bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2021–11–07
twenty-six papers selected by
Catalina Vasilescu, University of Helsinki
  1. Translation of MT-ATP6 pathogenic variants reveals distinct regulatory consequences from the co-translational quality control of mitochondrial protein synthesis.
  2. Primary mitochondrial myopathies in childhood.
  3. Implications of mitochondrial DNA mutations in human induced pluripotent stem cells.
  4. The integrity and assay performance of tissue mitochondrial DNA is considerably affected by choice of isolation method.
  5. Subcellular Specialization of Mitochondrial Form and Function in Skeletal Muscle Cells.
  6. Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.
  7. Blood biomarkers for assessment of mitochondrial dysfunction: An expert review.
  8. First mitochondrial genome wide association study with metabolomics.
  9. Distinct Mitochondrial Remodeling During Mesoderm Differentiation in a Human-Based Stem Cell Model.
  10. Mice with disrupted mitochondria used to model Parkinson's disease.
  11. The dominant-negative mitochondrial calcium uniporter subunit MCUb drives macrophage polarization during skeletal muscle regeneration.
  12. Mitochondrial NDUFA4L2 is a novel regulator of skeletal muscle mass and force.
  13. Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation.
  14. ND3 Cys39 in complex I is exposed during mitochondrial respiration.
  15. Mitonuclear interactions alter sex-specific longevity in a species without sex chromosomes.
  16. Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease.
  17. Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease.
  18. Disruption of mitochondrial complex I induces progressive parkinsonism.
  19. In-cell structures of conserved supramolecular protein arrays at the mitochondria-cytoskeleton interface in mammalian sperm.
  20. Emerging roles of ATG7 in human health and disease.
  21. Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells.
  22. Adiponectin receptor agonist AdipoRon blocks skin inflamm-ageing by regulating mitochondrial dynamics.
  23. Alternative Mitophagy Protects the Heart Against Obesity-Associated Cardiomyopathy.
  24. Infantile-onset Myoclonic Developmental and Epileptic Encephalopathy: a new RARS2 phenotype.
  25. Mitochondrial DNA genetic variants are associated with systemic lupus erythematosus susceptibility, glucocorticoids efficacy, and prognosis.
  26. Whole genome sequencing helps pinpoint a genetic diagnosis for patients.
  1. Hum Mol Genet. 2021 Oct 28. pii: ddab314. [Epub ahead of print]
    Translation of MT-ATP6 pathogenic variants reveals distinct regulatory consequences from the co-translational quality control of mitochondrial protein synthesis.
    Kah Ying Ng, Uwe Richter, Christopher B Jackson, Sara Seneca, Brendan J Battersby.
      Pathogenic variants that disrupt human mitochondrial protein synthesis are associated with a clinically heterogenous group of diseases. Despite an impairment in oxidative phosphorylation being a common phenotype, the underlying molecular pathogenesis is more complex than simply a bioenergetic deficiency. Currently, we have limited mechanistic understanding on the scope by which a primary defect in mitochondrial protein synthesis contributes to organelle dysfunction. Since the proteins encoded in the mitochondrial genome are hydrophobic and need co-translational insertion into a lipid bilayer, responsive quality control mechanisms are required to resolve aberrations that arise with the synthesis of truncated and misfolded proteins. Here, we show that defects in the OXA1L-mediated insertion of MT-ATP6 nascent chains into the mitochondrial inner membrane are rapidly resolved by the AFG3L2 protease complex. Using pathogenic MT-ATP6 variants, we then reveal discrete steps in this quality control mechanism and the differential functional consequences to mitochondrial gene expression. The inherent ability of a given cell type to recognize and resolve impairments in mitochondrial protein synthesis may in part contribute at the molecular level to the wide clinical spectrum of these disorders.
    DOI:  https://doi.org/10.1093/hmg/ddab314
  2. Neuromuscul Disord. 2021 Oct;pii: S0960-8966(21)00607-6. [Epub ahead of print]31(10): 978-987
    Primary mitochondrial myopathies in childhood.
    Catarina Olimpio, May Yung Tiet, Rita Horvath.
      Primary mitochondrial myopathies are genetic metabolic disorders of mitochondrial dysfunction affecting mainly, but not exclusively, skeletal muscle. Although individually rare, they are the most common inherited metabolic disorders in childhood. They can be similar to other childhood muscle diseases such as congenital myopathies, dystrophies, myasthenic syndromes or metabolic myopathies and a muscle biopsy and genetic testing are important in the differential diagnosis. Mitochondrial myopathies can present at any age but typically childhood onset myopathies have more significant muscle involvement and are caused by genes encoded in the nuclear DNA. Mitochondrial myopathy in infants presents with hypotonia, muscle weakness and difficulty feeding. In toddlers and older children delayed motor development, exercise intolerance and premature fatigue are common. A number of nuclear DNA and mitochondrial DNA encoded genes are known to cause isolated myopathy in childhood and they are important in a range of mitochondrial functions such as oxidative phosphorylation, mitochondrial transcription/translation and mitochondrial fusion/fission. A rare cause of isolated myopathy in children, reversible infantile respiratory chain deficiency myopathy, is non-progressive and typically associated with spontaneous full recovery. Promising targeted treatments have been reported for a number or mitochondrial myopathies including riboflavin in ACAD9 and ETFDH-myopathies and deoxynucleoside for TK2-related disease.
    Keywords:  Differential diagnosis; Mitochondria; Mitochondrial myopathy; Muscle; Next-generation sequencing; Treatment
    DOI:  https://doi.org/10.1016/j.nmd.2021.08.005
  3. Nat Rev Genet. 2021 Nov 02.
    Implications of mitochondrial DNA mutations in human induced pluripotent stem cells.
    Valerio Carelli, Michio Hirano, José Antonio Enríquez, Patrick F Chinnery.
      
    DOI:  https://doi.org/10.1038/s41576-021-00430-z
  4. Mitochondrion. 2021 Oct 30. pii: S1567-7249(21)00145-8. [Epub ahead of print]
    The integrity and assay performance of tissue mitochondrial DNA is considerably affected by choice of isolation method.
    Bruno Marçal Repolês, Choco Michael Gorospe, Phong Tran, Anna Karin Nilsson, Paulina H Wanrooij.
      The integrity of mitochondrial DNA (mtDNA) isolated from solid tissues is critical for analyses such as long-range PCR, but is typically assessed under conditions that fail to provide information on the individual mtDNA strands. Using denaturing gel electrophoresis, we show that commonly-used isolation procedures generate mtDNA containing several single-strand breaks per strand. Through systematic comparison of DNA isolation methods, we identify a procedure yielding the highest integrity of mtDNA that we demonstrate displays improved performance in downstream assays. Our results highlight the importance of isolation method choice, and serve as a resource to researchers requiring high-quality mtDNA from solid tissues.
    Keywords:  DNA integrity; long-range PCR; mitochondrial DNA; mtDNA; nuclease activity
    DOI:  https://doi.org/10.1016/j.mito.2021.10.005
  5. Front Cell Dev Biol. 2021 ;9 757305
    Subcellular Specialization of Mitochondrial Form and Function in Skeletal Muscle Cells.
    T Bradley Willingham, Peter T Ajayi, Brian Glancy.
      Across different cell types and within single cells, mitochondria are heterogeneous in form and function. In skeletal muscle cells, morphologically and functionally distinct subpopulations of mitochondria have been identified, but the mechanisms by which the subcellular specialization of mitochondria contributes to energy homeostasis in working muscles remains unclear. Here, we discuss the current data regarding mitochondrial heterogeneity in skeletal muscle cells and highlight potential new lines of inquiry that have emerged due to advancements in cellular imaging technologies.
    Keywords:  bioenergetics; intermyofibrillar mitochondria; mitochondrial connectivity; mitochondrial respiration; organelle interactions; paranuclear mitochondria; paravascular mitochondria; subsarcolemmal mitochondria
    DOI:  https://doi.org/10.3389/fcell.2021.757305
  6. BMJ. 2021 11 03. 375 e066288
    Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.
    Genomics England Research Consortium
       OBJECTIVE: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease.
    DESIGN: Cohort study.
    SETTING: National Health Service, England, including secondary and tertiary care.
    PARTICIPANTS: 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018.
    INTERVENTION: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants.
    MAIN OUTCOME MEASURE: Definite or probable genetic diagnosis.
    RESULTS: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis.
    CONCLUSION: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.
    DOI:  https://doi.org/10.1136/bmj-2021-066288
  7. Mitochondrion. 2021 Nov 02. pii: S1567-7249(21)00148-3. [Epub ahead of print]
    Blood biomarkers for assessment of mitochondrial dysfunction: An expert review.
    W H G Hubens, A Vallbona-Garcia, I F M de Coo, F H J van Tienen, C A B Webers, H J M Smeets, T G M F Gorgels.
      Although mitochondrial dysfunction is the known cause of primary mitochondrial disease, mitochondrial dysfunction is often difficult to measure and prove, especially when biopsies of affected tissue are not available. In order to identify blood biomarkers of mitochondrial dysfunction, we reviewed studies that measured blood biomarkers in genetically, clinically or biochemically confirmed primary mitochondrial disease patients. In this way, we were certain that there was an underlying mitochondrial dysfunction which could validate the biomarker. We found biomarkers of three classes: 1) functional markers measured in blood cells, 2) biochemical markers of serum/plasma and 3) DNA markers. While none of the reviewed single biomarkers may perfectly reveal all underlying mitochondrial dysfunction, combining biomarkers that cover different aspects of mitochondrial impairment probably is a good strategy. This biomarker panel may assist in the diagnosis of primary mitochondrial disease patients. As mitochondrial dysfunction may also play a significant role in the pathophysiology of multifactorial disorders such as Alzheimer's disease and glaucoma, the panel may serve to assess mitochondrial dysfunction in complex multifactorial diseases as well and enable selection of patients who could benefit from therapies targeting mitochondria.
    Keywords:  Mitochondrial disorder; biomarkers; blood; mitochondrial dysfunction; multifactorial diseases
    DOI:  https://doi.org/10.1016/j.mito.2021.10.008
  8. Hum Mol Genet. 2021 Oct 27. pii: ddab312. [Epub ahead of print]
    First mitochondrial genome wide association study with metabolomics.
    Brahim Aboulmaouahib, Gabi Kastenmüller, Karsten Suhre, Sebastian Zöllner, Hansi Weissensteiner, Christian Gieger, Rui Wang-Sattler, Peter Lichtner, Konstantin Strauch, Antònia Flaquer.
       INTRODUCTION: In the era of personalized medicine with more and more patient specific targeted therapies being used, we need reliable, dynamic, faster, and sensitive biomarkers both to track the causes of disease and to develop and evolve therapies during the course of treatment. Metabolomics recently has shown substantial evidence to support its emerging role in disease diagnosis and prognosis. Aside from biomarkers and development of therapies, it is also an important goal to understand the involvement of mitochondrial DNA mtDNA in metabolic regulation, aging, and disease development. Somatic mutations of the mitochondrial genome are also heavily implicated in age-related disease and aging. The general hypothesis is that an alteration in the concentration of metabolite profiles (possibly conveyed by lifestyle and environmental factors) influences the increase of mutation rate in the mtDNA, and thereby contributes to a range of pathophysiological alterations observed in complex diseases.
    METHODS: We performed an inverted mitochondrial genome wide association analysis between mitochondrial nucleotide variants (mtSNVs) and concentration of metabolites. We used 151 metabolites and the whole sequenced mitochondrial genome from 2718 individuals to identify genetic variants associated with metabolite profiles. Because of the high coverage, next generation sequencing-based analysis of the mitochondrial genome allows for an accurate detection of mitochondrial heteroplasmy and for identification of variants associated with the metabolome.
    RESULTS: The strongest association was found for mt715G > A located in the MT-12SrRNA with the metabolite ratio C2/C10:1 (p-value = 6.82*10-09, β = 0.909). The second most significant mtSNV was found for mt3714A > G located in the MT-ND1 with the metabolite ratio PC ae C42:5/PC ae C44:5 (p-value = 1.02*10-08, β = 3.631). A large number of significant metabolite ratios were observed involving PC aa C36:6 and the variant mt10689G > A, located in the MT-ND4L gene.
    CONCLUSION: These results show an important interconnection between mitochondria and metabolite concentrations. Considering that some of the significant metabolites found in this study have been previously related to complex diseases such as neurological disorders and metabolic conditions, these associations found here might play a crucial role for further investigations of such complex diseases. Understanding the mechanisms that control human health and disease, in particular the role of genetic predispositions and their interaction with environmental factors is a prerequisite for the development of safe and efficient therapies for complex disorders.
    DOI:  https://doi.org/10.1093/hmg/ddab312
  9. Front Cell Dev Biol. 2021 ;9 744777
    Distinct Mitochondrial Remodeling During Mesoderm Differentiation in a Human-Based Stem Cell Model.
    Sepideh Mostafavi, Novin Balafkan, Ina Katrine Nitschke Pettersen, Gonzalo S Nido, Richard Siller, Charalampos Tzoulis, Gareth J Sullivan, Laurence A Bindoff.
      Given the considerable interest in using stem cells for modeling and treating disease, it is essential to understand what regulates self-renewal and differentiation. Remodeling of mitochondria and metabolism, with the shift from glycolysis to oxidative phosphorylation (OXPHOS), plays a fundamental role in maintaining pluripotency and stem cell fate. It has been suggested that the metabolic "switch" from glycolysis to OXPHOS is germ layer-specific as glycolysis remains active during early ectoderm commitment but is downregulated during the transition to mesoderm and endoderm lineages. How mitochondria adapt during these metabolic changes and whether mitochondria remodeling is tissue specific remain unclear. Here, we address the question of mitochondrial adaptation by examining the differentiation of human pluripotent stem cells to cardiac progenitors and further to differentiated mesodermal derivatives, including functional cardiomyocytes. In contrast to recent findings in neuronal differentiation, we found that mitochondrial content decreases continuously during mesoderm differentiation, despite increased mitochondrial activity and higher levels of ATP-linked respiration. Thus, our work highlights similarities in mitochondrial remodeling during the transition from pluripotent to multipotent state in ectodermal and mesodermal lineages, while at the same time demonstrating cell-lineage-specific adaptations upon further differentiation. Our results improve the understanding of how mitochondrial remodeling and the metabolism interact during mesoderm differentiation and show that it is erroneous to assume that increased OXPHOS activity during differentiation requires a simultaneous expansion of mitochondrial content.
    Keywords:  OXPHOS; cardiomyocyte; development; metabolism; mitochondria; stem cells
    DOI:  https://doi.org/10.3389/fcell.2021.744777
  10. Nature. 2021 Nov 03.
    Mice with disrupted mitochondria used to model Parkinson's disease.
    Zak Doric, Ken Nakamura.
      
    Keywords:  Neurodegeneration; Parkinson's disease
    DOI:  https://doi.org/10.1038/d41586-021-02955-z
  11. Sci Signal. 2021 Nov 02. 14(707): eabf3838
    The dominant-negative mitochondrial calcium uniporter subunit MCUb drives macrophage polarization during skeletal muscle regeneration.
    Simona Feno, Fabio Munari, Denis Vecellio Reane, Rosanna Gissi, Dieu-Huong Hoang, Alessandra Castegna, Bénédicte Chazaud, Antonella Viola, Rosario Rizzuto, Anna Raffaello.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/scisignal.abf3838
  12. FASEB J. 2021 Dec;35(12): e22010
    Mitochondrial NDUFA4L2 is a novel regulator of skeletal muscle mass and force.
    Zhengye Liu, Thomas Chaillou, Estela Santos Alves, Theresa Mader, Baptiste Jude, Duarte M S Ferreira, Heidi Hynynen, Arthur J Cheng, William O Jonsson, Gianluigi Pironti, Daniel C Andersson, Ellinor Kenne, Jorge L Ruas, Pasi Tavi, Johanna T Lanner.
      The hypoxia-inducible nuclear-encoded mitochondrial protein NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 (NDUFA4L2) has been demonstrated to decrease oxidative phosphorylation and production of reactive oxygen species in neonatal cardiomyocytes, brain tissue and hypoxic domains of cancer cells. Prolonged local hypoxia can negatively affect skeletal muscle size and tissue oxidative capacity. Although skeletal muscle is a mitochondrial rich, oxygen sensitive tissue, the role of NDUFA4L2 in skeletal muscle has not previously been investigated. Here we ectopically expressed NDUFA4L2 in mouse skeletal muscles using adenovirus-mediated expression and in vivo electroporation. Moreover, femoral artery ligation (FAL) was used as a model of peripheral vascular disease to induce hind limb ischemia and muscle damage. Ectopic NDUFA4L2 expression resulted in reduced mitochondrial respiration and reactive oxygen species followed by lowered AMP, ADP, ATP, and NAD+ levels without affecting the overall protein content of the mitochondrial electron transport chain. Furthermore, ectopically expressed NDUFA4L2 caused a ~20% reduction in muscle mass that resulted in weaker muscles. The loss of muscle mass was associated with increased gene expression of atrogenes MurF1 and Mul1, and apoptotic genes caspase 3 and Bax. Finally, we showed that NDUFA4L2 was induced by FAL and that the Ndufa4l2 mRNA expression correlated with the reduced capacity of the muscle to generate force after the ischemic insult. These results show, for the first time, that mitochondrial NDUFA4L2 is a novel regulator of skeletal muscle mass and force. Specifically, induced NDUFA4L2 reduces mitochondrial activity leading to lower levels of important intramuscular metabolites, including adenine nucleotides and NAD+ , which are hallmarks of mitochondrial dysfunction and hence shows that dysfunctional mitochondrial activity may drive muscle wasting.
    Keywords:  NDUFA4L2; mitochondria; muscle mass; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202100066R
  13. Nat Commun. 2021 Nov 04. 12(1): 6409
    Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation.
    Chih-Yao Chung, Kritarth Singh, Vassilios N Kotiadis, Gabriel E Valdebenito, Jee Hwan Ahn, Emilie Topley, Joycelyn Tan, William D Andrews, Benoit Bilanges, Robert D S Pitceathly, Gyorgy Szabadkai, Mariia Yuneva, Michael R Duchen.
      Mutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are very limited. Most mtDNA diseases show heteroplasmy - tissues express both wild-type and mutant mtDNA. While the level of heteroplasmy broadly correlates with disease severity, the relationships between specific mtDNA mutations, heteroplasmy, disease phenotype and severity are poorly understood. We have carried out extensive bioenergetic, metabolomic and RNAseq studies on heteroplasmic patient-derived cells carrying the most prevalent disease related mtDNA mutation, the m.3243 A > G. These studies reveal that the mutation promotes changes in metabolites which are associated with the upregulation of the PI3K-Akt-mTORC1 axis in patient-derived cells and tissues. Remarkably, pharmacological inhibition of PI3K, Akt, or mTORC1 reduced mtDNA mutant load and partially rescued cellular bioenergetic function. The PI3K-Akt-mTORC1 axis thus represents a potential therapeutic target that may benefit people suffering from the consequences of the m.3243 A > G mutation.
    DOI:  https://doi.org/10.1038/s41467-021-26746-2
  14. Cell Chem Biol. 2021 Nov 02. pii: S2451-9456(21)00444-X. [Epub ahead of print]
    ND3 Cys39 in complex I is exposed during mitochondrial respiration.
    Nils Burger, Andrew M James, John F Mulvey, Kurt Hoogewijs, Shujing Ding, Ian M Fearnley, Marta Loureiro-López, Abigail A I Norman, Sabine Arndt, Amin Mottahedin, Olga Sauchanka, Richard C Hartley, Thomas Krieg, Michael P Murphy.
      Mammalian complex I can adopt catalytically active (A-) or deactive (D-) states. A defining feature of the reversible transition between these two defined states is thought to be exposure of the ND3 subunit Cys39 residue in the D-state and its occlusion in the A-state. As the catalytic A/D transition is important in health and disease, we set out to quantify it by measuring Cys39 exposure using isotopic labeling and mass spectrometry, in parallel with complex I NADH/CoQ oxidoreductase activity. To our surprise, we found significant Cys39 exposure during NADH/CoQ oxidoreductase activity. Furthermore, this activity was unaffected if Cys39 alkylation occurred during complex I-linked respiration. In contrast, alkylation of catalytically inactive complex I irreversibly blocked the reactivation of NADH/CoQ oxidoreductase activity by NADH. Thus, Cys39 of ND3 is exposed in complex I during mitochondrial respiration, with significant implications for our understanding of the A/D transition and the mechanism of complex I.
    Keywords:  Cys39; NADH:ubiquinone oxidoreductase; active/deactive transition; complex I; ischemia-reperfusion (IR) injury; mitochondria; redox regulation; reverse electron transport (RET)
    DOI:  https://doi.org/10.1016/j.chembiol.2021.10.010
  15. Proc Biol Sci. 2021 Nov 10. 288(1962): 20211813
    Mitonuclear interactions alter sex-specific longevity in a species without sex chromosomes.
    Ben A Flanagan, Ning Li, Suzanne Edmands.
      Impaired mitochondrial function can lead to senescence and the ageing phenotype. Theory predicts degenerative ageing phenotypes and mitochondrial pathologies may occur more frequently in males due to the matrilineal inheritance pattern of mitochondrial DNA observed in most eukaryotes. Here, we estimated the sex-specific longevity for parental and reciprocal F1 hybrid crosses for inbred lines derived from two allopatric Tigriopus californicus populations with over 20% mitochondrial DNA divergence. T. californicus lacks sex chromosomes allowing for more direct testing of mitochondrial function in sex-specific ageing. To better understand the ageing mechanism, we estimated two age-related phenotypes (mtDNA content and 8-hydroxy-20-deoxyguanosine (8-OH-dG) DNA damage) at two time points in the lifespan. Sex differences in lifespan depended on the mitochondrial and nuclear backgrounds, including differences between reciprocal F1 crosses which have different mitochondrial haplotypes on a 50 : 50 nuclear background, with nuclear contributions coming from alternative parents. Young females showed the highest mtDNA content which decreased with age, while DNA damage in males increased with age and exceed that of females 56 days after hatching. The adult sex ratio was male-biased and was attributed to complex mitonuclear interactions. Results thus demonstrate that sex differences in ageing depend on mitonuclear interactions in the absence of sex chromosomes.
    Keywords:  DNA damage; Tigriopus californicus; ageing; hybridization; sex ratio
    DOI:  https://doi.org/10.1098/rspb.2021.1813
  16. Cell Metab. 2021 Nov 02. pii: S1550-4131(21)00488-5. [Epub ahead of print]33(11): 2260-2276.e7
    Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease.
    Daniel Erny, Nikolaos Dokalis, Charlotte Mezö, Angela Castoldi, Omar Mossad, Ori Staszewski, Maximilian Frosch, Matteo Villa, Vidmante Fuchs, Arun Mayer, Jana Neuber, Janika Sosat, Stefan Tholen, Oliver Schilling, Andreas Vlachos, Thomas Blank, Mercedes Gomez de Agüero, Andrew J Macpherson, Edward J Pearce, Marco Prinz.
      As tissue macrophages of the central nervous system (CNS), microglia constitute the pivotal immune cells of this organ. Microglial features are strongly dependent on environmental cues such as commensal microbiota. Gut bacteria are known to continuously modulate microglia maturation and function by the production of short-chain fatty acids (SCFAs). However, the precise mechanism of this crosstalk is unknown. Here we determined that the immature phenotype of microglia from germ-free (GF) mice is epigenetically imprinted by H3K4me3 and H3K9ac on metabolic genes associated with substantial functional alterations including increased mitochondrial mass and specific respiratory chain dysfunctions. We identified acetate as the essential microbiome-derived SCFA driving microglia maturation and regulating the homeostatic metabolic state, and further showed that it is able to modulate microglial phagocytosis and disease progression during neurodegeneration. These findings indicate that acetate is an essential bacteria-derived molecule driving metabolic pathways and functions of microglia during health and perturbation.
    Keywords:  Alzheimer’s disease; SCFA; acetate; germ-free; metabolism; microbiota; microglia; mitochondria; respiratory chain
    DOI:  https://doi.org/10.1016/j.cmet.2021.10.010
  17. Commun Biol. 2021 Nov 04. 4(1): 1262
    Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease.
    Aine Fairbrother-Browne, Aminah T Ali, Regina H Reynolds, Sonia Garcia-Ruiz, David Zhang, Zhongbo Chen, Mina Ryten, Alan Hodgkinson.
      Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases. The mitochondrial genome encodes core respiratory chain proteins, but the vast majority of mitochondrial proteins are nuclear-encoded, making interactions between the two genomes vital for cell function. Here, we examine these relationships by comparing mitochondrial and nuclear gene expression across different regions of the human brain in healthy and disease cohorts. We find strong regional patterns that are modulated by cell-type and reflect functional specialisation. Nuclear genes causally implicated in sporadic Parkinson's and Alzheimer's disease (AD) show much stronger relationships with the mitochondrial genome than expected by chance, and mitochondrial-nuclear relationships are highly perturbed in AD cases, particularly through synaptic and lysosomal pathways, potentially implicating the regulation of energy balance and removal of dysfunction mitochondria in the etiology or progression of the disease. Finally, we present MitoNuclearCOEXPlorer, a tool to interrogate key mitochondria-nuclear relationships in multi-dimensional brain data.
    DOI:  https://doi.org/10.1038/s42003-021-02792-w
  18. Nature. 2021 Nov 03.
    Disruption of mitochondrial complex I induces progressive parkinsonism.
    Patricia González-Rodríguez, Enrico Zampese, Kristen A Stout, Jaime N Guzman, Ema Ilijic, Ben Yang, Tatiana Tkatch, Mihaela A Stavarache, David L Wokosin, Lin Gao, Michael G Kaplitt, José López-Barneo, Paul T Schumacker, D James Surmeier.
      Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease1. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm3,4.
    DOI:  https://doi.org/10.1038/s41586-021-04059-0
  19. Proc Natl Acad Sci U S A. 2021 Nov 09. pii: e2110996118. [Epub ahead of print]118(45):
    In-cell structures of conserved supramolecular protein arrays at the mitochondria-cytoskeleton interface in mammalian sperm.
    Miguel Ricardo Leung, Riccardo Zenezini Chiozzi, Marc C Roelofs, Johannes F Hevler, Ravi Teja Ravi, Paula Maitan, Min Zhang, Heiko Henning, Elizabeth G Bromfield, Stuart C Howes, Bart M Gadella, Albert J R Heck, Tzviya Zeev-Ben-Mordehai.
      Mitochondria-cytoskeleton interactions modulate cellular physiology by regulating mitochondrial transport, positioning, and immobilization. However, there is very little structural information defining mitochondria-cytoskeleton interfaces in any cell type. Here, we use cryofocused ion beam milling-enabled cryoelectron tomography to image mammalian sperm, where mitochondria wrap around the flagellar cytoskeleton. We find that mitochondria are tethered to their neighbors through intermitochondrial linkers and are anchored to the cytoskeleton through ordered arrays on the outer mitochondrial membrane. We use subtomogram averaging to resolve in-cell structures of these arrays from three mammalian species, revealing they are conserved across species despite variations in mitochondrial dimensions and cristae organization. We find that the arrays consist of boat-shaped particles anchored on a network of membrane pores whose arrangement and dimensions are consistent with voltage-dependent anion channels. Proteomics and in-cell cross-linking mass spectrometry suggest that the conserved arrays are composed of glycerol kinase-like proteins. Ordered supramolecular assemblies may serve to stabilize similar contact sites in other cell types in which mitochondria need to be immobilized in specific subcellular environments, such as in muscles and neurons.
    Keywords:  cross-linking mass spectrometry; cryo-FIB milling; cryoelectron tomography; mitochondria–cytoskeleton contacts; subtomogram averaging
    DOI:  https://doi.org/10.1073/pnas.2110996118
  20. EMBO Mol Med. 2021 Nov 02. e14824
    Emerging roles of ATG7 in human health and disease.
    Jack J Collier, Fumi Suomi, Monika Oláhová, Thomas G McWilliams, Robert W Taylor.
      The cardinal stages of macroautophagy are driven by core autophagy-related (ATG) proteins, whose ablation largely abolishes intracellular turnover. Disrupting ATG genes is paradigmatic of studying autophagy deficiency, yet emerging data suggest that ATG proteins have extensive biological importance beyond autophagic elimination. An important example is ATG7, an essential autophagy effector enzyme that in concert with other ATG proteins, also regulates immunity, cell death and protein secretion, and independently regulates the cell cycle and apoptosis. Recently, a direct association between ATG7 dysfunction and disease was established in patients with biallelic ATG7 variants and childhood-onset neuropathology. Moreover, a prodigious body of evidence supports a role for ATG7 in protecting against complex disease states in model organisms, although how dysfunctional ATG7 contributes to manifestation of these diseases, including cancer, neurodegeneration and infection, in humans remains unclear. Here, we systematically review the biological functions of ATG7, discussing the impact of its impairment on signalling pathways and human pathology. Future studies illuminating the molecular relationship between ATG7 dysfunction and disease will expedite therapies for disorders involving ATG7 deficiency and/or impaired autophagy.
    Keywords:  ATG7; autophagy; disease; neurodegeneration; therapeutics
    DOI:  https://doi.org/10.15252/emmm.202114824
  21. Elife. 2021 Nov 02. pii: e65109. [Epub ahead of print]10
    Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells.
    Michael C Kiritsy, Katelyn McCann, Daniel Mott, Stephen M Holland, Samuel M Behar, Christopher M Sassetti, Andrew J Olive.
      The immunological synapse allows antigen presenting cells (APC) to convey a wide array of functionally distinct signals to T cells, which ultimately shape the immune response. The relative effect of stimulatory and inhibitory signals is influenced by the activation state of the APC, which is determined by an interplay between signal transduction and metabolic pathways. While pathways downstream of toll-like receptors rely on glycolytic metabolism for the proper expression of inflammatory mediators, little is known about the metabolic dependencies of other critical signals such as interferon gamma (IFNg). Using CRISPR-Cas9, we performed a series of genome-wide knockout screens in murine macrophages to identify the regulators of IFNg-inducible T cell stimulatory or inhibitory proteins MHCII, CD40, and PD-L1. Our multi-screen approach enabled us to identify novel pathways that control these functionally distinct markers. Further integration of these screening data implicated complex I of the mitochondrial respiratory chain in the expression of all three markers, and by extension the IFNg signaling pathway. We report that the IFNg response requires mitochondrial respiration, and APCs are unable to activate T cells upon genetic or chemical inhibition of complex I. These findings suggest a dichotomous metabolic dependency between IFNg and toll-like receptor signaling, implicating mitochondrial function as a fulcrum of innate immunity.
    Keywords:  human; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.65109
  22. Cell Prolif. 2021 Nov 01. e13155
    Adiponectin receptor agonist AdipoRon blocks skin inflamm-ageing by regulating mitochondrial dynamics.
    Jiachen Sun, Xinzhu Liu, Chuan'an Shen, Wen Zhang, Yuezeng Niu.
       INTRODUCTION: Skin is susceptible to senescence-associated secretory phenotype (SASP) and inflamm-ageing partly owing to the degeneration of mitochondria. AdipoRon (AR) has protective effects on mitochondria in metabolic diseases such as diabetes. We explored the role of AR on mitochondria damage induced by skin inflamm-ageing and its underlying mechanism.
    METHODS: Western blot, immunofluorescence and TUNEL staining were used to detect inflammatory factors and apoptosis during skin ageing. Transmission electron microscopy, ATP determination kit, CellLight Mitochondria GFP (Mito-GFP), mitochondrial stress test, MitoSOX and JC-1 staining were used to detect mitochondrial changes. Western blot was applied to explore the underlying mechanism. Flow cytometry, scratch test, Sulforhodamine B assay and wound healing test were used to detect the effects of AR on cell apoptosis, migration and proliferation.
    RESULTS: AR attenuated inflammatory factors and apoptosis that increased in aged skin, and improved mitochondrial morphology and function. This process at least partly depended on the suppression of dynamin-related protein 1 (Drp1)-mediated excessive mitochondrial division. More specifically, AR up-regulated the phosphorylation of Drp1 at Serine 637 by activating AMP-activated protein kinase (AMPK), thereby inhibiting the mitochondrial translocation of Drp1. Moreover, AR reduced mitochondrial fragmentation and the production of superoxide, preserved the membrane potential and permeability of mitochondria and accelerated wound healing in aged skin.
    CONCLUSION: AR rescues the mitochondria in aged skin by suppressing its excessive division mediated by Drp1.
    Keywords:  AdipoRon; Dynamin-related protein 1 (Drp1); SASP; inflamm-ageing; mitochondria; skin
    DOI:  https://doi.org/10.1111/cpr.13155
  23. Circ Res. 2021 Nov 02.
    Alternative Mitophagy Protects the Heart Against Obesity-Associated Cardiomyopathy.
    Mingming Tong, Toshiro Saito, Peiyong Zhai, Shin-Ichi Oka, Wataru Mizushima, Michinari Nakamura, Shohei Ikeda, Akihiro Shirakabe, Junichi Sadoshima.
      Rationale: Obesity-associated cardiomyopathy characterized by hypertrophy and mitochondrial dysfunction. Mitochondrial quality control mechanisms, including mitophagy, are essential for the maintenance of cardiac function in obesity-associated cardiomyopathy. However, autophagic flux peaks at around 6 weeks of high fat diet (HFD) consumption and declines thereafter. Objective: We investigated whether mitophagy is activated during the chronic phase of cardiomyopathy associated with obesity (obesity cardiomyopathy) after general autophagy is downregulated and, if so, what the underlying mechanism and the functional significance are. Methods and Results: Mice were fed either a normal diet (ND) or a HFD (60 kcal % fat). Mitophagy, evaluated using Mito-Keima, was increased after 3 weeks of HFD consumption and continued to increase after conventional mechanisms of autophagy were inactivated, at least until 24 weeks. HFD consumption time-dependently up-regulated both Ser555-phosphorylated Ulk1 and Rab9 in the mitochondrial fraction. Mitochondria were sequestrated by Rab9-positive ring-like structures in cardiomyocytes isolated from mice after 20 weeks of HFD consumption, consistent with the activation of alternative mitophagy. Increases in mitophagy induced by HFD consumption for 20 weeks were abolished in cardiac-specific ulk1 knockout mouse hearts, in which both diastolic and systolic dysfunction were exacerbated. Rab9 S179A knock-in mice, in which alternative mitophagy is selectively suppressed, exhibited impaired mitophagy and more severe cardiac dysfunction than control mice following HFD consumption for 20 weeks. Overexpression of Rab9 in the heart increased mitophagy and protected against cardiac dysfunction during HFD consumption. HFD-induced activation of Rab9-dependent mitophagy was accompanied by upregulation of TFE3, which plays an essential role in transcriptional activation of mitophagy. Conclusions: Ulk1-Rab9-dependent alternative mitophagy is activated during the chronic phase of HFD consumption and serves as an essential mitochondrial quality control mechanism, thereby protecting the heart against obesity cardiomyopathy.
    DOI:  https://doi.org/10.1161/CIRCRESAHA.121.319377
  24. Epilepsia Open. 2021 Oct 30.
    Infantile-onset Myoclonic Developmental and Epileptic Encephalopathy: a new RARS2 phenotype.
    Guillem de Valles-Ibáñez, Michael S Hildebrand, Melanie Bahlo, Chontelle King, Matthew Coleman, Timothy E Green, John Goldsmith, Suzanne Davis, Deepak Gill, Simone Mandelstam, Ingrid E Scheffer, Lynette G Sadleir.
      Recessive variants in RARS2, a nuclear gene encoding a mitochondrial protein, were initially reported in pontocerebellar hypoplasia. Subsequently, a recessive RARS2 early-infantile (<12 weeks) developmental and epileptic encephalopathy was described with hypoglycaemia and lactic acidosis. Here, we describe two unrelated patients with a novel RARS2 phenotype and reanalyse the published RARS2 epilepsy phenotypes and variants. Our novel cases had infantile-onset myoclonic developmental and epileptic encephalopathy, presenting with a progressive movement disorder from 9 months on a background of normal development. Development plateaued and regressed thereafter, with mild to profound impairment. Multiple drug-resistant generalized and focal seizures occurred with episodes of non-convulsive status epilepticus. Seizure types included absence, atonic, myoclonic and focal seizures. Electroencephalograms showed diffuse slowing, multifocal and generalised spike-wave activity, activated by sleep. Both patients had compound heterozygous RARS2 variants with likely impact on splicing and transcription. Remarkably, of the now 52 RARS2 variants reported in 54 patients, our reanalysis found that 44 (85%) have been shown to or are predicted to affect splicing or gene expression leading to protein truncation or nonsense-mediated decay. We expand the RARS2 phenotypic spectrum to include infantile encephalopathy, and suggest this gene is enriched for pathogenic variants that disrupt splicing.
    Keywords:   RARS2 ; developmental and epileptic encephalopathy; epilepsy; infantile; movement disorder; myoclonic
    DOI:  https://doi.org/10.1002/epi4.12553
  25. Rheumatology (Oxford). 2021 Oct 29. pii: keab806. [Epub ahead of print]
    Mitochondrial DNA genetic variants are associated with systemic lupus erythematosus susceptibility, glucocorticoids efficacy, and prognosis.
    Ying Teng, Zi-Ye Yan, Lin-Lin Wang, Yu-Hua Wang, Ting-Yu Zhang, Zhen Li, Shuang Liu, Jing Cai, Yang-Fan Chen, Mu Li, Sheng-Xiu Liu, Zhou-Zhou Xu, Hai-Liang Huang, Fang Wang, Fa-Ming Pan, Hai-Feng Pan, Hong Su, Yan-Feng Zou.
       OBJECTIVE: To investigate the associations of mitochondrial DNA (mtDNA) genetic variants with systemic lupus erythematosus (SLE) susceptibility, glucocorticoids (GCs) efficacy, and prognosis.
    METHODS: Our study was done in two stages. First, we performed the whole mitochondrial genome sequencing in 100 patients and 100 controls to initially screen potential mtDNA variants associated with disease and glucocorticoids efficacy. Then, we validated the results in an independent set of samples. In total, 605 SLE patients and 604 normal controls were included in our two-stage study. A two-stage efficacy study was conducted in 512 patients treated with GCs for 12 weeks. We also explored the association between mtDNA variants and SLE prognosis.
    RESULTS: In the combined sample, four mtDNA variants (A4833G, T5108C, G14569A, CA514-515-) were associated with SLE susceptibility (all P  BH<0.05). We confirmed that T16362C was related to GCs efficacy (P  BH=0.014). Significant associations were detected between T16362C and T16519C and the efficacy of GCs in females with SLE (P  BH<0.05). In the prognosis study, variants A4833G (P  BH=0.003) and G14569A (P  BH=9.744 × 1 0 -4) substantially increased SLE relapse risk. Female patients harbouring variants T5108C and T16362C were more prone to relapse (P  BH<0.05). Haplotype analysis showed that haplogroup G was linked with SLE susceptibility (P  BH=0.001) and prognosis (P  BH=0.013). Moreover, mtDNA variants-environment interactions were observed.
    CONCLUSION: We identified novel mtDNA genetic variants that were associated with SLE susceptibility, GCs efficacy, and prognosis. Interactions between mtDNA variants and environmental factors were related to SLE risk and GCs efficacy. Our findings provide important information for future understanding the occurrence and development of SLE.
    Keywords:  genetic variants; glucocorticoids; mitochondrial DNA; prognosis; systemic lupus erythematosus
    DOI:  https://doi.org/10.1093/rheumatology/keab806
  26. BMJ. 2021 11 03. 375 n2680
    Whole genome sequencing helps pinpoint a genetic diagnosis for patients.
    Katherine Schon.
      
    DOI:  https://doi.org/10.1136/bmj.n2680
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