabolic diseases, especially pathologic muscle conditions associated with enhanced muscle proteolysis and aberrant myogenesis. Increases in PDK4 are associated with perturbation of mitochondria-associated membranes and mitochondrial quality control, which are emerging as a central mechanism in the pathogenesis of metabolic disease-associated muscle atrophy. Here, we review how mitochondrial dysfunction affects sarcopenia, focusing on the role of PDK4 in mitochondrial homeostasis. We discuss the molecular mechanisms underlying the effects of PDK4 on mitochondrial dysfunction in sarcopenia and show that targeting mitochondria could be a therapeutic target for treating sarcopenia.
    Keywords:  Metabolic diseases; Mitochondria; Muscular atrophy; Pyruvate dehydrogenase acetyl-transferring kinase; Pyruvate dehydrogenase complex; Sarcopenia
    DOI:  https://doi.org/10.4093/dmj.2022.0305
  9. Elife. 2023 Jan 09. pii: e84424. [Epub ahead of print]12
    Cryo-EM structures of mitochondrial respiratory complex I from Drosophila melanogaster.
    Ahmed-Noor A Agip, Injae Chung, Alvaro Sanchez-Martinez, Alexander J Whitworth, Judy Hirst.
      Respiratory complex I powers ATP synthesis by oxidative phosphorylation, exploiting the energy from NADH oxidation by ubiquinone to drive protons across an energy-transducing membrane. Drosophila melanogaster is a candidate model organism for complex I due to its high evolutionary conservation with the mammalian enzyme, well-developed genetic toolkit, and complex physiology for studies in specific cell types and tissues. Here, we isolate complex I from Drosophila and determine its structure, revealing a 43-subunit assembly with high structural homology to its 45-subunit mammalian counterpart, including a hitherto unknown homologue to subunit NDUFA3. The major conformational state of the Drosophila enzyme is the mammalian-type 'ready-to-go' active resting state, with a fully ordered and enclosed ubiquinone-binding site, but a subtly altered global conformation related to changes in subunit ND6. The mammalian-type 'deactive' pronounced resting state is not observed: in two minor states the ubiquinone-binding site is unchanged, but a deactive-type p-bulge is present in ND6-TMH3. Our detailed structural knowledge of Drosophila complex I provides a foundation for new approaches to disentangle mechanisms of complex I catalysis and regulation in bioenergetics and physiology.
    Keywords:  D. melanogaster; molecular biophysics; structural biology
    DOI:  https://doi.org/10.7554/eLife.84424
  10. Sci Adv. 2023 Jan 13. 9(2): eadd5163
    Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study.
    Helena A K Lapatto, Minna Kuusela, Aino Heikkinen, Maheswary Muniandy, Birgitta W van der Kolk, Swetha Gopalakrishnan, Noora Pöllänen, Martin Sandvik, Mark S Schmidt, Sini Heinonen, Sina Saari, Juho Kuula, Antti Hakkarainen, Janne Tampio, Tuure Saarinen, Marja-Riitta Taskinen, Nina Lundbom, Per-Henrik Groop, Marja Tiirola, Pekka Katajisto, Marko Lehtonen, Charles Brenner, Jaakko Kaprio, Satu Pekkala, Miina Ollikainen, Kirsi H Pietiläinen, Eija Pirinen.
      Nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide riboside (NR) has emerged as a promising compound to improve obesity-associated mitochondrial dysfunction and metabolic syndrome in mice. However, most short-term clinical trials conducted so far have not reported positive outcomes. Therefore, we aimed to determine whether long-term NR supplementation boosts mitochondrial biogenesis and metabolic health in humans. Twenty body mass index (BMI)-discordant monozygotic twin pairs were supplemented with an escalating dose of NR (250 to 1000 mg/day) for 5 months. NR improved systemic NAD+ metabolism, muscle mitochondrial number, myoblast differentiation, and gut microbiota composition in both cotwins. NR also showed a capacity to modulate epigenetic control of gene expression in muscle and adipose tissue in both cotwins. However, NR did not ameliorate adiposity or metabolic health. Overall, our results suggest that NR acts as a potent modifier of NAD+ metabolism, muscle mitochondrial biogenesis and stem cell function, gut microbiota, and DNA methylation in humans irrespective of BMI.
    DOI:  https://doi.org/10.1126/sciadv.add5163
  11. Int J Mol Sci. 2022 Dec 21. pii: 124. [Epub ahead of print]24(1):
    Remarks on Mitochondrial Myopathies.
    Patrizia Bottoni, Giulia Gionta, Roberto Scatena.
      Mitochondrial myopathies represent a heterogeneous group of diseases caused mainly by genetic mutations to proteins that are related to mitochondrial oxidative metabolism. Meanwhile, a similar etiopathogenetic mechanism (i.e., a deranged oxidative phosphorylation and a dramatic reduction of ATP synthesis) reveals that the evolution of these myopathies show significant differences. However, some physiological and pathophysiological aspects of mitochondria often reveal other potential molecular mechanisms that could have a significant pathogenetic role in the clinical evolution of these disorders, such as: i. a deranged ROS production both in term of signaling and in terms of damaging molecules; ii. the severe modifications of nicotinamide adenine dinucleotide (NAD)+/NADH, pyruvate/lactate, and α-ketoglutarate (α-KG)/2- hydroxyglutarate (2-HG) ratios. A better definition of the molecular mechanisms at the basis of their pathogenesis could improve not only the clinical approach in terms of diagnosis, prognosis, and therapy of these myopathies but also deepen the knowledge of mitochondrial medicine in general.
    Keywords:  electron respiratory chain; mitochondria; mitochondrial DNA; mutations; oxidative metabolism; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms24010124
  12. Essays Biochem. 2023 Jan 13. pii: EBC20220094. [Epub ahead of print]
    Mitochondrial Ca2+ handling as a cell signaling hub: lessons from astrocyte function.
    João Victor Cabral-Costa, Alicia J Kowaltowski.
      Astrocytes are a heterogenous population of macroglial cells spread throughout the central nervous system with diverse functions, expression signatures, and intricate morphologies. Their subcellular compartments contain a distinct range of mitochondria, with functional microdomains exhibiting widespread activities, such as controlling local metabolism and Ca2+ signaling. Ca2+ is an ion of utmost importance, both physiologically and pathologically, and participates in critical central nervous system processes, including synaptic plasticity, neuron-astrocyte integration, excitotoxicity, and mitochondrial physiology and metabolism. The mitochondrial Ca2+ handling system is formed by the mitochondrial Ca2+ uniporter complex (MCUc), which mediates Ca2+ influx, and the mitochondrial Na+/Ca2+ exchanger (NCLX), responsible for most mitochondrial Ca2+ efflux, as well as additional components, including the mitochondrial permeability transition pore (mtPTP). Over the last decades, mitochondrial Ca2+ handling has been shown to be key for brain homeostasis, acting centrally in physiopathological processes such as astrogliosis, astrocyte-neuron activity integration, energy metabolism control, and neurodegeneration. In this review, we discuss the current state of knowledge regarding the mitochondrial Ca2+ handling system molecular composition, highlighting its impact on astrocytic homeostasis.
    Keywords:  MCU; NCLX; astrocytes; calcium signalling; metabolism; mitochondria
    DOI:  https://doi.org/10.1042/EBC20220094
  13. Nucleic Acids Res. 2023 Jan 09. pii: gkac1229. [Epub ahead of print]
    DPC29 promotes post-initiation mitochondrial translation in Saccharomyces cerevisiae.
    Kyle A Hubble, Michael F Henry.
      Mitochondrial ribosomes synthesize essential components of the oxidative phosphorylation (OXPHOS) system in a tightly regulated process. In the yeast Saccharomyces cerevisiae, mitochondrial mRNAs require specific translational activators, which orchestrate protein synthesis by recognition of their target gene's 5'-untranslated region (UTR). Most of these yeast genes lack orthologues in mammals, and only one such gene-specific translational activator has been proposed in humans-TACO1. The mechanism by which TACO1 acts is unclear because mammalian mitochondrial mRNAs do not have significant 5'-UTRs, and therefore must promote translation by alternative mechanisms. In this study, we examined the role of the TACO1 orthologue in yeast. We found this 29 kDa protein to be a general mitochondrial translation factor, Dpc29, rather than a COX1-specific translational activator. Its activity was necessary for the optimal expression of OXPHOS mtDNA reporters, and mutations within the mitoribosomal large subunit protein gene MRP7 produced a global reduction of mitochondrial translation in dpc29Δ cells, indicative of a general mitochondrial translation factor. Northern-based mitoribosome profiling of dpc29Δ cells showed higher footprint frequencies at the 3' ends of mRNAs, suggesting a role in translation post-initiation. Additionally, human TACO1 expressed at native levels rescued defects in dpc29Δ yeast strains, suggesting that the two proteins perform highly conserved functions.
    DOI:  https://doi.org/10.1093/nar/gkac1229
  14. PLoS Genet. 2023 Jan 06. 19(1): e1010573
    A role for BCL2L13 and autophagy in germline purifying selection of mtDNA.
    Laura S Kremer, Lyuba V Bozhilova, Diana Rubalcava-Gracia, Roberta Filograna, Mamta Upadhyay, Camilla Koolmeister, Patrick F Chinnery, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) is inherited uniparentally through the female germline without undergoing recombination. This poses a major problem as deleterious mtDNA mutations must be eliminated to avoid a mutational meltdown over generations. At least two mechanisms that can decrease the mutation load during maternal transmission are operational: a stochastic bottleneck for mtDNA transmission from mother to child, and a directed purifying selection against transmission of deleterious mtDNA mutations. However, the molecular mechanisms controlling these processes remain unknown. In this study, we systematically tested whether decreased autophagy contributes to purifying selection by crossing the C5024T mouse model harbouring a single pathogenic heteroplasmic mutation in the tRNAAla gene of the mtDNA with different autophagy-deficient mouse models, including knockouts of Parkin, Bcl2l13, Ulk1, and Ulk2. Our study reveals a statistically robust effect of knockout of Bcl2l13 on the selection process, and weaker evidence for the effect of Ulk1 and potentially Ulk2, while no statistically significant impact is seen for knockout of Parkin. This points at distinctive roles of these players in germline purifying selection. Overall, our approach provides a framework for investigating the roles of other important factors involved in the enigmatic process of purifying selection and guides further investigations for the role of BCL2L13 in the elimination of non-synonymous mutations in protein-coding genes.
    DOI:  https://doi.org/10.1371/journal.pgen.1010573
  15. STAR Protoc. 2023 Jan 06. pii: S2666-1667(22)00876-0. [Epub ahead of print]4(1): 101996
    Protocol for direct measurement of stability and activity of mitochondria electron transport chain complex II.
    Himangshu S Bose, Nicole E Doetch.
      Mitochondria electron transport chain (ETC) complex II is essential for steroid metabolism. Here, we present a protocol to measure the stability and activity of mitochondria ETC complex II. We first describe mitochondria isolation from cell lines and tissues. We then detail how to determine the stability of ETC complex II using isothermal calorimetry and quantification of steroidogenesis using activity assays in parallel. Finally, we describe the steps to perform radioimmunoassay (RIA) to confirm the activity of ETC complex II. For complete details on the use and execution of this protocol, please refer to Bose et al. (2020).1.
    Keywords:  Cell Isolation; Cell-based Assays; Metabolism; Protein Biochemistry
    DOI:  https://doi.org/10.1016/j.xpro.2022.101996
  16. Nat Chem Biol. 2023 Jan 12.
    Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction.
    Yingjie Guo, Huan Zhang, Chen Yan, Birong Shen, Yue Zhang, Xiangyang Guo, Sha Sun, Fan Yu, Jiayun Yan, Ronghe Liu, Qianping Zhang, Di Zhang, Haiyang Liu, Yang Liu, Yaoyao Zhang, Wenlei Li, Jiangyu Qin, He Lv, Zhaoxia Wang, Yun Yuan, Jie-Feng Yang, Ya-Ting Zhong, Song Gao, Bing Zhou, Lei Liu, Deling Kong, Xiaojiang Hao, Junjie Hu, Quan Chen.
      Membrane dynamics are important to the integrity and function of mitochondria. Defective mitochondrial fusion underlies the pathogenesis of multiple diseases. The ability to target fusion highlights the potential to fight life-threatening conditions. Here we report a small molecule agonist, S89, that specifically promotes mitochondrial fusion by targeting endogenous MFN1. S89 interacts directly with a loop region in the helix bundle 2 domain of MFN1 to stimulate GTP hydrolysis and vesicle fusion. GTP loading or competition by S89 dislodges the loop from the GTPase domain and unlocks the molecule. S89 restores mitochondrial and cellular defects caused by mitochondrial DNA mutations, oxidative stress inducer paraquat, ferroptosis inducer RSL3 or CMT2A-causing mutations by boosting endogenous MFN1. Strikingly, S89 effectively eliminates ischemia/reperfusion (I/R)-induced mitochondrial damage and protects mouse heart from I/R injury. These results reveal the priming mechanism for MFNs and provide a therapeutic strategy for mitochondrial diseases when additional mitochondrial fusion is beneficial.
    DOI:  https://doi.org/10.1038/s41589-022-01224-y
  17. Int J Mol Sci. 2022 Dec 29. pii: 608. [Epub ahead of print]24(1):
    Advances in Human Mitochondria-Based Therapies.
    Gang Zhong, Jagadeesh K Venkatesan, Henning Madry, Magali Cucchiarini.
      Mitochondria are the key biological generators of eukaryotic cells, controlling the energy supply while providing many important biosynthetic intermediates. Mitochondria act as a dynamic, functionally and structurally interconnected network hub closely integrated with other cellular compartments via biomembrane systems, transmitting biological information by shuttling between cells and tissues. Defects and dysregulation of mitochondrial functions are critically involved in pathological mechanisms contributing to aging, cancer, inflammation, neurodegenerative diseases, and other severe human diseases. Mediating and rejuvenating the mitochondria may therefore be of significant benefit to prevent, reverse, and even treat such pathological conditions in patients. The goal of this review is to present the most advanced strategies using mitochondria to manage such disorders and to further explore innovative approaches in the field of human mitochondria-based therapies.
    Keywords:  aging; cancer; inflammatory diseases; mitochondria; mitochondrial diseases; oxidative disorders; regenerative medicine
    DOI:  https://doi.org/10.3390/ijms24010608
  18. Int J Mol Sci. 2023 Jan 03. pii: 886. [Epub ahead of print]24(1):
    Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization.
    Andrey V Kuznetsov, Michael J Ausserlechner.
      Mitochondria have been recognized as the energy (in the form of ATP)-producing cell organelles, required for cell viability, survival and normal cell function [...].
    DOI:  https://doi.org/10.3390/ijms24010886
  19. Cells. 2022 Dec 27. pii: 107. [Epub ahead of print]12(1):
    Regulation of Mitochondrial Hydrogen Peroxide Availability by Protein S-glutathionylation.
    Ryan J Mailloux, Cathryn Grayson, Olivia Koufos.
      BACKGROUND: It has been four decades since protein S-glutathionylation was proposed to serve as a regulator of cell metabolism. Since then, this redox-sensitive covalent modification has been identified as a cell-wide signaling platform required for embryonic development and regulation of many physiological functions.SCOPE OF THE REVIEW: Mitochondria use hydrogen peroxide (H2O2) as a second messenger, but its availability must be controlled to prevent oxidative distress and promote changes in cell behavior in response to stimuli. Experimental data favor the function of protein S-glutathionylation as a feedback loop for the inhibition of mitochondrial H2O2 production.
    MAJOR CONCLUSIONS: The glutathione pool redox state is linked to the availability of H2O2, making glutathionylation an ideal mechanism for preventing oxidative distress whilst playing a part in desensitizing mitochondrial redox signals.
    GENERAL SIGNIFICANCE: The biological significance of glutathionylation is rooted in redox status communication. The present review critically evaluates the experimental evidence supporting its role in negating mitochondrial H2O2 production for cell signaling and prevention of electrophilic stress.
    Keywords:  bioenergetics; glutathionylation; hydrogen peroxide; mitochondria; redox signaling
    DOI:  https://doi.org/10.3390/cells12010107
  20. J Cell Sci. 2023 Jan 01. pii: jcs260705. [Epub ahead of print]136(1):
    Microtubule-mitochondrial attachment facilitates cell division symmetry and mitochondrial partitioning in fission yeast.
    Leeba Ann Chacko, Felix Mikus, Nicholas Ariotti, Gautam Dey, Vaishnavi Ananthanarayanan.
      Association with microtubules inhibits the fission of mitochondria in Schizosaccharomyces pombe. Here, we show that this attachment of mitochondria to microtubules is an important cell-intrinsic factor in determining cell division symmetry. By comparing mutant cells that exhibited enhanced attachment and no attachment of mitochondria to microtubules (Dnm1Δ and Mmb1Δ, respectively), we show that microtubules in these mutants displayed aberrant dynamics compared to wild-type cells, which resulted in errors in nuclear positioning. This translated to cell division asymmetry in a significant proportion of both Dnm1Δ and Mmb1Δ cells. Asymmetric division in Dnm1Δ and Mmb1Δ cells resulted in unequal distribution of mitochondria, with the daughter cell that received more mitochondria growing faster than the other daughter cell. Taken together, we show the existence of homeostatic feedback controls between mitochondria and microtubules in fission yeast, which directly influence mitochondrial partitioning and, thereby, cell growth. This article has an associated First Person interview with the first author of the paper.
    Keywords:  Cell division; Microtubules; Mitochondria; Mitochondrial partitioning
    DOI:  https://doi.org/10.1242/jcs.260705
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