bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2022‒12‒11
fifty papers selected by
Catalina Vasilescu
Helmholz Munich
  1. Mitochondrial biology and dysfunction in secondary mitochondrial disease.
  2. A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome.
  3. Mitochondrial RNA stimulates heat production in young adipocytes to reduce obesity.
  4. Inner mitochondrial membrane structure and fusion dynamics are altered in senescent human iPSC-derived and primary rat cardiomyocytes.
  5. Novel biallelic mutations in TMEM126B cause splicing defects and lead to Leigh-like syndrome with severe complex I deficiency.
  6. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson's disease.
  7. A multi-omics longitudinal aging dataset in primary human fibroblasts with mitochondrial perturbations.
  8. Current advances in gene therapy of mitochondrial diseases.
  9. Xenotopic expression of alternative oxidase (AOX) to study mechanisms of mitochondrial disease.
  10. Mitochondrial cristae architecture protects against mtDNA release and inflammation.
  11. Mitochondrial PARP1 regulates NAD+-dependent poly ADP-ribosylation of mitochondrial nucleoids.
  12. NAD precursors cycle between host tissues and the gut microbiome.
  13. Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules.
  14. DJ-1 promotes energy balance by regulating both mitochondrial and autophagic homeostasis.
  15. Enzymatically dissociated muscle fibers display rapid dedifferentiation and impaired mitochondrial calcium control.
  16. Parvalbumin basket cell myelination accumulates axonal mitochondria to internodes.
  17. Uncoupling of energy production.
  18. Astrocyte heterogeneity within white matter tracts and a unique subpopulation of optic nerve head astrocytes.
  19. The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila.
  20. Challenges of genetic diagnosis of inborn errors of metabolism in a major tertiary care center in Lebanon.
  21. dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.
  22. Mitolysosome exocytosis: a novel mitochondrial quality control pathway linked with parkinsonism-like symptoms.
  23. The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction.
  24. Mitochondrial dysfunction of induced pluripotent stem cells-based neurodegenerative disease modeling and therapeutic strategy.
  25. Substitution of PINK1 Gly411 modulates substrate receptivity and turnover.
  26. Eukaryotic evolution: Spatial proteomics sheds light on mitochondrial reduction.
  27. OLA1 Phosphorylation Governs the Mitochondrial Bioenergetic Function of Pulmonary Vascular Cells.
  28. FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM.
  29. Indentification of novel MSTO1 compound heterozygous mutations in a Chinese family with recessive cerebellar atrophy and ataxia.
  30. Stress-induced reversible cell-cycle arrest requires PRC2/PRC1-mediated control of mitophagy in Drosophila germline stem cells and human iPSCs.
  31. A versatile functional assay for genetic variants in human disease.
  32. Retrograde response to mitochondrial dysfunctions associated to LOF variations in FLAD1 exon 2: unraveling the importance of RFVT2.
  33. Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function.
  34. Mitochondrial mutations in protein coding genes of respiratory chain including complexes IV, V, and mt-tRNA genes are associated risk factors for congenital heart disease.
  35. Targeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project.
  36. Whole Genome Sequencing for Detection of Structural Variants in Patients with Retinitis Pigmentosa.
  37. Consumption and Metabolism of Extracellular Pyruvate by Cultured Rat Brain Astrocytes.
  38. Heme-dependent induction of mitophagy program during murine erythroid cell differentiation.
  39. Principles of mitoribosomal small subunit assembly in eukaryotes.
  40. Haematopoietic stem cell quiescence exposed using mitochondrial membrane potential.
  41. Clinical Evaluation of Patients with Retinitis Pigmentosa.
  42. Electroretinogram (ERG) to Evaluate the Retina in Cases of Retinitis Pigmentosa (RP).
  43. The roles of NADPH and isocitrate dehydrogenase in cochlear mitochondrial antioxidant defense and aging.
  44. Mitochondria need their sleep: Sleep-wake cycling and the role of redox, bioenergetics, and temperature regulation, involving cysteine-mediated redox signaling, uncoupling proteins, and substrate cycles.
  45. Molecular Genetic Testing Approaches for Retinitis Pigmentosa.
  46. Glia of C. elegans coordinate a protective organismal heat shock response independent of the neuronal thermosensory circuit.
  47. The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD.
  48. Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.
  49. Teaching old drugs new tricks.
  50. Closing the autophagosome is easy-PC.
  1. Open Biol. 2022 Dec;12(12): 220274
    Mitochondrial biology and dysfunction in secondary mitochondrial disease.
    Megan J Baker, Jordan J Crameri, David R Thorburn, Ann E Frazier, Diana Stojanovski.
      Mitochondrial diseases are a broad, genetically heterogeneous class of metabolic disorders characterized by deficits in oxidative phosphorylation (OXPHOS). Primary mitochondrial disease (PMD) defines pathologies resulting from mutation of mitochondrial DNA (mtDNA) or nuclear genes affecting either mtDNA expression or the biogenesis and function of the respiratory chain. Secondary mitochondrial disease (SMD) arises due to mutation of nuclear-encoded genes independent of, or indirectly influencing OXPHOS assembly and operation. Despite instances of novel SMD increasing year-on-year, PMD is much more widely discussed in the literature. Indeed, since the implementation of next generation sequencing (NGS) techniques in 2010, many novel mitochondrial disease genes have been identified, approximately half of which are linked to SMD. This review will consolidate existing knowledge of SMDs and outline discrete categories within which to better understand the diversity of SMD phenotypes. By providing context to the biochemical and molecular pathways perturbed in SMD, we hope to further demonstrate the intricacies of SMD pathologies outside of their indirect contribution to mitochondrial energy generation.
    Keywords:  mitochondria; mitochondrial protein import; mitochondrial quality control; secondary mitochondrial disease
    DOI:  https://doi.org/10.1098/rsob.220274
  2. Nat Biomed Eng. 2022 Dec 05.
    A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome.
    Pedro Silva-Pinheiro, Christian D Mutti, Lindsey Van Haute, Christopher A Powell, Pavel A Nash, Keira Turner, Michal Minczuk.
      The development of curative treatments for mitochondrial diseases, which are often caused by mutations in mitochondrial DNA (mtDNA) that impair energy metabolism and other aspects of cellular homoeostasis, is hindered by an incomplete understanding of the underlying biology and a scarcity of cellular and animal models. Here we report the design and application of a library of double-stranded-DNA deaminase-derived cytosine base editors optimized for the precise ablation of every mtDNA protein-coding gene in the mouse mitochondrial genome. We used the library, which we named MitoKO, to produce near-homoplasmic knockout cells in vitro and to generate a mouse knockout with high heteroplasmy levels and no off-target edits. MitoKO should facilitate systematic and comprehensive investigations of mtDNA-related pathways and their impact on organismal homoeostasis, and aid the generation of clinically meaningful in vivo models of mtDNA dysfunction.
    DOI:  https://doi.org/10.1038/s41551-022-00968-1
  3. Nat Metab. 2022 Dec 06.
    Mitochondrial RNA stimulates heat production in young adipocytes to reduce obesity.
      
    DOI:  https://doi.org/10.1038/s42255-022-00686-7
  4. Biochim Biophys Acta Bioenerg. 2022 Dec 06. pii: S0005-2728(22)00419-4. [Epub ahead of print] 148949
    Inner mitochondrial membrane structure and fusion dynamics are altered in senescent human iPSC-derived and primary rat cardiomyocytes.
    Silke Morris, Isidora Molina-Riquelme, Gonzalo Barrientos, Francisco Bravo, Geraldine Aedo, Wileidy Gómez, Daniel Lagos, Hugo Verdejo, Stefan Peischard, Guiscard Seebohm, Olympia Ekaterini Psathaki, Verónica Eisner, Karin B Busch.
      Dysfunction of the aging heart is a major cause of death in the human population. Amongst other tasks, mitochondria are pivotal to supply the working heart with ATP. The mitochondrial inner membrane (IMM) ultrastructure is tailored to meet these demands and to provide nano-compartments for specific tasks. Thus, function and morphology are closely coupled. Senescent cardiomyocytes from the mouse heart display alterations of the inner mitochondrial membrane. To study the relation between inner mitochondrial membrane architecture, dynamics and function is hardly possible in living organisms. Here, we present two cardiomyocyte senescence cell models that allow in cellular studies of mitochondrial performance. We show that doxorubicin treatment transforms human iPSC-derived cardiomyocytes and rat neonatal cardiomyocytes in an aged phenotype. The treated cardiomyocytes display double-strand breaks in the nDNA, have β-galactosidase activity, possess enlarged nuclei, and show p21 upregulation. Most importantly, they also display a compromised inner mitochondrial structure. This prompted us to test whether the dynamics of the inner membrane was also altered. We found that the exchange of IMM components after organelle fusion was faster in doxorubicin-treated cells than in control cells, with no change in mitochondrial fusion dynamics at the meso-scale. Such altered IMM morphology and dynamics may have important implications for local OXPHOS protein organization, exchange of damaged components, and eventually the mitochondrial bioenergetics function of the aged cardiomyocyte.
    Keywords:  Cardiomyocytes; Cristae structure; Doxorubicin; Inner mitochondrial membrane dynamics; Mitochondrial fusion and fission dynamics; Senescence
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148949
  5. J Hum Genet. 2022 Dec 08.
    Novel biallelic mutations in TMEM126B cause splicing defects and lead to Leigh-like syndrome with severe complex I deficiency.
    Xiyue Zhou, Xiaoting Lou, Yuwei Zhou, Yaojun Xie, Xinyu Han, Qiyu Dong, Xiaojie Ying, Mahlatsi Refiloe Laurentinah, Luyi Zhang, Zhehui Chen, Dongxiao Li, Hezhi Fang, Jianxin Lyu, Yanling Yang, Ya Wang.
      Leigh syndrome (LS)/Leigh-like syndrome (LLS) is one of the most common mitochondrial disease subtypes, caused by mutations in either the nuclear or mitochondrial genomes. Here, we identified a novel intronic mutation (c.82-2 A > G) and a novel exonic insertion mutation (c.290dupT) in TMEM126B from a Chinese patient with clinical manifestations of LLS. In silico predictions, minigene splicing assays and patients' RNA analyses determined that the c.82-2 A > G mutation resulted in complete exon 2 skipping, and the c.290dupT mutation provoked partial and complete exon 3 skipping, leading to translational frameshifts and premature termination. Functional analysis revealed the impaired mitochondrial function in patient-derived lymphocytes due to severe complex I content and assembly defect. Altogether, this is the first report of LLS in a patient carrying mutations in TMEM126B. Our data uncovers the functional effect and the molecular mechanism of the pathogenic variants c.82-2 A > G and c.290dupT, which expands the gene mutation spectrum of LLS and clinical spectrum caused by TMEM126B mutations, and thus help to clinical diagnosis of TMEM126B mutation-related mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s10038-022-01102-4
  6. Brain. 2022 Dec 07. pii: awac464. [Epub ahead of print]
    Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson's disease.
    Joanne Trinh, Andrew A Hicks, Inke R König, Sylvie Delcambre, Theresa Lüth, Susen Schaake, Kobi Wasner, Jenny Ghelfi, Max Borsche, Carles Vilariño-Güell, Faycel Hentati, Elisabeth L Germer, Peter Bauer, Masashi Takanashi, Vladimir Kostić, Anthony E Lang, Norbert Brüggemann, Peter P Pramstaller, Irene Pichler, Alex Rajput, Nobutaka Hattori, Matthew J Farrer, Katja Lohmann, Hansi Weissensteiner, Patrick May, Christine Klein, Anne Grünewald.
      Biallelic mutations in PINK1/PRKN cause recessive Parkinson's disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as disease modifiers in carriers of mutations in these genes. MtDNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson's disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC = 0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and postmortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Lastly, the heteroplasmic mtDNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, p = 0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner.
    Keywords:  PINK1; PRKN; modifiers; mtDNA heteroplasmy; penetrance
    DOI:  https://doi.org/10.1093/brain/awac464
  7. Sci Data. 2022 Dec 03. 9(1): 751
    A multi-omics longitudinal aging dataset in primary human fibroblasts with mitochondrial perturbations.
    Gabriel Sturm, Anna S Monzel, Kalpita R Karan, Jeremy Michelson, Sarah A Ware, Andres Cardenas, Jue Lin, Céline Bris, Balaji Santhanam, Michael P Murphy, Morgan E Levine, Steve Horvath, Daniel W Belsky, Shuang Wang, Vincent Procaccio, Brett A Kaufman, Michio Hirano, Martin Picard.
      Aging is a process of progressive change. To develop biological models of aging, longitudinal datasets with high temporal resolution are needed. Here we report a multi-omics longitudinal dataset for cultured primary human fibroblasts measured across their replicative lifespans. Fibroblasts were sourced from both healthy donors (n = 6) and individuals with lifespan-shortening mitochondrial disease (n = 3). The dataset includes cytological, bioenergetic, DNA methylation, gene expression, secreted proteins, mitochondrial DNA copy number and mutations, cell-free DNA, telomere length, and whole-genome sequencing data. This dataset enables the bridging of mechanistic processes of aging as outlined by the "hallmarks of aging", with the descriptive characterization of aging such as epigenetic age clocks. Here we focus on bridging the gap for the hallmark mitochondrial metabolism. Our dataset includes measurement of healthy cells, and cells subjected to over a dozen experimental manipulations targeting oxidative phosphorylation (OxPhos), glycolysis, and glucocorticoid signaling, among others. These experiments provide opportunities to test how cellular energetics affect the biology of cellular aging. All data are publicly available at our webtool: https://columbia-picard.shinyapps.io/shinyapp-Lifespan_Study/.
    DOI:  https://doi.org/10.1038/s41597-022-01852-y
  8. J Transl Med. 2022 Dec 05. 20(1): 562
    Current advances in gene therapy of mitochondrial diseases.
    Vladislav O Soldatov, Marina V Kubekina, Marina Yu Skorkina, Andrei E Belykh, Tatiana V Egorova, Mikhail V Korokin, Mikhail V Pokrovskiy, Alexey V Deykin, Plamena R Angelova.
      Mitochondrial diseases (MD) are a heterogeneous group of multisystem disorders involving metabolic errors. MD are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystem dysfunction with different clinical courses. Most primary MD are autosomal recessive but maternal inheritance (from mtDNA), autosomal dominant, and X-linked inheritance is also known. Mitochondria are unique energy-generating cellular organelles designed to survive and contain their own unique genetic coding material, a circular mtDNA fragment of approximately 16,000 base pairs. The mitochondrial genetic system incorporates closely interacting bi-genomic factors encoded by the nuclear and mitochondrial genomes. Understanding the dynamics of mitochondrial genetics supporting mitochondrial biogenesis is especially important for the development of strategies for the treatment of rare and difficult-to-diagnose diseases. Gene therapy is one of the methods for correcting mitochondrial disorders.
    Keywords:  Energy metabolism; Gene therapy; Heteroplasmy; Mitochondrial DNA; Mitochondrial diseases
    DOI:  https://doi.org/10.1186/s12967-022-03685-0
  9. Biochim Biophys Acta Bioenerg. 2022 Dec 05. pii: S0005-2728(22)00417-0. [Epub ahead of print] 148947
    Xenotopic expression of alternative oxidase (AOX) to study mechanisms of mitochondrial disease.
    Carlo Viscomi, Anthony L Moore, Massimo Zeviani, Marten Szibor.
      The mitochondrial respiratory chain or electron transport chain (ETC) facilitates redox reactions which ultimately lead to the reduction of oxygen to water (respiration). Energy released by this process is used to establish a proton electrochemical gradient which drives ATP formation (oxidative phosphorylation, OXPHOS). It also plays an important role in vital processes beyond ATP formation and cellular metabolism, such as heat production, redox and ion homeostasis. Dysfunction of the ETC can thus impair cellular and organismal viability and is thought to be the underlying cause of a heterogeneous group of so-called mitochondrial diseases. Plants, yeasts, and many lower organisms, but not insects and vertebrates, possess an enzymatic mechanism that confers resistance to respiratory stress conditions, i.e. the alternative oxidase (AOX). Even in cells that naturally lack AOX, it is autonomously imported into the mitochondrial compartment upon xenotopic expression, where it refolds and becomes catalytically engaged when the cytochrome segment of the ETC is blocked. AOX was therefore proposed as a tool to study disease etiologies. To this end, AOX has been xenotopically expressed in mammalian cells and disease models of the fruit fly and mouse. Surprisingly, AOX showed remarkable rescue effects in some cases, whilst in others it had no effect or even exacerbated a condition. Here we summarize what has been learnt from the use of AOX in various disease models and discuss issues which still need to be addressed in order to understand the role of the ETC in health and disease.
    Keywords:  Alternative oxidase; Disease models; Mitochondria; Mitochondrial disease; Mouse; Xenogene
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148947
  10. Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01657-6. [Epub ahead of print]41(10): 111774
    Mitochondrial cristae architecture protects against mtDNA release and inflammation.
    Baiyu He, Huatong Yu, Shanshan Liu, Huayun Wan, Song Fu, Siqi Liu, Jun Yang, Zihan Zhang, Huanwei Huang, Qi Li, Fengchao Wang, Zhaodi Jiang, Qinghua Liu, Hui Jiang.
      Mitochondrial damage causes mitochondrial DNA (mtDNA) release to activate the type I interferon (IFN-I) response via the cGAS-STING pathway. mtDNA-induced inflammation promotes autoimmune- and aging-related degenerative disorders. However, the global picture of inflammation-inducing mitochondrial damages remains obscure. Here, we have performed a mitochondria-targeted CRISPR knockout screen for regulators of the IFN-I response. Strikingly, our screen reveals dozens of hits enriched with key regulators of cristae architecture, including phospholipid cardiolipin and protein complexes such as OPA1, mitochondrial contact site and cristae organization (MICOS), sorting and assembly machinery (SAM), mitochondrial intermembrane space bridging (MIB), prohibitin (PHB), and the F1Fo-ATP synthase. Disrupting these cristae organizers consistently induces mtDNA release and the STING-dependent IFN-I response. Furthermore, knocking out MTX2, a subunit of the SAM complex whose null mutations cause progeria in humans, induces a robust STING-dependent IFN-I response in mouse liver. Taken together, beyond revealing the central role of cristae architecture to prevent mtDNA release and inflammation, our results mechanistically link mitochondrial cristae disorganization and inflammation, two emerging hallmarks of aging and aging-related degenerative diseases.
    Keywords:  CP: Cell biology; CP: Molecular biology; MICOS; Metaxin2; OPA1; SAM; cGAS-STING; cristae architecture; inflammation; mtDNA release; type I interferon response
    DOI:  https://doi.org/10.1016/j.celrep.2022.111774
  11. Exp Mol Med. 2022 Dec 06.
    Mitochondrial PARP1 regulates NAD+-dependent poly ADP-ribosylation of mitochondrial nucleoids.
    Jong-Hyuk Lee, Mansoor Hussain, Edward W Kim, Shang-Jung Cheng, Anthony K L Leung, Nima Borhan Fakouri, Deborah L Croteau, Vilhelm A Bohr.
      PARPs play fundamental roles in multiple DNA damage recognition and repair pathways. Persistent nuclear PARP activation causes cellular NAD+ depletion and exacerbates cellular aging. However, very little is known about mitochondrial PARP (mtPARP) and poly ADP-ribosylation (PARylation). The existence of mtPARP is controversial, and the biological roles of mtPARP-induced mitochondrial PARylation are unclear. Here, we demonstrate the presence of PARP1 and PARylation in purified mitochondria. The addition of the PARP1 substrate NAD+ to isolated mitochondria induced PARylation, which was suppressed by treatment with the inhibitor olaparib. Mitochondrial PARylation was also evaluated by enzymatic labeling of terminal ADP-ribose (ELTA). To further confirm the presence of mtPARP1, we evaluated mitochondrial nucleoid PARylation by ADP ribose-chromatin affinity purification (ADPr-ChAP) and PARP1 chromatin immunoprecipitation (ChIP). We observed that NAD+ stimulated PARylation and TFAM occupancy on the mtDNA regulatory region D-loop, inducing mtDNA transcription. These findings suggest that PARP1 is integrally involved in mitochondrial PARylation and that NAD+-dependent mtPARP1 activity contributes to mtDNA transcriptional regulation.
    DOI:  https://doi.org/10.1038/s12276-022-00894-x
  12. Cell Metab. 2022 Dec 06. pii: S1550-4131(22)00495-8. [Epub ahead of print]34(12): 1947-1959.e5
    NAD precursors cycle between host tissues and the gut microbiome.
    Karthikeyani Chellappa, Melanie R McReynolds, Wenyun Lu, Xianfeng Zeng, Mikhail Makarov, Faisal Hayat, Sarmistha Mukherjee, Yashaswini R Bhat, Siddharth R Lingala, Rafaella T Shima, Hélène C Descamps, Timothy Cox, Lixin Ji, Connor Jankowski, Qingwei Chu, Shawn M Davidson, Christoph A Thaiss, Marie E Migaud, Joshua D Rabinowitz, Joseph A Baur.
      Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor in mammals and microbes. Here we use isotope tracing to investigate the precursors supporting NAD synthesis in the gut microbiome of mice. We find that dietary NAD precursors are absorbed in the proximal part of the gastrointestinal tract and not available to microbes in the distal gut. Instead, circulating host nicotinamide enters the gut lumen and supports microbial NAD synthesis. The microbiome converts host-derived nicotinamide into nicotinic acid, which is used for NAD synthesis in host tissues and maintains circulating nicotinic acid levels even in the absence of dietary consumption. Moreover, the main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome. Thus, we establish the capacity for circulating host micronutrients to feed the gut microbiome, and in turn be transformed in a manner that enhances host metabolic flexibility.
    Keywords:  NAD; flux; gastrointestinal; microbe; microbiome; mononucleotide; niacin; nicotinamide; nicotinic acid; riboside
    DOI:  https://doi.org/10.1016/j.cmet.2022.11.004
  13. Elife. 2022 Dec 08. pii: e77460. [Epub ahead of print]11
    Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules.
    Yuzuru Itoh, Vivek Singh, Anas Khawaja, Andreas Naschberger, Minh Duc Nguyen, Joanna Rorbach, Alexey Amunts.
      The mitoribosome regulates cellular energy production, and its dysfunction is associated with aging. Inhibition of the mitoribosome can be caused by off-target binding of antimicrobial drugs and was shown to be coupled with a bilateral decreased visual acuity. Previously, we reported mitochondria-specific protein aspects of the mitoribosome, and in this article we present a 2.4-Å resolution structure of the small subunit in a complex with the anti-tuberculosis drug streptomycin that reveals roles of non-protein components. We found iron-sulfur clusters that are coordinated by different mitoribosomal proteins, nicotinamide adenine dinucleotide (NAD) associated with rRNA insertion, and posttranslational modifications. This is the first evidence of inter-protein coordination of iron-sulfur, and the finding of iron-sulfur clusters and NAD as fundamental building blocks of the mitoribosome directly links to mitochondrial disease and aging. We also report details of streptomycin interactions, suggesting that the mitoribosome-bound streptomycin is likely to be in hydrated gem-diol form and can be subjected to other modifications by the cellular milieu. The presented approach of adding antibiotics to cultured cells can be used to define their native structures in a bound form under more physiological conditions, and since streptomycin is a widely used drug for treatment, the newly resolved features can serve as determinants for targeting.
    Keywords:  Fe–S cluster; aging; antibiotics; human; mitochondria; mitoribosome; molecular biophysics; structural biology; translation
    DOI:  https://doi.org/10.7554/eLife.77460
  14. Neurobiol Dis. 2022 Dec 05. pii: S0969-9961(22)00333-3. [Epub ahead of print]176 105941
    DJ-1 promotes energy balance by regulating both mitochondrial and autophagic homeostasis.
    Federica De Lazzari, Francesco Agostini, Nicoletta Plotegher, Michele Sandre, Elisa Greggio, Aram Megighian, Luigi Bubacco, Federica Sandrelli, Alexander J Whitworth, Marco Bisaglia.
      The protein DJ-1 is mutated in rare familial forms of recessive Parkinson's disease and in parkinsonism accompanied by amyotrophic lateral sclerosis symptoms and dementia. DJ-1 is considered a multitasking protein able to confer protection under various conditions of stress. However, the precise cellular function still remains elusive. In the present work, we evaluated fruit flies lacking the expression of the DJ-1 homolog dj-1β as compared to control aged-matched individuals. Behavioral evaluations included lifespan, locomotion in an open field arena, sensitivity to oxidative insults, and resistance to starvation. Molecular analyses were carried out by analyzing the mitochondrial morphology and functionality, and the autophagic response. We demonstrated that dj-1β null mutant flies are hypoactive and display higher sensitivity to oxidative insults and food deprivation. Analysis of mitochondrial homeostasis revealed that loss of dj-1β leads to larger and more circular mitochondria, characterized by impaired complex-I-linked respiration while preserving ATP production capacity. Additionally, dj-1β null mutant flies present an impaired autophagic response, which is suppressed by treatment with the antioxidant molecule N-Acetyl-L-Cysteine. Overall, our data point to a mechanism whereby DJ-1 plays a critical role in the maintenance of energy homeostasis, by sustaining mitochondrial homeostasis and affecting the autophagic flux through the maintenance of the cellular redox state. In light of the involvement of DJ-1 in neurodegenerative diseases and considering that neurons are highly energy-demanding cells, particularly sensitive to redox stress, our study sheds light on a key role of DJ-1 in the maintenance of cellular homeostasis.
    Keywords:  Autophagy; DJ-1; Energy balance; Mitochondria; Redox homeostasis
    DOI:  https://doi.org/10.1016/j.nbd.2022.105941
  15. iScience. 2022 Dec 22. 25(12): 105654
    Enzymatically dissociated muscle fibers display rapid dedifferentiation and impaired mitochondrial calcium control.
    Charlotte Gineste, Sonia Youhanna, Sabine U Vorrink, Sara Henriksson, Andrés Hernández, Arthur J Cheng, Thomas Chaillou, Andreas Buttgereit, Dominik Schneidereit, Oliver Friedrich, Kjell Hultenby, Joseph D Bruton, Niklas Ivarsson, Linda Sandblad, Volker M Lauschke, Håkan Westerblad.
      Cells rapidly lose their physiological phenotype upon disruption of their extracellular matrix (ECM)-intracellular cytoskeleton interactions. By comparing adult mouse skeletal muscle fibers, isolated either by mechanical dissection or by collagenase-induced ECM digestion, we investigated acute effects of ECM disruption on cellular and mitochondrial morphology, transcriptomic signatures, and Ca2+ handling. RNA-sequencing showed striking differences in gene expression patterns between the two isolation methods with enzymatically dissociated fibers resembling myopathic phenotypes. Mitochondrial appearance was grossly similar in the two groups, but 3D electron microscopy revealed shorter and less branched mitochondria following enzymatic dissociation. Repeated contractions resulted in a prolonged mitochondrial Ca2+ accumulation in enzymatically dissociated fibers, which was partially prevented by cyclophilin inhibitors. Of importance, muscle fibers of mice with severe mitochondrial myopathy show pathognomonic mitochondrial Ca2+ accumulation during repeated contractions and this accumulation was concealed with enzymatic dissociation, making this an ambiguous method in studies of native intracellular Ca2+ fluxes.
    Keywords:  Cell biology; Cellular physiology; Developmental biology; Functional aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105654
  16. Nat Commun. 2022 Dec 09. 13(1): 7598
    Parvalbumin basket cell myelination accumulates axonal mitochondria to internodes.
    Koen Kole, Bas J B Voesenek, Maria E Brinia, Naomi Petersen, Maarten H P Kole.
      Parvalbumin-expressing (PV+) basket cells are fast-spiking inhibitory interneurons that exert critical control over local circuit activity and oscillations. PV+ axons are often myelinated, but the electrical and metabolic roles of interneuron myelination remain poorly understood. Here, we developed viral constructs allowing cell type-specific investigation of mitochondria with genetically encoded fluorescent probes. Single-cell reconstructions revealed that mitochondria selectively cluster to myelinated segments of PV+ basket cells, confirmed by analyses of a high-resolution electron microscopy dataset. In contrast to the increased mitochondrial densities in excitatory axons cuprizone-induced demyelination abolished mitochondrial clustering in PV+ axons. Furthermore, with genetic deletion of myelin basic protein the mitochondrial clustering was still observed at internodes wrapped by noncompacted myelin, indicating that compaction is dispensable. Finally, two-photon imaging of action potential-evoked calcium (Ca2+) responses showed that interneuron myelination attenuates both the cytosolic and mitochondrial Ca2+ transients. These findings suggest that oligodendrocyte ensheathment of PV+ axons assembles mitochondria to branch selectively fine-tune metabolic demands.
    DOI:  https://doi.org/10.1038/s41467-022-35350-x
  17. Cell Metab. 2022 Dec 06. pii: S1550-4131(22)00499-5. [Epub ahead of print]34(12): 1901-1903
    Uncoupling of energy production.
    Yi Shiau Ng, Doug M Turnbull.
      Mitochondrial genetic diseases are a very diverse group of conditions. A recent report by Mootha and colleagues in NEJM describes the underlying genetic defect and clinical findings in monozygotic twins with uncoupling of ATP production.
    DOI:  https://doi.org/10.1016/j.cmet.2022.11.008
  18. iScience. 2022 Dec 22. 25(12): 105568
    Astrocyte heterogeneity within white matter tracts and a unique subpopulation of optic nerve head astrocytes.
    Arpan G Mazumder, Amélie M Julé, Paul F Cullen, Daniel Sun.
      Much of what we know about astrocyte form and function is derived from the study of gray matter protoplasmic astrocytes, whereas white matter fibrous astrocytes remain relatively unexplored. Here, we used the ribotag approach to isolate ribosome-associated mRNA and investigated the transcriptome of uninjured fibrous astrocytes from three regions: unmyelinated optic nerve head, myelinated optic nerve proper, and corpus callosum. Astrocytes from each region were transcriptionally distinct and we identified region-specific astrocyte genes and pathways. Energy metabolism, particularly oxidative phosphorylation and mitochondrial protein translation emerged as key differentiators of astrocyte populations. Optic nerve astrocytes expressed higher levels of neuroinflammatory pathways than corpus callosum astrocytes and we further identified CARTPT as a new marker of optic nerve head astrocytes. These previously uncharacterized transcriptional profiles of white matter astrocyte types reveal their functional diversity and a greater heterogeneity than previously appreciated.
    Keywords:  Sensory neuroscience; cell biology; transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2022.105568
  19. Elife. 2022 Dec 07. pii: e80245. [Epub ahead of print]11
    The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila.
    Arnau Llobet Rosell, Maria Paglione, Jonathan Gilley, Magdalena Kocia, Giulia Perillo, Massimiliano Gasparrini, Lucia Cialabrini, Nadia Raffaelli, Carlo Angeletti, Giuseppe Orsomando, Pei-Hsuan Wu, Michael P Coleman, Andrea Loreto, Lukas Jakob Neukomm.
      Axon degeneration contributes to the disruption of neuronal circuit function in diseased and injured nervous systems. Severed axons degenerate following the activation of an evolutionarily conserved signaling pathway, which culminates in the activation of SARM1 in mammals to execute the pathological depletion of the metabolite NAD+. SARM1 NADase activity is activated by the NAD+ precursor nicotinamide mononucleotide (NMN). In mammals, keeping NMN levels low potently preserves axons after injury. However, it remains unclear whether NMN is also a key mediator of axon degeneration and dSarm activation in flies. Here, we demonstrate that lowering NMN levels in Drosophila through the expression of a newly generated prokaryotic NMN-Deamidase (NMN-D) preserves severed axons for months and keeps them circuit-integrated for weeks. NMN-D alters the NAD+ metabolic flux by lowering NMN, while NAD+ remains unchanged in vivo. Increased NMN synthesis, by the expression of mouse nicotinamide phosphoribosyltransferase (mNAMPT), leads to faster axon degeneration after injury. We also show that NMN-induced activation of dSarm mediates axon degeneration in vivo. Finally, NMN-D delays neurodegeneration caused by loss of the sole NMN-consuming and NAD+-synthesizing enzyme dNmnat. Our results reveal a critical role for NMN in neurodegeneration in the fly, which extends beyond axonal injury. The potent neuroprotection by reducing NMN levels is similar to the interference with other essential mediators of axon degeneration in Drosophila.
    Keywords:  D. melanogaster; cell biology; neuroscience
    DOI:  https://doi.org/10.7554/eLife.80245
  20. Front Genet. 2022 ;13 1029947
    Challenges of genetic diagnosis of inborn errors of metabolism in a major tertiary care center in Lebanon.
    Doaa O Salman, Rami Mahfouz, Elio R Bitar, Jinane Samaha, Pascale E Karam.
      Background: Inborn errors of metabolism are rare genetic disorders; however, these are prevalent in countries with high consanguinity rates, like Lebanon. Patients are suspected, based on a combination of clinical and biochemical features; however, the final confirmation relies on genetic testing. Using next generation sequencing, as a new genetic investigational tool, carries several challenges for the physician, the geneticist, and the families. Methods: In this retrospective study, we analyzed the clinical, biochemical, and genetic profile of inborn errors of metabolism suspected patients, seen at a major tertiary care center in Lebanon, between 2015 and 2018. Genetic testing was performed using next generation sequencing. Genotype-phenotype correlation and diagnostic yield of each testing modality were studied. Results: Out of 211 patients genetically tested, 126 were suspected to have an inborn error of metabolism. The diagnostic yield of next generation sequencing reached 64.3%. Single gene testing was requested in 53%, whole exome sequencing in 36% and gene panels in 10%. Aminoacid disorders were mostly diagnosed followed by storage disorders, organic acidemias and mitochondrial diseases. Targeted testing was performed in 77% of aminoacid and organic acid disorders and half of suspected storage disorders. Single gene sequencing was positive in 75%, whereas whole exome sequencing diagnostic yield for complex cases, like mitochondrial disorders, reached 49%. Good clinical and biochemical correlation allowed the interpretation of variants of unknown significance and negative mutations as well as therapeutic management of most patients. Conclusion: Tailoring the choice of test modality, by next generation sequencing, to the category of suspected inborn errors of metabolism may lead to rapid diagnosis, shortcutting the cost of repeated testing. Whole exome sequencing as a first-tier investigation may be considered mainly for suspected mitochondrial diseases, whereas targeted sequencing can be offered upon suspicion of a specific enzyme deficiency. Timing and modality of gene test remain challenging, in view of the cost incurred by families.
    Keywords:  Arab countries; diagnostic yield; inborn errors of metabolism (IEM); next gen sequencing; whole exome sequencing
    DOI:  https://doi.org/10.3389/fgene.2022.1029947
  21. J Mol Cell Cardiol. 2022 Dec 02. pii: S0022-2828(22)00570-3. [Epub ahead of print]
    dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.
    Ketaki N Mhatre, Jason D Murray, Galina Flint, Timothy S McMillen, Gerhard Weber, Majid Shakeri, An-Yue Tu, Sonette Steczina, Robert Weiss, David J Marcinek, Charles E Murry, Daniel Raftery, Rong Tian, Farid Moussavi-Harami, Michael Regnier.
      Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ~1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB-CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.
    Keywords:  Cardiac DRX; Cardiomyocyte metabolism; Contraction; Mitochondrial remodeling; Myosin activator; dATP
    DOI:  https://doi.org/10.1016/j.yjmcc.2022.11.010
  22. Biochem Soc Trans. 2022 Dec 09. pii: BST20220726. [Epub ahead of print]
    Mitolysosome exocytosis: a novel mitochondrial quality control pathway linked with parkinsonism-like symptoms.
    Feixiang Bao, Lingyan Zhou, Jiahui Xiao, Xingguo Liu.
      Quality control of mitochondria is essential for their homeostasis and function. Light chain 3 (LC3) associated autophagosomes-mediated mitophagy represents a canonical mitochondrial quality control pathway. Alternative quality control processes, such as mitochondrial-derived vesicles (MDVs), have been discovered, but the intact mitochondrial quality control remains unknown. We recently discovered a novel mitolysosome exocytosis mechanism for mitochondrial quality control in flunarizine (FNZ)-induced mitochondria clearance, where autophagosomes are not required, but rather mitochondria are engulfed directly by lysosomes, mediating mitochondrial secretion. As FNZ results in parkinsonism, we propose that excessive mitolysosome exocytosis is the cause.
    Keywords:  extracellular vesicles; lysosome; mitochondria-free; mitochondrial quality control; parkinsonism
    DOI:  https://doi.org/10.1042/BST20220726
  23. Nat Commun. 2022 Dec 08. 13(1): 7576
    The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction.
    Guanlan Hu, Catriona Ling, Lijun Chi, Mehakpreet K Thind, Samuel Furse, Albert Koulman, Jonathan R Swann, Dorothy Lee, Marjolein M Calon, Celine Bourdon, Christian J Versloot, Barbara M Bakker, Gerard Bryan Gonzales, Peter K Kim, Robert H J Bandsma.
      Mortality in children with severe malnutrition is strongly related to signs of metabolic dysfunction, such as hypoglycemia. Lower circulating tryptophan levels in children with severe malnutrition suggest a possible disturbance in the tryptophan-nicotinamide adenine dinucleotide (TRP-NAD+) pathway and subsequently in NAD+  dependent metabolism regulator sirtuin1 (SIRT1). Here we show that severe malnutrition in weanling mice, induced by 2-weeks of low protein diet feeding from weaning, leads to an impaired TRP-NAD+  pathway with decreased NAD+ levels and affects hepatic mitochondrial turnover and function. We demonstrate that stimulating the TRP-NAD+  pathway with NAD+  precursors improves hepatic mitochondrial and overall metabolic function through SIRT1 modulation. Activating SIRT1 is sufficient to induce improvement in metabolic functions. Our findings indicate that modulating the TRP-NAD+  pathway can improve liver metabolic function in a mouse model of severe malnutrition. These results could lead to the development of new interventions for children with severe malnutrition.
    DOI:  https://doi.org/10.1038/s41467-022-35317-y
  24. Front Cell Dev Biol. 2022 ;10 1030390
    Mitochondrial dysfunction of induced pluripotent stem cells-based neurodegenerative disease modeling and therapeutic strategy.
    Hong-Mei Luo, Jia Xu, Dan-Xia Huang, Yun-Qiang Chen, Yi-Zhou Liu, Ya-Jie Li, Hong Chen.
      Neurodegenerative diseases (NDDs) are disorders in which neurons are lost owing to various factors, resulting in a series of dysfunctions. Their rising prevalence and irreversibility have brought physical pain to patients and economic pressure to both individuals and society. However, the pathogenesis of NDDs has not yet been fully elucidated, hampering the use of precise medication. Induced pluripotent stem cell (IPSC) modeling provides a new method for drug discovery, and exploring the early pathological mechanisms including mitochondrial dysfunction, which is not only an early but a prominent pathological feature of NDDs. In this review, we summarize the iPSC modeling approach of Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis, as well as outline typical mitochondrial dysfunction and recapitulate corresponding therapeutic strategies.
    Keywords:  IPSCs (induced pluripotent stem cells); mitochondrial dynamic; mitochondrial dysfunction; mitochondrial energy metabolism; mitochondrial transport; neurodegenerative diseases; therapeutic strategy
    DOI:  https://doi.org/10.3389/fcell.2022.1030390
  25. Autophagy. 2022 Dec 05. 1-22
    Substitution of PINK1 Gly411 modulates substrate receptivity and turnover.
    Fabienne C Fiesel, Dominika Fričová, Caleb S Hayes, Mathew A Coban, Roman Hudec, Jenny M Bredenberg, Benjamin J Broadway, Briana N Markham, Tingxiang Yan, Paige K Boneski, Gabriella Fiorino, Jens O Watzlawik, Xu Hou, Arthur M McCarty, Laura J Lewis-Tuffin, Jun Zhong, Benjamin J Madden, Alban Ordureau, Heeseon An, Andreas Puschmann, Zbigniew K Wszolek, Owen A Ross, J Wade Harper, Thomas R Caulfield, Wolfdieter Springer.
      The ubiquitin (Ub) kinase-ligase pair PINK1-PRKN mediates the degradation of damaged mitochondria by macroautophagy/autophagy (mitophagy). PINK1 surveils mitochondria and upon stress accumulates on the mitochondrial surface where it phosphorylates serine 65 of Ub to activate PRKN and to drive mitochondrial turnover. While loss of either PINK1 or PRKN is genetically linked to Parkinson disease (PD) and activating the pathway seems to have great therapeutic potential, there is no formal proof that stimulation of mitophagy is always beneficial. Here we used biochemical and cell biological methods to study single nucleotide variants in the activation loop of PINK1 to modulate the enzymatic function of this kinase. Structural modeling and in vitro kinase assays were used to investigate the molecular mechanism of the PINK1 variants. In contrast to the PD-linked PINK1G411S mutation that diminishes Ub kinase activity, we found that the PINK1G411A variant significantly boosted Ub phosphorylation beyond levels of PINK1 wild type. This resulted in augmented PRKN activation, mitophagy rates and increased viability after mitochondrial stress in midbrain-derived, gene-edited neurons. Mechanistically, the G411A variant stabilizes the kinase fold of PINK1 and transforms Ub to adopt the preferred, C-terminally retracted conformation for improved substrate turnover. In summary, we identify a critical role of residue 411 for substrate receptivity that may now be exploited for drug discovery to increase the enzymatic function of PINK1. The genetic substitution of Gly411 to Ala increases mitophagy and may be useful to confirm neuroprotection in vivo and might serve as a critical positive control during therapeutic development.Abbreviations: ATP: adenosine triphosphate; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; Ub-CR: ubiquitin with C-terminally retracted tail; CTD: C-terminal domain (of PINK1); ELISA: enzyme-linked immunosorbent assay; HCI: high-content imaging; IB: immunoblot; IF: immunofluorescence; NPC: neuronal precursor cells; MDS: molecular dynamics simulation; PD: Parkinson disease; p-S65-Ub: ubiquitin phosphorylated at Ser65; RMSF: root mean scare fluctuation; TOMM: translocase of outer mitochondrial membrane; TVLN: ubiquitin with T66V and L67N mutation, mimics Ub-CR; Ub: ubiquitin; WT: wild-type.
    Keywords:  Mitophagy; PINK1; PRKN; parkin; parkinson disease; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2022.2151294
  26. Curr Biol. 2022 Dec 05. pii: S0960-9822(22)01687-6. [Epub ahead of print]32(23): R1308-R1311
    Eukaryotic evolution: Spatial proteomics sheds light on mitochondrial reduction.
    Michelle M Leger, Courtney Stairs.
      Multi-organelle spatial proteomics has revolutionized animal cell biology, but its use in protists has so far been limited. A new study delivers the first such proteome of a free-living protist, uncovering a previously overlooked function of highly reduced mitochondria.
    DOI:  https://doi.org/10.1016/j.cub.2022.10.039
  27. Am J Respir Cell Mol Biol. 2022 Dec 08.
    OLA1 Phosphorylation Governs the Mitochondrial Bioenergetic Function of Pulmonary Vascular Cells.
    Paul Sidlowski, Amanda Czerwinski, Yong Liu, Pengyuan Liu, Ru-Jeng Teng, Suresh Kumar, Clive Wells, Kirkwood Pritchard, Girija G Konduri, Adeleye J Afolayan.
      Mitochondrial function and metabolic homeostasis are integral to cardiovascular function and influence how vascular cells respond to stress. However, little is known regarding how mitochondrial redox control mechanisms and metabolic regulation interact in the developing lungs. Here we show that human Obg-like ATPase-1 (OLA1) couples redox signals to the metabolic response pathway by activating metabolic gene transcription in the nucleus. We observed that OLA1 phosphorylation at Ser232/Tyr236 triggers its translocation from the cytoplasm/mitochondria into the nucleus. Subsequent phosphorylation of OLA1 at Thr325 effectively changes its biochemical function from ATPase to GTPase, promoting the expression of genes involved in the mitochondrial bioenergetic function. This process is regulated by extracellular-regulated kinases (ERK1/2), which were restrained by protein phosphatases 1A (PP1A) when stress abated. Knockdowns of ERK1 or OLA1 mutated to a phosphoresistant T325A mutant blocked its nuclear translocation, compromised the expression of nuclear-encoded mitochondrial genes, and as a consequence, led to cellular energy depletion. Moreover, the lungs of OLA1 knockout mice have fewer numbers of mitochondria, lower cellular ATP levels, and higher lactate levels. The ensuing mitochondrial metabolic dysfunction resulted in abnormal behaviors of pulmonary vascular cells and significant vascular remodeling. Our findings demonstrate that OLA1 is an important component of the mitochondrial retrograde communication pathways that couple stress signals with metabolic genes in the nucleus. Thus, phosphorylation-dependent nuclear OLA1 localization that governs cellular energy metabolism is critical to cardiovascular function.
    Keywords:  OLA1; mitochondrial energy metabolism; phosphorylation; pulmonary hypertension; pulmonary vascular cells
    DOI:  https://doi.org/10.1165/rcmb.2022-0186OC
  28. Cell Death Dis. 2022 Dec 05. 13(12): 1020
    FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM.
    Yaguang Bi, Haixia Xu, Xiang Wang, Hong Zhu, Junbo Ge, Jun Ren, Yingmei Zhang.
      Doxorubicin (DOX) is an effective anthracycline chemotherapeutic anticancer drug with its life-threatening cardiotoxicity severely limiting its clinical application. Mitochondrial damage-induced cardiomyocyte death is considered an essential cue for DOX cardiotoxicity. FUN14 domain containing 1 (FUNDC1) is a mitochondrial membrane protein participating in the regulation of mitochondrial integrity in multiple diseases although its role in DOX cardiomyopathy remains elusive. Here, we examined whether PANoptosis, a novel type of programmed cell death closely associated with mitochondrial damage, was involved in DOX-induced heart injury, and FUNDC1-mediated regulation of cardiomyocyte PANoptosis, if any. FUNDC1 was downregulated in heart tissues in patients with dilated cardiomyopathy (DCM) and DOX-challenged mice. FUNDC1 deficiency aggravated DOX-induced cardiac dysfunction, mitochondrial injury, and cardiomyocyte PANoptosis. Further examination revealed that FUNDC1 countered cytoplasmic release of mitochondrial DNA (mtDNA) and activation of PANoptosome through interaction with mitochondrial Tu translation elongation factor (TUFM), a key factor in the translational expression and repair of mitochondrial DNA, via its 96-133 amino acid domain. TUFM intervention reversed FUNDC1-elicited protection against DOX-induced mtDNA cytosolic release and cardiomyocyte PANoptosis. Our findings shed light toward a beneficial role of FUNDC1 in DOX cardiotoxicity and cardiomyocyte PANoptosis, thus offering therapeutic promises in DOX-induced cardiotoxicity.
    DOI:  https://doi.org/10.1038/s41419-022-05460-x
  29. Front Neurol. 2022 ;13 988519
    Indentification of novel MSTO1 compound heterozygous mutations in a Chinese family with recessive cerebellar atrophy and ataxia.
    Jia Chen, Junfang Xiao, Ge Chen, Qiang Xu, Xingwu Wu, Lifeng Tian, Zhihui Huang, Cailin Xin, Yan Zhao, Zhen Guo, Yang Zou, Qiongfang Wu.
      Misato mitochondrial distribution and morphology regulator 1 (MSTO1) is a nuclear-encoded cytoplasmic protein involved in mitochondrial fusion and distribution. Its disruption causes an extremely rare mitochondrial disorder characterized by early-onset myopathy and cerebellar ataxia. The genotype-phenotype correlation in the MSTO1 gene is rarely studied before 2017, and only 25 mutations have been described in the patients. Here, we reported two siblings with progressive cerebellar atrophy and ataxia in a Chinese family. Two compound heterozygous mutations in the MSTO1 gene, a novel missense mutation c.571C>T (p.Arg191Trp), and a reported frameshift mutation c.1259delG (p.Gly420ValfsTer2) were identified in the patients by whole exome sequencing. in vitro experiments found both of the mutations lead to reduced protein abundance and link to decreased mtDNA content. Except for ataxia and delayed motor, both of the siblings also have low birth weights, learning difficulties, and dysarthria. Our report enriched the genotype and phenotype spectrums of the MSTO1-related disorder and supported the recessive inheritance of the disease.
    Keywords:  MSTO1; missense variant; mitochondrial disorders; myopathy and ataxia; whole exome sequencing
    DOI:  https://doi.org/10.3389/fneur.2022.988519
  30. Stem Cell Reports. 2022 Nov 22. pii: S2213-6711(22)00537-9. [Epub ahead of print]
    Stress-induced reversible cell-cycle arrest requires PRC2/PRC1-mediated control of mitophagy in Drosophila germline stem cells and human iPSCs.
    Tommy H Taslim, Abdiasis M Hussein, Riya Keshri, Julien R Ishibashi, Tung C Chan, Bich N Nguyen, Shuozhi Liu, Daniel Brewer, Stuart Harper, Scott Lyons, Ben Garver, Jimmy Dang, Nanditaa Balachandar, Samriddhi Jhajharia, Debra Del Castillo, Julie Mathieu, Hannele Ruohola-Baker.
      Following acute genotoxic stress, both normal and tumorous stem cells can undergo cell-cycle arrest to avoid apoptosis and later re-enter the cell cycle to regenerate daughter cells. However, the mechanism of protective, reversible proliferative arrest, "quiescence," remains unresolved. Here, we show that mitophagy is a prerequisite for reversible quiescence in both irradiated Drosophila germline stem cells (GSCs) and human induced pluripotent stem cells (hiPSCs). In GSCs, mitofission (Drp1) or mitophagy (Pink1/Parkin) genes are essential to enter quiescence, whereas mitochondrial biogenesis (PGC1α) or fusion (Mfn2) genes are crucial for exiting quiescence. Furthermore, mitophagy-dependent quiescence lies downstream of mTOR- and PRC2-mediated repression and relies on the mitochondrial pool of cyclin E. Mitophagy-dependent reduction of cyclin E in GSCs and in hiPSCs during mTOR inhibition prevents the usual G1/S transition, pushing the cells toward reversible quiescence (G0). This alternative method of G1/S control may present new opportunities for therapeutic purposes.
    Keywords:  PRC2; cyclin E; epigenetic; mTOR; mitochondria; mitophagy; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.stemcr.2022.11.004
  31. Nat Genet. 2022 Dec;54(12): 1778-1779
    A versatile functional assay for genetic variants in human disease.
      
    DOI:  https://doi.org/10.1038/s41588-022-01226-5
  32. Free Radic Res. 2022 Dec 08. 1-15
    Retrograde response to mitochondrial dysfunctions associated to LOF variations in FLAD1 exon 2: unraveling the importance of RFVT2.
    Maria Tolomeo, Guglielmina Chimienti, Martina Lanza, Roberto Barbaro, Alessia Nisco, Tiziana Latronico, Piero Leone, Giuseppe Petrosillo, Grazia Maria Liuzzi, Bryony Ryder, Michal Inbar-Feigenberg, Matilde Colella, Angela M S Lezza, Rikke K J Olsen, Maria Barile.
      Flavin adenine dinucleotide (FAD) synthase (EC 2.7.7.2), encoded by human flavin adenine dinucleotide synthetase 1 (FLAD1), catalyzes the last step of the pathway converting riboflavin (Rf) into FAD. FLAD1 variations were identified as a cause of LSMFLAD (lipid storage myopathy due to FAD synthase deficiency, OMIM #255100), resembling Multiple Acyl-CoA Dehydrogenase Deficiency, sometimes treatable with high doses of Rf; no alternative therapeutic strategies are available. We describe here cell morphological and mitochondrial alterations in dermal fibroblasts derived from a LSMFLAD patient carrying a homozygous truncating FLAD1 variant (c.745C > T) in exon 2. Despite a severe decrease in FAD synthesis rate, the patient had decreased cellular levels of Rf and flavin mononucleotide and responded to Rf treatment.We hypothesized that disturbed flavin homeostasis and Rf-responsiveness could be due to a secondary impairment in the expression of the Rf transporter 2 (RFVT2), encoded by SLC52A2, in the frame of an adaptive retrograde signaling to mitochondrial dysfunction. Interestingly, an antioxidant response element (ARE) is found in the region upstream of the transcriptional start site of SLC52A2. Accordingly, we found that abnormal mitochondrial morphology and impairments in bioenergetics were accompanied by increased cellular reactive oxygen species content and mtDNA oxidative damage. Concomitantly, an active response to mitochondrial stress is suggested by increased levels of PPARγ-co-activator-1α and Peroxiredoxin III. In this scenario, the treatment with high doses of Rf might compensate for the secondary RFVT2 molecular defect, providing a molecular rationale for the Rf responsiveness in patients with loss of function variants in FLAD1 exon 2.HIGHLIGHTSFAD synthase deficiency alters mitochondrial morphology and bioenergetics;FAD synthase deficiency triggers a mitochondrial retrograde response;FAD synthase deficiency evokes nuclear signals that adapt the expression of RFVT2.
    Keywords:  FLAD1; LSMFLAD; MADD; RFVT2; mitochondrial myopathy
    DOI:  https://doi.org/10.1080/10715762.2022.2146501
  33. Elife. 2022 Dec 06. pii: e82951. [Epub ahead of print]11
    Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function.
    Jeffrey Molendijk, Ronnie Blazev, Richard J Mills, Yaan-Kit Ng, Kevin I Watt, Daryn Chau, Paul Gregorevic, Peter J Crouch, James B W Hilton, Leszek Lisowski, Peixiang Zhang, Karen Reue, Aldons J Lusis, James Hudson, David E James, Marcus M Seldin, Benjamin L Parker.
      Improving muscle function has great potential to improve the quality of life. To identify novel regulators of skeletal muscle metabolism and function, we performed a proteomic analysis of gastrocnemius muscle from 73 genetically distinct inbred mouse strains, and integrated the data with previously acquired genomics and >300 molecular/phenotypic traits via quantitative trait loci mapping and correlation network analysis. These data identified thousands of associations between protein abundance and phenotypes and can be accessed online (https://muscle.coffeeprot.com/) to identify regulators of muscle function. We used this resource to prioritize targets for a functional genomic screen in human bioengineered skeletal muscle. This identified several negative regulators of muscle function including UFC1, an E2 ligase for protein UFMylation. We show UFMylation is up-regulated in a mouse model of amyotrophic lateral sclerosis, a disease that involves muscle atrophy. Furthermore, in vivo knockdown of UFMylation increased contraction force, implicating its role as a negative regulator of skeletal muscle function.
    Keywords:  computational biology; human; mouse; systems biology
    DOI:  https://doi.org/10.7554/eLife.82951
  34. EXCLI J. 2022 ;21 1306-1330
    Mitochondrial mutations in protein coding genes of respiratory chain including complexes IV, V, and mt-tRNA genes are associated risk factors for congenital heart disease.
    Mohammad Mehdi Heidari, Mehri Khatami, Akram Kamalipour, Mustafa Kalantari, Mahsa Movahed, Mohammad Hayet Emmamy, Mehdi Hadadzadeh, José Bragança, Mohsen Namnabat, Bahareh Mazrouei.
      Most studies aiming at unraveling the molecular events associated with cardiac congenital heart disease (CHD) have focused on the effect of mutations occurring in the nuclear genome. In recent years, a significant role has been attributed to mitochondria for correct heart development and maturation of cardiomyocytes. Moreover, numerous heart defects have been associated with nucleotide variations occurring in the mitochondrial genome, affecting mitochondrial functions and cardiac energy metabolism, including genes encoding for subunits of respiratory chain complexes. Therefore, mutations in the mitochondrial genome may be a major cause of heart disease, including CHD, and their identification and characterization can shed light on pathological mechanisms occurring during heart development. Here, we have analyzed mitochondrial genetic variants in previously reported mutational genome hotspots and the flanking regions of mt-ND1, mt-ND2, mt-COXI, mt-COXII, mt-ATPase8, mt-ATPase6, mt-COXIII, and mt-tRNAs (Ile, Gln, Met, Trp, Ala, Asn, Cys, Tyr, Ser, Asp, and Lys) encoding genes by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) in 200 patients with CHD, undergoing cardiac surgery. A total of 23 mitochondrial variations (5 missense mutations, 8 synonymous variations, and 10 nucleotide changes in tRNA encoding genes) were identified and included 16 novel variants. Additionally, we showed that intracellular ATP was significantly reduced (P=0.002) in CHD patients compared with healthy controls, suggesting that the mutations have an impact on mitochondrial energy production. Functional and structural alterations caused by the mitochondrial nucleotide variations in the gene products were studied in-silico and predicted to convey a predisposing risk factor for CHD. Further studies are necessary to better understand the mechanisms by which the alterations identified in the present study contribute to the development of CHD in patients.
    Keywords:  congenital heart disease; in-silico analysis; mitochondrial genome; mt-tRNA; mutation
    DOI:  https://doi.org/10.17179/excli2022-5298
  35. Hum Genet. 2022 Dec 07.
    Targeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project.
    Genomics England Consortium
      BACKGROUND: Genome sequencing was first offered clinically in the UK through the 100,000 Genomes Project (100KGP). Analysis was restricted to predefined gene panels associated with the patient's phenotype. However, panels rely on clearly characterised phenotypes and risk missing diagnoses outside of the panel(s) applied. We propose a complementary method to rapidly identify pathogenic variants, including those missed by 100KGP methods.METHODS: The Loss-of-function Observed/Expected Upper-bound Fraction (LOEUF) score quantifies gene constraint, with low scores correlated with haploinsufficiency. We applied DeNovoLOEUF, a filtering strategy to sequencing data from 13,949 rare disease trios in the 100KGP, by filtering for rare, de novo, loss-of-function variants in disease genes with a LOEUF score < 0.2. We compared our findings with the corresponding patient's diagnostic reports.
    RESULTS: 324/332 (98%) of the variants identified using DeNovoLOEUF were diagnostic or partially diagnostic (whereby the variant was responsible for some of the phenotype). We identified 39 diagnoses that were "missed" by 100KGP standard analyses, which are now being returned to patients.
    CONCLUSION: We have demonstrated a highly specific and rapid method with a 98% positive predictive value that has good concordance with standard analysis, low false-positive rate, and can identify additional diagnoses. Globally, as more patients are being offered genome sequencing, we anticipate that DeNovoLOEUF will rapidly identify new diagnoses and facilitate iterative analyses when new disease genes are discovered.
    DOI:  https://doi.org/10.1007/s00439-022-02509-x
  36. Methods Mol Biol. 2023 ;2560 73-79
    Whole Genome Sequencing for Detection of Structural Variants in Patients with Retinitis Pigmentosa.
    Alexander H Chai.
      Retinitis pigmentosa (RP) is a group of inherited retinal diseases characterized by the progressive degeneration of rod then cone photoreceptors. Most of the known mutations that cause RP reside in the protein-coding portions of DNA; however, a growing number of pathogenic mutations have been identified within the non-coding portions. This chapter details a brief method for the detection of structural variants throughout the genome for the identification of novel mutations and to ultimately provide patients with a precise molecular diagnosis.
    Keywords:  PacBio Sequel; Retinitis pigmentosa; Structural variants; Whole genome sequencing; ngmlr (coNvex Gap-cost alignMents for Long Reads); pbsv (Pacific Biosciences structural variant calling and analysis tools)
    DOI:  https://doi.org/10.1007/978-1-0716-2651-1_6
  37. Neurochem Res. 2022 Dec 10.
    Consumption and Metabolism of Extracellular Pyruvate by Cultured Rat Brain Astrocytes.
    Nadine Denker, Antonia R Harders, Christian Arend, Ralf Dringen.
      Brain astrocytes are considered as glycolytic cell type, but these cells also produce ATP via mitochondrial oxidative phosphorylation. Exposure of cultured primary astrocytes in a glucose-free medium to extracellular substrates that are known to be metabolised by mitochondrial pathways, including pyruvate, lactate, beta-hydroxybutyrate, alanine and acetate, revealed that among the substrates investigated extracellular pyruvate was most efficiently consumed by astrocytes. Extracellular pyruvate was consumed by the cells almost proportional to time over hours in a concentration-dependent manner with apparent Michaelis-Menten kinetics [Km = 0.6 ± 0.1 mM, Vmax = 5.1 ± 0.8 nmol/(min × mg protein)]. The astrocytic consumption of pyruvate was strongly impaired in the presence of the monocarboxylate transporter 1 (MCT1) inhibitor AR-C155858 or by application of a 10-times excess of the MCT1 substrates lactate or beta-hydroxybutyrate. Pyruvate consumption by viable astrocytes was inhibited in the presence of UK5099, an inhibitor of the mitochondrial pyruvate carrier, or after application of the respiratory chain inhibitor antimycin A. In contrast, the mitochondrial uncoupler BAM15 strongly accelerated cellular pyruvate consumption. Lactate and alanine accounted after 3 h of incubation with pyruvate for around 60% and 10%, respectively, of the pyruvate consumed by the cells. These results demonstrate that consumption of extracellular pyruvate by astrocytes involves uptake via MCT1 and that the velocity of pyruvate consumption is strongly modified by substances that affect the entry of pyruvate into mitochondria or the activity of mitochondrial respiration.
    Keywords:  Astrocytes; MCT1; Metabolism; Mitochondria; Pyruvate carrier; Transport
    DOI:  https://doi.org/10.1007/s11064-022-03831-6
  38. Exp Hematol. 2022 Dec 05. pii: S0301-472X(22)00811-6. [Epub ahead of print]
    Heme-dependent induction of mitophagy program during murine erythroid cell differentiation.
    Masatoshi Ikeda, Hiroki Kato, Hiroki Shima, Mitsuyo Matsumoto, Eijiro Furukawa, Yan Yan, Ruiqi Liao, Jian Xu, Akihiko Muto, Tohru Fujiwara, Hideo Harigae, Emery H Bresnick, Kazuhiko Igarashi.
      Although establishing and maintaining mitochondria are essential to produce massive amounts of heme in erythroblasts, mitochondria must be degraded upon terminal differentiation to red blood cells, thus creating a bi-phasic regulatory process. Previously, we reported that iron deficiency in mice promotes mitochondria retention in red blood cells, suggesting that the proper amount of iron and/or heme is necessary for the degradation of mitochondria during erythroblast maturation. Since the transcription factor GATA1 regulates autophagy in erythroid cells, which involves mitochondrial clearance (mitophagy), we investigated the relationship between iron, heme and mitophagy by analyzing the expression of genes related to GATA1 and autophagy and the impact of iron or heme restriction on the amount of mitochondria. We found that heme promotes the expression of GATA1-regulated mitophagy-related genes and induction of mitophagy. GATA1 might induce the expression of autophagy-related genes Atg4d and Stk11 for mitophagy through a heme-dependent mechanism in murine erythroleukemia (MEL) cells and in a genetic rescue system with G1E-ER-GATA1 erythroblast cells derived from Gata1-null murine embryonic stem cells. These results provide evidence for a bi-phasic mechanism in which mitochondria are essential for heme generation, and the heme generated during differentiation promotes mitophagy and mitochondria disposal. This mechanism provides a molecular framework for understanding this fundamentally important cell biological process.
    Keywords:  GATA transcription factor; autophagy; erythropoiesis; heme; iron; mitochondria
    DOI:  https://doi.org/10.1016/j.exphem.2022.11.007
  39. Nature. 2022 Dec 08.
    Principles of mitoribosomal small subunit assembly in eukaryotes.
    Nathan J Harper, Chloe Burnside, Sebastian Klinge.
      Mitochondrial ribosomes (mitoribosomes) synthesize proteins encoded within the mitochondrial genome that are assembled into oxidative phosphorylation complexes. Thus, mitoribosome biogenesis is essential for ATP production and cellular metabolism1. Here we used cryo-electron microscopy to determine 9 structures of native yeast and human mitoribosomal small subunit assembly intermediates at resolutions from 2.4 to 3.8 Å, illuminating the mechanistic basis for how GTPases are employed to control early steps of decoding center formation, how initial rRNA folding and processing events are mediated, and how mitoribosomal proteins play active roles during assembly. Furthermore, this series of intermediates from two species with divergent mitoribosomal architecture uncovers both conserved principles and species-specific adaptations that govern the maturation of mitoribosomal small subunits in eukaryotes. By revealing the dynamic interplay between assembly factors, mitoribosomal proteins, and rRNA required to generate functional subunits, our structural analysis provides a vignette for how molecular complexity and diversity can evolve in large ribonucleoprotein assemblies.
    DOI:  https://doi.org/10.1038/s41586-022-05621-0
  40. Curr Opin Hematol. 2022 Nov 25.
    Haematopoietic stem cell quiescence exposed using mitochondrial membrane potential.
    Saghi Ghaffari.
      PURPOSE OF REVIEW: Quiescence is a fundamental property of haematopoietic stem cells (HSCs). Despite the importance of quiescence in predicting the potency of HSCs, tools that measure routinely the degree of quiescence or select for quiescent HSCs have been lacking. This Commentary discusses recent findings that address this fundamental gap in the HSC toolbox.RECENT FINDINGS: Highly purified, phenotypically-defined HSCs are heterogeneous in their mitochondrial membrane potential (MMP). The lowest MMP subsets are enriched in greatly quiescent HSCs with the highest potency within the purified HSC population. MMP provides an intrinsic probe to select HSC subsets with unique cell cycle properties and distinct stem cell potential. Using this approach, new and unanticipated metabolic properties of quiescent HSCs' exit have been discovered. This methodology may improve the mechanistic understanding, of HSCs' exit from and entry to, quiescence.
    SUMMARY: Selecting HSCs using MMP is likely to lead to discoveries of new HSC properties, may improve the ex vivo maintenance of HSCs and has implications for the clinic, including for improving HSC transplantations.
    DOI:  https://doi.org/10.1097/MOH.0000000000000746
  41. Methods Mol Biol. 2023 ;2560 31-39
    Clinical Evaluation of Patients with Retinitis Pigmentosa.
    Sitara H Hirji.
      This chapter describes the clinical evaluation process of patients with retinitis pigmentosa (RP). The clinical evaluation consists of a complete history and ophthalmic examination. Here, we outline the aspects of the history and ophthalmic exam that are most important for the evaluation of RP patients. In addition, the expected findings of RP patients and the etiology of these findings are discussed.
    Keywords:  Clinical evaluation; Cystoid macular edema; Genetic retinopathy; Optic nerve pallor; Pigment epithelium; Retinitis pigmentosa; Vitreous
    DOI:  https://doi.org/10.1007/978-1-0716-2651-1_3
  42. Methods Mol Biol. 2023 ;2560 111-122
    Electroretinogram (ERG) to Evaluate the Retina in Cases of Retinitis Pigmentosa (RP).
    Wan-Chun Huang, Pei-Kang Liu, Nan-Kai Wang.
      Electroretinogram (ERG) captures the electrical responses of photoreceptors, the summation of action potentials from all neurons in the retina elicited by illumination. ERG testing is an incredibly useful tool in obtaining more specific information regarding a retinal dystrophy. Specifically, ERGs are typically used to test photoreceptors and inner retinal function in humans and animals, to diagnose retinal dystrophies, and to monitor disease progression. In this chapter, we will introduce the components of ERGs and the standard ERG protocols for clinical examination. We will also introduce the various specialized ERG tests, which can help to differentiate retinitis pigmentosa (RP) from other retinal disorders. Lastly, we will elaborate on how to use ERGs to predict visual prognosis in RP.
    Keywords:  Electroretinogram (ERG); Full-field ERG; Retinitis pigmentosa (RP); The International Society for Clinical Electrophysiology of Vision (ISCEV); a-wave; b-wave
    DOI:  https://doi.org/10.1007/978-1-0716-2651-1_10
  43. Hear Res. 2022 Nov 24. pii: S0378-5955(22)00227-1. [Epub ahead of print]427 108659
    The roles of NADPH and isocitrate dehydrogenase in cochlear mitochondrial antioxidant defense and aging.
    Karessa White, Shinichi Someya.
      Hearing loss is the third most prevalent chronic health condition affecting older adults. Age-related hearing loss affects one in three adults over 65 years of age and is caused by both extrinsic and intrinsic factors, including genetics, aging, and exposure to noise and toxins. All cells possess antioxidant defense systems that play an important role in protecting cells against these factors. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) serves as a co-factor for antioxidant enzymes such as glutathione reductase and thioredoxin reductase and is produced by glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, isocitrate dehydrogenase 1 (IDH1) or malic enzyme 1 in the cytosol, while in the mitochondria, NADPH is generated from mitochondrial transhydrogenase, glutamate dehydrogenase, malic enzyme 3 or IDH2. There are three isoforms of IDH: cytosolic IDH1, and mitochondrial IDH2 and IDH3. Of these, IDH2 is thought to be the major supplier of NADPH to the mitochondrial antioxidant defense system. The NADP+/NADPH and NAD+/NADH couples are essential for maintaining a large array of biological processes, including cellular redox state, and energy metabolism, mitochondrial function. A growing body of evidence indicates that mitochondrial dysfunction contributes to age-related structural or functional changes of cochlear sensory hair cells and neurons, leading to hearing impairments. In this review, we describe the current understanding of the roles of NADPH and IDHs in cochlear mitochondrial antioxidant defense and aging.
    Keywords:  antioxidant defense; cochlea; inner ear; isocitrate dehydrogenase; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1016/j.heares.2022.108659
  44. Free Radic Biol Med. 2022 Nov 30. pii: S0891-5849(22)01013-9. [Epub ahead of print]
    Mitochondria need their sleep: Sleep-wake cycling and the role of redox, bioenergetics, and temperature regulation, involving cysteine-mediated redox signaling, uncoupling proteins, and substrate cycles.
    Richard B Richardson, Ryan J Mailloux.
      There is a dearth of evidence-based reports linking the generation of free radicals and associated redox modifications with other major physiological changes of the sleep-wake cycle. To address this shortcoming, we examine and hypothesize that circadian/ultradian interaction of the redoxome, bioenergetics, and thermal signaling strongly regulate the differential activities of the sleep-wake cycle. Post-translational modifications of proteins by reversible cysteine oxoforms, S-glutathionylation and S-nitrosylation, are shown to play a major role regulating mitochondrial reactive oxygen species production, protein synthesis, respiration, and metabolomics. Protein synthesis and nuclear DNA repair are maximized during the wake state, whereas the redoxome is restored and mitochondrial protection is maximized during sleep. Hence, our analysis of redox/bioenergetics/temperature cycling indicates that the wake phase is more restorative and protective to the nucleus, whereas sleep is more restorative and protective to mitochondria. The redox/bioenergetics/temperature regulatory hypothesis adds to the understanding of mitochondrial respiratory uncoupling, substrate or futile cycling control, sudden infant death syndrome, torpor and hibernation and space radiation effects. Similarly, the hypothesis clarifies how the oscillatory redox/bioenergetics/temperature-regulated sleep-wake states, when perturbed by mitochondrial interactome disturbances, contribute to aging and the pathogenesis of diseases of the metabolism and cerebral nervous system.
    Keywords:  Circadian; Mitochondria; Nuclear; Oxidative stress; Redoxome; S-glutathionylation; S-nitrosylation; Sleep; Substrate cycles; Uncoupling
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.11.036
  45. Methods Mol Biol. 2023 ;2560 41-66
    Molecular Genetic Testing Approaches for Retinitis Pigmentosa.
    Megan Soucy, Akemi Joy Tanaka, Avinash Dharmadhikari.
      Retinitis pigmentosa (RP) affects approximately 1 in 4000 individuals. It has many different genetic etiologies and therefore diagnosis can be challenging. Understanding the different testing methodologies is beneficial for clinicians and researchers in order to select the best testing method, whether it be panel testing, whole exome sequencing, or whole genome sequencing for individuals affected with RP. The Methods section also outlines the steps required to complete a WES assay, which has become a popular method for identifying the molecular diagnosis for individuals with RP.
    Keywords:  Next-generation sequencing; Retinitis pigmentosa; Whole exome sequencing whole genome sequencing
    DOI:  https://doi.org/10.1007/978-1-0716-2651-1_4
  46. Sci Adv. 2022 Dec 09. 8(49): eabq3970
    Glia of C. elegans coordinate a protective organismal heat shock response independent of the neuronal thermosensory circuit.
    Holly K Gildea, Phillip A Frankino, Sarah U Tronnes, Corinne L Pender, Jenni Durieux, Julian G Dishart, Hyun Ok Choi, Tayla D Hunter, Shannon S Cheung, Ashley E Frakes, Edward Sukarto, Kevin Wickham, Andrew Dillin.
      Aging organisms lose the ability to induce stress responses, becoming vulnerable to protein toxicity and tissue damage. Neurons can signal to peripheral tissues to induce protective organelle-specific stress responses. Recent work shows that glia can independently induce such responses. Here, we show that overexpression of heat shock factor 1 (hsf-1) in the four astrocyte-like cephalic sheath cells of Caenorhabditis elegans induces a non-cell-autonomous cytosolic unfolded protein response, also known as the heat shock response (HSR). These animals have increased lifespan and heat stress resistance and decreased protein aggregation. Glial HSR regulation is independent of canonical thermosensory circuitry and known neurotransmitters but requires the small clear vesicle release protein UNC-13. HSF-1 and the FOXO transcription factor DAF-16 are partially required in peripheral tissues for non-cell-autonomous HSR, longevity, and thermotolerance. Cephalic sheath glial hsf-1 overexpression also leads to pathogen resistance, suggesting a role for this signaling pathway in immune function.
    DOI:  https://doi.org/10.1126/sciadv.abq3970
  47. Front Immunol. 2022 ;13 1028953
    The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD.
    Jessica Astorga, Naschla Gasaly, Karen Dubois-Camacho, Marjorie De la Fuente, Glauben Landskron, Klaas Nico Faber, Félix A Urra, Marcela A Hermoso.
      Inflammatory Bowel Disease (IBD) is characterized by a loss of intestinal barrier function caused by an aberrant interaction between the immune response and the gut microbiota. In IBD, imbalance in cholesterol homeostasis and mitochondrial bioenergetics have been identified as essential events for activating the inflammasome-mediated response. Mitochondrial alterations, such as reduced respiratory complex activities and reduced production of tricarboxylic acid (TCA) cycle intermediates (e.g., citric acid, fumarate, isocitric acid, malate, pyruvate, and succinate) have been described in in vitro and clinical studies. Under inflammatory conditions, mitochondrial architecture in intestinal epithelial cells is dysmorphic, with cristae destruction and high dynamin-related protein 1 (DRP1)-dependent fission. Likewise, these alterations in mitochondrial morphology and bioenergetics promote metabolic shifts towards glycolysis and down-regulation of antioxidant Nuclear erythroid 2-related factor 2 (Nrf2)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling. Although the mechanisms underlying the mitochondrial dysfunction during mucosal inflammation are not fully understood at present, metabolic intermediates and cholesterol may act as signals activating the NLRP3 inflammasome in IBD. Notably, dietary phytochemicals exhibit protective effects against cholesterol imbalance and mitochondrial function alterations to maintain gastrointestinal mucosal renewal in vitro and in vivo conditions. Here, we discuss the role of cholesterol and mitochondrial metabolism in IBD, highlighting the therapeutic potential of dietary phytochemicals, restoring intestinal metabolism and function.
    Keywords:  IBD - inflammatory bowel disease; NLRP3 inflammasome; diet phytochemicals; inflammasome; intracellular cholesterol accumulation; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fimmu.2022.1028953
  48. Nat Commun. 2022 Dec 08. 13(1): 7592
    Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.
    Marsha M Wheeler, Adrienne M Stilp, Shuquan Rao, Bjarni V Halldórsson, Doruk Beyter, Jia Wen, Anna V Mihkaylova, Caitlin P McHugh, John Lane, Min-Zhi Jiang, Laura M Raffield, Goo Jun, Fritz J Sedlazeck, Ginger Metcalf, Yao Yao, Joshua B Bis, Nathalie Chami, Paul S de Vries, Pinkal Desai, James S Floyd, Yan Gao, Kai Kammers, Wonji Kim, Jee-Young Moon, Aakrosh Ratan, Lisa R Yanek, Laura Almasy, Lewis C Becker, John Blangero, Michael H Cho, Joanne E Curran, Myriam Fornage, Robert C Kaplan, Joshua P Lewis, Ruth J F Loos, Braxton D Mitchell, Alanna C Morrison, Michael Preuss, Bruce M Psaty, Stephen S Rich, Jerome I Rotter, Hua Tang, Russell P Tracy, Eric Boerwinkle, Goncalo R Abecasis, Thomas W Blackwell, Albert V Smith, Andrew D Johnson, Rasika A Mathias, Deborah A Nickerson, Matthew P Conomos, Yun Li, Unnur Þorsteinsdóttir, Magnús K Magnússon, Kari Stefansson, Nathan D Pankratz, Daniel E Bauer, Paul L Auer, Alex P Reiner.
      Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.
    DOI:  https://doi.org/10.1038/s41467-022-35354-7
  49. Elife. 2022 Dec 08. pii: e84702. [Epub ahead of print]11
    Teaching old drugs new tricks.
    Alexandre Faille, Alan J Warren.
      Understanding the mechanism by which streptomycin binds to the small subunit of the mitoribosome may help researchers design less toxic derivatives of this antibiotic.
    Keywords:  Fe-S cluster; antibiotics; bacteria; human; mitochondria; mitoribosome; molecular biophysics; ototoxicity; structural biology
    DOI:  https://doi.org/10.7554/eLife.84702
  50. EMBO J. 2022 Dec 07. e113046
    Closing the autophagosome is easy-PC.
    Devin M Fuller, Thomas J Melia.
      In their recent article, Polyansky et al identify phosphatidylcholine (PC) as the most abundant lipid in the autophagosome membrane and demonstrate that eliminating de novo PC synthesis sharply impairs autophagic processing. In the absence of PC synthesis, open cup-like structures accumulate, implicating PC as a key component in the closure of autophagosomes.
    DOI:  https://doi.org/10.15252/embj.2022113046
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