bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒01‒23
twenty-one papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial DNA copy number and disease.
  2. Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome.
  3. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.
  4. Biallelic Variants in PYROXD2 Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function.
  5. The Mysterious Multitude: Structural Perspective on the Accessory Subunits of Respiratory Complex I.
  6. Mitochondrial Membrane Remodeling.
  7. Spinal Cord Involvement in Adult Mitochondrial Diseases: A Cohort Study.
  8. Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
  9. OPA1 Modulates Mitochondrial Ca2+ Uptake Through ER-Mitochondria Coupling.
  10. NAD supplementation improves mitochondrial performance of cardiolipin mutants.
  11. HEK293T Cells with TFAM Disruption by CRISPR-Cas9 as a Model for Mitochondrial Regulation.
  12. Cryo-electron microscopy reveals how acetogenins inhibit mitochondrial respiratory complex I.
  13. Human germline nuclear transfer to overcome mitochondrial disease and failed fertilization after ICSI.
  14. Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations.
  15. Muscle mitochondrial energetics predicts mobility decline in well-functioning older adults: The baltimore longitudinal study of aging.
  16. Cellular senescence: all roads lead to mitochondria.
  17. Enrichment of the exocytosis protein STX4 in skeletal muscle remediates peripheral insulin resistance and alters mitochondrial dynamics via Drp1.
  18. Effects of Endurance Training on the Coenzyme Q Redox State in Rat Heart, Liver, and Brain at the Tissue and Mitochondrial Levels: Implications for Reactive Oxygen Species Formation and Respiratory Chain Remodeling.
  19. Nuclear and mitochondrial DNA editing in human cells with zinc finger deaminases.
  20. Testing Mitochondrial-Targeted Drugs in iPSC-RPE from Patients with Age-Related Macular Degeneration.
  21. Reversing mitochondrial defects in aged hearts: Role of mitochondrial calpain activation.
  1. Nat Rev Genet. 2022 Jan 21.
    Mitochondrial DNA copy number and disease.
    Dorothy Clyde.
      
    DOI:  https://doi.org/10.1038/s41576-022-00451-2
  2. JCI Insight. 2022 Jan 20. pii: e156522. [Epub ahead of print]
    Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome.
    Julia C Stokes, Rebecca L Bornstein, Katerina James, Kyung Yeon Park, Kira A Spencer, Katie Vo, John C Snell, Brittany M Johnson, Philip G Morgan, Margaret M Sedensky, Nathan A Baertsch, Simon C Johnson.
      Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of LS. Depleting leukocytes with a colony-stimulating factor 1 receptor inhibitor disrupts disease progression, including suppression of CNS lesion formation and a substantial extension of survival. Leukocyte depletion rescues diverse symptoms including seizures, respiratory center function, hyperlactemia, and neurologic sequelae. These data reveal a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement is causal in disease. This work has significant implications for the mechanisms of mitochondrial disease and may lead to novel therapeutic strategies.
    Keywords:  Genetic diseases; Inflammation; Mitochondria; Mouse models; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.156522
  3. Cell. 2022 Jan 14. pii: S0092-8674(21)01563-4. [Epub ahead of print]
    Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.
    Tara E Tracy, Jesus Madero-Pérez, Danielle L Swaney, Timothy S Chang, Michelle Moritz, Csaba Konrad, Michael E Ward, Erica Stevenson, Ruth Hüttenhain, Grant Kauwe, Maria Mercedes, Lauren Sweetland-Martin, Xu Chen, Sue-Ann Mok, Man Ying Wong, Maria Telpoukhovskaia, Sang-Won Min, Chao Wang, Peter Dongmin Sohn, Jordie Martin, Yungui Zhou, Wenjie Luo, John Q Trojanowski, Virginia M Y Lee, Shiaoching Gong, Giovanni Manfredi, Giovanni Coppola, Nevan J Krogan, Daniel H Geschwind, Li Gan.
      Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established interactions of Tau with presynaptic vesicle proteins during activity-dependent Tau secretion and mapped the Tau-binding sites to the cytosolic domains of integral synaptic vesicle proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau's interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multimodal and dynamic Tau interactomes with exquisite spatial resolution shed light on Tau's role in neuronal function and disease and highlight potential therapeutic targets to block Tau-mediated pathogenesis.
    Keywords:  APEX; Tau; Tau secretion; affinity purification mass spectrometry; interactome; mitochondria; neurodegeneration; protein-protein interaction; synapse; tauopathies
    DOI:  https://doi.org/10.1016/j.cell.2021.12.041
  4. Int J Mol Sci. 2022 Jan 17. pii: 986. [Epub ahead of print]23(2):
    Biallelic Variants in PYROXD2 Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function.
    Nicole J Van Bergen, Daniella H Hock, Lucy Spencer, Sean Massey, Tegan Stait, Zornitza Stark, Sebastian Lunke, Ain Roesley, Heidi Peters, Joy Yaplito Lee, Anna Le Fevre, Oliver Heath, Cristina Mignone, Joseph Yuan-Mou Yang, Monique M Ryan, Colleen D'Arcy, Margot Nash, Sile Smith, Nikeisha J Caruana, David R Thorburn, David A Stroud, Susan M White, John Christodoulou, Natasha J Brown.
      Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein's precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child's clinical presentation.
    Keywords:  PYROXD2; genome sequencing; mitochondria; mitoribosome; oxidative phosphorylation; reactive oxygen species; ultrarapid genomics
    DOI:  https://doi.org/10.3390/ijms23020986
  5. Front Mol Biosci. 2021 ;8 798353
    The Mysterious Multitude: Structural Perspective on the Accessory Subunits of Respiratory Complex I.
    Abhilash Padavannil, Maria G Ayala-Hernandez, Eimy A Castellanos-Silva, James A Letts.
      Complex I (CI) is the largest protein complex in the mitochondrial oxidative phosphorylation electron transport chain of the inner mitochondrial membrane and plays a key role in the transport of electrons from reduced substrates to molecular oxygen. CI is composed of 14 core subunits that are conserved across species and an increasing number of accessory subunits from bacteria to mammals. The fact that adding accessory subunits incurs costs of protein production and import suggests that these subunits play important physiological roles. Accordingly, knockout studies have demonstrated that accessory subunits are essential for CI assembly and function. Furthermore, clinical studies have shown that amino acid substitutions in accessory subunits lead to several debilitating and fatal CI deficiencies. Nevertheless, the specific roles of CI's accessory subunits have remained mysterious. In this review, we explore the possible roles of each of mammalian CI's 31 accessory subunits by integrating recent high-resolution CI structures with knockout, assembly, and clinical studies. Thus, we develop a framework of experimentally testable hypotheses for the function of the accessory subunits. We believe that this framework will provide inroads towards the complete understanding of mitochondrial CI physiology and help to develop strategies for the treatment of CI deficiencies.
    Keywords:  accessory subunits; electron transport chain; mitochondrial complex I; mitochondrial diseases; oxidative phosphorylation (OXPHOS)
    DOI:  https://doi.org/10.3389/fmolb.2021.798353
  6. Front Bioeng Biotechnol. 2021 ;9 786806
    Mitochondrial Membrane Remodeling.
    Ziyun Yang, Liang Wang, Cheng Yang, Shiming Pu, Ziqi Guo, Qiong Wu, Zuping Zhou, Hongxia Zhao.
      Mitochondria are key regulators of many important cellular processes and their dysfunction has been implicated in a large number of human disorders. Importantly, mitochondrial function is tightly linked to their ultrastructure, which possesses an intricate membrane architecture defining specific submitochondrial compartments. In particular, the mitochondrial inner membrane is highly folded into membrane invaginations that are essential for oxidative phosphorylation. Furthermore, mitochondrial membranes are highly dynamic and undergo constant membrane remodeling during mitochondrial fusion and fission. It has remained enigmatic how these membrane curvatures are generated and maintained, and specific factors involved in these processes are largely unknown. This review focuses on the current understanding of the molecular mechanism of mitochondrial membrane architectural organization and factors critical for mitochondrial morphogenesis, as well as their functional link to human diseases.
    Keywords:  Mitochondrial disease; cardiolipin; crista junctions; cristae; membrane curvature; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.3389/fbioe.2021.786806
  7. Life (Basel). 2021 Dec 21. pii: 5. [Epub ahead of print]12(1):
    Spinal Cord Involvement in Adult Mitochondrial Diseases: A Cohort Study.
    Guido Primiano, Paolo Mariotti, Ida Turrini, Cristina Sancricca, Andrea Sabino, Alessandra Torraco, Rosalba Carrozzo, Serenella Servidei.
      The central nervous system is metabolically very demanding and consequently vulnerable to defects of the mitochondrial respiratory chain. While the clinical manifestations and the corresponding radiological findings of the brain involvement in mitochondrial diseases (e.g., stroke-like episodes, signal changes of the basal ganglia, cerebral and cerebellar atrophy) are well known, at present there are few data on the spinal-cord abnormalities in these pathologies, in particular in adult subjects. In this study, we present a cross-sectional cohort study on the prevalence and characterization of spinal-cord involvement in adult patients with genetically defined mitochondrial diseases.
    Keywords:  MRI; biomarkers; mitochondrial diseases; mtDNA; spinal cord
    DOI:  https://doi.org/10.3390/life12010005
  8. Neuron. 2022 Jan 13. pii: S0896-6273(21)01046-1. [Epub ahead of print]
    Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
    Juliet Goldsmith, Alban Ordureau, J Wade Harper, Erika L F Holzbaur.
      Neurons depend on autophagy to maintain cellular homeostasis, and defects in autophagy are pathological hallmarks of neurodegenerative disease. To probe the role of basal autophagy in the maintenance of neuronal health, we isolated autophagic vesicles from mouse brain tissue and used proteomics to identify the major cargos engulfed within autophagosomes, validating our findings in rodent primary and human iPSC-derived neurons. Mitochondrial proteins were identified as a major cargo in the absence of mitophagy adaptors such as OPTN. We found that nucleoid-associated proteins are enriched compared with other mitochondrial components. In the axon, autophagic engulfment of nucleoid-enriched mitochondrial fragments requires the mitochondrial fission machinery Drp1. We proposed that localized Drp1-dependent fission of nucleoid-enriched fragments in proximity to the sites of autophagosome biogenesis enhances their capture. The resulting efficient autophagic turnover of nucleoids may prevent accumulation of mitochondrial DNA in the neuron, thus mitigating activation of proinflammatory pathways that contribute to neurodegeneration.
    Keywords:  Drp1; TFAM; autophagy; mitochondria; mitochondrial division; mitochondrial nucleoids; mitophagy; neurodegeneration; neuronal homeostasis
    DOI:  https://doi.org/10.1016/j.neuron.2021.12.029
  9. Front Cell Dev Biol. 2021 ;9 774108
    OPA1 Modulates Mitochondrial Ca2+ Uptake Through ER-Mitochondria Coupling.
    Benjamín Cartes-Saavedra, Josefa Macuada, Daniel Lagos, Duxan Arancibia, María E Andrés, Patrick Yu-Wai-Man, György Hajnóczky, Verónica Eisner.
      Autosomal Dominant Optic Atrophy (ADOA), a disease that causes blindness and other neurological disorders, is linked to OPA1 mutations. OPA1, dependent on its GTPase and GED domains, governs inner mitochondrial membrane (IMM) fusion and cristae organization, which are central to oxidative metabolism. Mitochondrial dynamics and IMM organization have also been implicated in Ca2+ homeostasis and signaling but the specific involvements of OPA1 in Ca2+ dynamics remain to be established. Here we studied the possible outcomes of OPA1 and its ADOA-linked mutations in Ca2+ homeostasis using rescue and overexpression strategies in Opa1-deficient and wild-type murine embryonic fibroblasts (MEFs), respectively and in human ADOA-derived fibroblasts. MEFs lacking Opa1 required less Ca2+ mobilization from the endoplasmic reticulum (ER) to induce a mitochondrial matrix [Ca2+] rise ([Ca2+]mito). This was associated with closer ER-mitochondria contacts and no significant changes in the mitochondrial calcium uniporter complex. Patient cells carrying OPA1 GTPase or GED domain mutations also exhibited altered Ca2+ homeostasis, and the mutations associated with lower OPA1 levels displayed closer ER-mitochondria gaps. Furthermore, in Opa1 -/- MEF background, we found that acute expression of OPA1 GTPase mutants but no GED mutants, partially restored cytosolic [Ca2+] ([Ca2+]cyto) needed for a prompt [Ca2+]mito rise. Finally, OPA1 mutants' overexpression in WT MEFs disrupted Ca2+ homeostasis, partially recapitulating the observations in ADOA patient cells. Thus, OPA1 modulates functional ER-mitochondria coupling likely through the OPA1 GED domain in Opa1 -/- MEFs. However, the co-existence of WT and mutant forms of OPA1 in patients promotes an imbalance of Ca2+ homeostasis without a domain-specific effect, likely contributing to the overall ADOA progress.
    Keywords:  ADOA; OPA1; calcium; endoplasmic reticulum; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2021.774108
  10. Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Jan 17. pii: S1388-1981(21)00222-5. [Epub ahead of print] 159094
    NAD supplementation improves mitochondrial performance of cardiolipin mutants.
    Jiajia Ji, Deena Damschroder, Denise Bessert, Pablo Lazcano, Robert Wessells, Christian A Reynolds, Miriam L Greenberg.
      Cardiolipin (CL) deficiency causes mitochondrial dysfunction and aberrant metabolism that are associated in humans with the severe disease Barth syndrome (BTHS). Several metabolic abnormalities are observed in BTHS patients and model systems, including decreased oxidative phosphorylation, reduced tricarboxylic acid (TCA) cycle flux, and accumulated lactate and D-β-hydroxybutyrate, which strongly suggests that nicotinamide adenine dinucleotide (NAD) redox metabolism may be altered in CL-deficient cells. In this study, we identified abnormal NAD+ metabolism in multiple BTHS model systems and demonstrate that supplementation of NAD+ precursors such as nicotinamide mononucleotide (NMN) improves mitochondrial function. Improved mitochondrial function in the Drosophila model was associated with restored exercise endurance, which suggests a potential therapeutic benefit of NAD+ precursor supplementation in the management of BTHS patients.
    Keywords:  Barth syndrome; Cardiolipin deficiency; Mitochondrial function; NAD(+) precursors; NAD(+) redox; Nicotinamide mononucleotide
    DOI:  https://doi.org/10.1016/j.bbalip.2021.159094
  11. Life (Basel). 2021 Dec 24. pii: 22. [Epub ahead of print]12(1):
    HEK293T Cells with TFAM Disruption by CRISPR-Cas9 as a Model for Mitochondrial Regulation.
    Vanessa Cristina de Oliveira, Kelly Cristine Santos Roballo, Clésio Gomes Mariano Junior, Sarah Ingrid Pinto Santos, Fabiana Fernandes Bressan, Marcos Roberto Chiaratti, Elena J Tucker, Erica E Davis, Jean-Paul Concordet, Carlos Eduardo Ambrósio.
      The mitochondrial transcription factor A (TFAM) is considered a key factor in mitochondrial DNA (mtDNA) copy number. Given that the regulation of active copies of mtDNA is still not fully understood, we investigated the effects of CRISPR-Cas9 gene editing of TFAM in human embryonic kidney (HEK) 293T cells on mtDNA copy number. The aim of this study was to generate a new in vitro model by CRISPR-Cas9 system by editing the TFAM locus in HEK293T cells. Among the resulting single-cell clones, seven had high mutation rates (67-96%) and showed a decrease in mtDNA copy number compared to control. Cell staining with Mitotracker Red showed a reduction in fluorescence in the edited cells compared to the non-edited cells. Our findings suggest that the mtDNA copy number is directly related to TFAM control and its disruption results in interference with mitochondrial stability and maintenance.
    Keywords:  CRISPR-Cas9; HEK293T cells; TFAM; gene editing; mitochondrial DNA
    DOI:  https://doi.org/10.3390/life12010022
  12. J Biol Chem. 2022 Jan 18. pii: S0021-9258(22)00042-4. [Epub ahead of print] 101602
    Cryo-electron microscopy reveals how acetogenins inhibit mitochondrial respiratory complex I.
    Daniel N Grba, James N Blaza, Hannah R Bridges, Ahmed-Noor A Agip, Zhan Yin, Masatoshi Murai, Hideto Miyoshi, Judy Hirst.
      Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a crucial enzyme in energy metabolism, captures the redox potential energy from NADH oxidation and ubiquinone reduction to create the proton motive force used to drive ATP synthesis in oxidative phosphorylation. Recent high-resolution cryo-EM analyses have provided detailed structural knowledge of the catalytic machinery of complex I, but not of the molecular principles of its energy transduction mechanism. Although ubiquinone is considered to bind in a long channel at the interface of the membrane-embedded and hydrophilic domains, and channel residues are likely involved in coupling substrate reduction to proton translocation, no structures with the channel fully occupied have yet been described. Here, we report the cryo-EM structure of mouse complex I with an extremely tight-binding natural-product acetogenin inhibitor, which resembles the native substrate, bound along the full length of the expected ubiquinone-binding channel. Our structure reveals the mode of acetogenin binding and the molecular basis for structure-activity relationships within the acetogenin family. It also shows that acetogenins are such potent inhibitors because they are highly hydrophobic molecules that contain two specific hydrophilic moieties ideally spaced to lock into two hydrophilic regions of the otherwise hydrophobic channel. The central hydrophilic section of the channel does not favor binding of the isoprenoid chain when the native substrate is fully bound, but stabilises the ubiquinone/ubiquinol headgroup as it transits to/from the active site. Therefore, the amphipathic nature of the channel supports both tight binding of the amphipathic inhibitor and rapid exchange of the ubiquinone/ubiquinol substrate and product.
    Keywords:  acetogenin; binding site; complex I; cryo-electron microscopy; inhibitor-bound structure
    DOI:  https://doi.org/10.1016/j.jbc.2022.101602
  13. J Assist Reprod Genet. 2022 Jan 22.
    Human germline nuclear transfer to overcome mitochondrial disease and failed fertilization after ICSI.
    Maoxing Tang, Annekatrien Boel, Noemi Castelluccio, Arantxa Cardona Barberán, Antonia Christodoulaki, Bieke Bekaert, Mina Popovic, Frauke Vanden Meerschaut, Petra De Sutter, Björn Menten, Sofie Symoens, Arnaud V Vanlander, Dominic Stoop, Paul J Coucke, Björn Heindryckx.
      PURPOSE: Providing additional insights on the efficacy of human nuclear transfer (NT). Here, and earlier, NT has been applied to minimize transmission risk of mitochondrial DNA (mtDNA) diseases. NT has also been proposed for treating infertility, but it is still unclear which infertility indications would benefit. In this work, we therefore additionally assess the applicability of NT to overcome failed fertilization.METHODS: Patient 1 carries a homoplasmic mtDNA mutation (m.11778G > A). Seventeen metaphase II (MII) oocytes underwent pre-implantation genetic testing (PGT), while five MII oocytes were used for spindle transfer (ST), and one in vitro matured (IVM) metaphase I oocyte underwent early pronuclear transfer (ePNT). Patients 2-3 experienced multiple failed intracytoplasmic sperm injection (ICSI) and ICSI-assisted oocyte activation (AOA) cycles. For these patients, the obtained MII oocytes underwent an additional ICSI-AOA cycle, while the IVM oocytes were subjected to ST.
    RESULTS: For patient 1, PGT-M confirmed mutation loads close to 100%. All ST-reconstructed oocytes fertilized and cleaved, of which one progressed to the blastocyst stage. The reconstructed ePNT-zygote reached the morula stage. These samples showed an average mtDNA carry-over rate of 2.9% ± 0.8%, confirming the feasibility of NT to reduce mtDNA transmission. For patient 2-3 displaying fertilization failure, ST resulted in, respectively, 4/5 and 6/6 fertilized oocytes, providing evidence, for the first time, that NT can enable successful fertilization in this patient population.
    CONCLUSION: Our study showcases the repertoire of disorders for which NT can be beneficial, to overcome either mitochondrial disease transmission or failed fertilization after ICSI-AOA.
    Keywords:  Female infertility; Fertilization failure; Mitochondrial DNA disease; Pronuclear transfer; Spindle transfer
    DOI:  https://doi.org/10.1007/s10815-022-02401-7
  14. Cell Mol Life Sci. 2022 Jan 17. 79(2): 74
    Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations.
    Marta Medina-Carbonero, Arabela Sanz-Alcázar, Elena Britti, Fabien Delaspre, Elisa Cabiscol, Joaquim Ros, Jordi Tamarit.
      Friedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease caused by mutations in the frataxin (FXN) gene. The most prevalent mutation is a GAA expansion in the first intron of the gene causing decreased frataxin expression. Some patients present the GAA expansion in one allele and a missense mutation in the other allele. One of these mutations, FXNI154F, was reported to result in decreased content of mature frataxin and increased presence of an insoluble intermediate proteoform in cellular models. By introducing this mutation into the murine Fxn gene (I151F, equivalent to human I154F) we have now analyzed the consequences of this pathological point mutation in vivo. We have observed that FXNI151F homozygous mice present low frataxin levels in all tissues, with no evidence of insoluble proteoforms. Moreover, they display neurological deficits resembling those observed in FA patients. Biochemical analysis of heart, cerebrum and cerebellum have revealed decreased content of components from OXPHOS complexes I and II, decreased aconitase activity, and alterations in antioxidant defenses. These mitochondrial alterations are more marked in the nervous system than in heart, precede the appearance of neurological symptoms, and are similar to those observed in other FA models. We conclude that the primary pathological mechanism underlying the I151F mutation is frataxin deficiency, like in patients carrying GAA expansions. Therefore, patients carrying the I154F mutation would benefit from frataxin replacement therapies. Furthermore, our results also show that the FXNI151F mouse is an excellent tool for analyzing tissue-specific consequences of frataxin deficiency and for testing new therapies.
    Keywords:  Friedreich Ataxia; Iron–sulfur; Mitochondria; OXPHOS; Oxidative stress
    DOI:  https://doi.org/10.1007/s00018-021-04100-5
  15. Aging Cell. 2022 Jan 20. e13552
    Muscle mitochondrial energetics predicts mobility decline in well-functioning older adults: The baltimore longitudinal study of aging.
    Qu Tian, Brendan A Mitchell, Marta Zampino, Kenneth W Fishbein, Richard G Spencer, Luigi Ferrucci.
      BACKGROUND: Muscle mitochondrial dysfunction is associated with poor mobility in aging. Whether mitochondrial dysfunction predicts subsequent mobility decline is unknown.METHODS: We examined 380 cognitively normal participants aged 60 and older (53%women, 22%Black) who were well-functioning (gait speed ≥ 1.0 m/s) and free of Parkinson's disease and stroke at baseline and had data on baseline skeletal muscle oxidative capacity and one or more mobility assessments during an average 2.5 years. Muscle oxidative capacity was measured by phosphorus magnetic resonance spectroscopy as the post-exercise recovery rate of phosphocreatine (kPCr ). Mobility was measured by four walking tests. Associations of baseline kPCr with mobility changes were examined using linear mixed-effects models, adjusted for covariates. In a subset, we examined whether changes in muscle strength and mass affected these associations by adjusting for longitudinal muscle strength, lean mass, and fat mass.
    RESULTS: Lower baseline kPCr was associated with greater decline in all four mobility measures (β, p-value: (0.036, 0.020) 6-m usual gait speed; (0.029, 0.038) 2.5-min usual gait speed; (0.034, 0.011) 6-m rapid gait speed; (-0.042, <0.001) 400-m time). In the subset, further adjustment for longitudinal muscle strength, lean mass, and fat mass attenuated longitudinal associations with changes in mobility (Δβ reduced 26-63%).
    CONCLUSION: Among initially well-functioning older adults, worse muscle mitochondrial function predicts mobility decline, and part of this longitudinal association is explained by decline in muscle strength and mass. Our findings suggest that worse mitochondrial function contributes to mobility decline with aging. These findings need to be verified in studies correlating longitudinal changes in mitochondrial function, muscle, and mobility performance.
    Keywords:  magnetic resonance spectroscopy; mitochondrial energetics; mobility decline; skeletal muscle; walking speed
    DOI:  https://doi.org/10.1111/acel.13552
  16. FEBS J. 2022 Jan 20.
    Cellular senescence: all roads lead to mitochondria.
    Hélène Martini, João F Passos.
      Senescence is a multi-functional cell fate, characterized by an irreversible cell-cycle arrest and a pro-inflammatory phenotype, commonly known as the Senescence-Associated secretory Phenotype (SASP). Emerging evidence indicates that accumulation of senescent cells in multiple tissues, drives tissue dysfunction and several age-related conditions. This has spurred the academic community and industry to identify new therapeutic interventions targeting this process. Mitochondrial dysfunction is an often-unappreciated hallmark of cellular senescence which plays important roles not only in the senescence growth arrest but also in the development of the SASP and resistance to cell-death. Here, we review the evidence that supports a role for mitochondria in the development of senescence and describe the underlying mechanisms. Finally, we propose that a detailed road map of mitochondrial biology in senescence will be crucial to guide the future development of senotherapies.
    Keywords:  Mitochondria; SASP; aging; senescence
    DOI:  https://doi.org/10.1111/febs.16361
  17. Nat Commun. 2022 Jan 20. 13(1): 424
    Enrichment of the exocytosis protein STX4 in skeletal muscle remediates peripheral insulin resistance and alters mitochondrial dynamics via Drp1.
    Karla E Merz, Jinhee Hwang, Chunxue Zhou, Rajakrishnan Veluthakal, Erika M McCown, Angelica Hamilton, Eunjin Oh, Wenting Dai, Patrick T Fueger, Lei Jiang, Janice M Huss, Debbie C Thurmond.
      Mitochondrial dysfunction is implicated in skeletal muscle insulin resistance. Syntaxin 4 (STX4) levels are reduced in human diabetic skeletal muscle, and global transgenic enrichment of STX4 expression improves insulin sensitivity in mice. Here, we show that transgenic skeletal muscle-specific STX4 enrichment (skmSTX4tg) in mice reverses established insulin resistance and improves mitochondrial function in the context of diabetogenic stress. Specifically, skmSTX4tg reversed insulin resistance caused by high-fat diet (HFD) without altering body weight or food consumption. Electron microscopy of wild-type mouse muscle revealed STX4 localisation at or proximal to the mitochondrial membrane. STX4 enrichment prevented HFD-induced mitochondrial fragmentation and dysfunction through a mechanism involving STX4-Drp1 interaction and elevated AMPK-mediated phosphorylation at Drp1 S637, which favors fusion. Our findings challenge the dogma that STX4 acts solely at the plasma membrane, revealing that STX4 localises at/proximal to and regulates the function of mitochondria in muscle. These results establish skeletal muscle STX4 enrichment as a candidate therapeutic strategy to reverse peripheral insulin resistance.
    DOI:  https://doi.org/10.1038/s41467-022-28061-w
  18. Int J Mol Sci. 2022 Jan 14. pii: 896. [Epub ahead of print]23(2):
    Effects of Endurance Training on the Coenzyme Q Redox State in Rat Heart, Liver, and Brain at the Tissue and Mitochondrial Levels: Implications for Reactive Oxygen Species Formation and Respiratory Chain Remodeling.
    Karolina Dominiak, Lukasz Galganski, Adrianna Budzinska, Andrzej Woyda-Ploszczyca, Jerzy A Zoladz, Wieslawa Jarmuszkiewicz.
      Sixteen adult, 4-month-old male Wistar rats were randomly assigned to the training group (n = 8) or the control group (n = 8). We elucidated the effects of 8 weeks of endurance training on coenzyme Q (Q) content and the formation of reactive oxygen species (ROS) at the tissue level and in isolated mitochondria of the rat heart, liver and brain. We demonstrated that endurance training enhanced mitochondrial biogenesis in all tested organs, while a significant increase in the Q redox state was observed in the heart and brain, indicating an elevated level of QH2 as an antioxidant. Moreover, endurance training increased the mQH2 antioxidant pool in the mitochondria of the heart and liver, but not in the brain. At the tissue and isolated mitochondria level, an increase in ROS formation was only observed in the heart. ROS formation observed in the mitochondria of individual rat tissues after training may be associated with changes in the activity/amount of individual components of the oxidative phosphorylation system and its molecular organization, as well as with the size of the oxidized pool of mitochondrial Q acting as an electron carrier in the respiratory chain. Our results indicate that tissue-dependent changes induced by endurance training in the cellular and mitochondrial QH2 pool acting as an antioxidant and in the mitochondrial Q pool serving the respiratory chain may serve important roles in energy metabolism, redox homeostasis and the level of oxidative stress.
    Keywords:  coenzyme Q; endurance training; mitochondrial energetics; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms23020896
  19. Nat Commun. 2022 Jan 18. 13(1): 366
    Nuclear and mitochondrial DNA editing in human cells with zinc finger deaminases.
    Kayeong Lim, Sung-Ik Cho, Jin-Soo Kim.
      Base editing in nuclear DNA and mitochondrial DNA (mtDNA) is broadly useful for biomedical research, medicine, and biotechnology. Here, we present a base editing platform, termed zinc finger deaminases (ZFDs), composed of custom-designed zinc-finger DNA-binding proteins, the split interbacterial toxin deaminase DddAtox, and a uracil glycosylase inhibitor (UGI), which catalyze targeted C-to-T base conversions without inducing unwanted small insertions and deletions (indels) in human cells. We assemble plasmids encoding ZFDs using publicly available zinc finger resources to achieve base editing at frequencies of up to 60% in nuclear DNA and 30% in mtDNA. Because ZFDs, unlike CRISPR-derived base editors, do not cleave DNA to yield single- or double-strand breaks, no unwanted indels caused by error-prone non-homologous end joining are produced at target sites. Furthermore, recombinant ZFD proteins, expressed in and purified from E. coli, penetrate cultured human cells spontaneously to induce targeted base conversions, demonstrating the proof-of-principle of gene-free gene therapy.
    DOI:  https://doi.org/10.1038/s41467-022-27962-0
  20. Pharmaceuticals (Basel). 2022 Jan 04. pii: 62. [Epub ahead of print]15(1):
    Testing Mitochondrial-Targeted Drugs in iPSC-RPE from Patients with Age-Related Macular Degeneration.
    Mara C Ebeling, Zhaohui Geng, Madilyn R Stahl, Rebecca J Kapphahn, Heidi Roehrich, Sandra R Montezuma, Deborah A Ferrington, James R Dutton.
      Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. No universally effective treatments exist for atrophic or "dry" AMD, which results from loss of the retinal pigment epithelium (RPE) and photoreceptors and accounts for ≈80% of all AMD patients. Prior studies provide evidence for the involvement of mitochondrial dysfunction in AMD pathology. This study used induced pluripotent stem cell (iPSC) RPE derived from five AMD patients to test the efficacy of three drugs (AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), Metformin, trehalose) that target key processes in maintaining optimal mitochondrial function. The patient iPSC-RPE lines were used in a proof-of-concept drug screen, utilizing an analysis of RPE mitochondrial function following acute and extended drug exposure. Results show considerable variability in drug response across patient cell lines, supporting the need for a personalized medicine approach for treating AMD. Furthermore, our results demonstrate the feasibility of using iPSC-RPE from AMD patients to develop a personalized drug treatment regime and provide a roadmap for the future clinical management of AMD.
    Keywords:  age-related macular degeneration; human-induced pluripotent stem cells; personalized drug testing; retinal pigment epithelium
    DOI:  https://doi.org/10.3390/ph15010062
  21. Am J Physiol Cell Physiol. 2022 Jan 19.
    Reversing mitochondrial defects in aged hearts: Role of mitochondrial calpain activation.
    Qun Chen, Jeremy Thompson, Ying Hu, Edward J Lesnefsky.
      Aging chronically increases endoplasmic reticulum (ER) stress that contributes to mitochondrial dysfunction. Activation of calpain 1 (CPN1) impairs mitochondrial function during acute ER stress. We proposed that aging-induced ER stress led to mitochondrial dysfunction by activating CPN1. We posit that attenuation of the ER stress or direct inhibition of CPN1 in aged hearts can decrease cardiac injury during ischemia-reperfusion by improving mitochondrial function. Male young (3 mo.) and aged mice (24 mo.) were used in the present study, and 4-phenylbutyrate (4-PBA) was used to decrease the ER stress in aged mice. Subsarcolemmal (SSM) and interfibrillar mitochondria (IFM) were isolated. Chronic 4-PBA treatment for two weeks decreased CPN1 activation as shown the decreased cleavage of spectrin in cytosol and AIF (apoptosis inducing factor) and the α1 subunit of pyruvate dehydrogenase (PDH) in mitochondria. Treatment improved oxidative phosphorylation in 24 mo. SSM and IFM at baseline compared to vehicle. When 4-PBA treated 24 mo. hearts were then subjected to ischemia-reperfusion, infarct size was decreased. These results support that attenuation of the ER stress decreased cardiac injury in aged hearts by improving mitochondrial function before ischemia. To challenge the role of CPN1 as an effector of the ER stress, aged mice were treated with MDL-28170 (MDL, an inhibitor of calpain 1). MDL treatment improved mitochondrial function in aged SSM and IFM. MDL-treated 24 mo. hearts sustained less cardiac injury following ischemia-reperfusion. These results support that age-induced ER stress augments cardiac injury during ischemia-reperfusion by impairing mitochondrial function through activation of CPN1.
    Keywords:  Aging; ER stress; electron transport chain; ischemia-reperfusion
    DOI:  https://doi.org/10.1152/ajpcell.00279.2021
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