bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2021–05–23
forty-two papers selected by
Catalina Vasilescu, University of Helsinki
  1. High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts.
  2. Genome-wide CRISPR/Cas9 deletion screen defines mitochondrial gene essentiality and identifies routes for tumour cell viability in hypoxia.
  3. Consolidating biallelic SDHD variants as a cause of mitochondrial complex II deficiency.
  4. Metabolic Complications in Cardiac Aging.
  5. Mutant TMEM230 induced neurodegeneration and impaired axonal mitochondrial transport.
  6. An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank.
  7. Modulation of cellular fate of vinyl triarylamines through structural fine tuning: to stay or not to stay in the mitochondria?
  8. Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development and disease.
  9. Recombination and biased segregation of mitochondrial genomes during crossing and meiosis of different Schizosaccharomyces pombe strains.
  10. Drp1-mediated mitochondrial fission regulates calcium and F-actin dynamics during wound healing.
  11. ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity.
  12. TMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis.
  13. COXPD9 in an individual from Puerto Rico and literature review.
  14. In vivo assay and modelling of protein and mitochondrial turnover during aging.
  15. Mitochondrial DNA instability in mammalian cells.
  16. Ammonia inhibits energy metabolism in astrocytes in a rapid and glutamate dehydrogenase 2-dependent manner.
  17. Mitochondrial-nuclear heme trafficking is regulated by GTPases in control of mitochondrial dynamics and ER contact sites.
  18. Mitochondrial cardiomyopathy and ventricular arrhythmias associated with biallelic variants in C1QBP.
  19. Adhesion-mediated mechanosignaling forces mitohormesis.
  20. Actin mixes up mitochondria for inheritance.
  21. Mitochondria Control mTORC1 Activity Linked Compartmentalization of eIF4E to Regulate Extracellular Export of microRNAs.
  22. Targeting the mitochondrial chaperone TRAP1: strategies and therapeutic perspectives.
  23. Successful orthotopic heart transplantation in CPTII deficiency.
  24. UCP1 governs liver extracellular succinate and inflammatory pathogenesis.
  25. Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability.
  26. ARAMIS: From systematic errors of NGS long reads to accurate assemblies.
  27. Impairment of the ER/mitochondria compartment in human cardiomyocytes with PLN p.Arg14del mutation.
  28. Improved mitochondrial coupling as a response to high mass-specific metabolic rate in extremely small mammals.
  29. Muscle mitochondrial capacity in high- and low-fitness females using near-infrared spectroscopy.
  30. Mitochondrial dysfunction triggers catabolic response in chondrocytes via ROS mediated activation of JNK/AP1 pathway.
  31. Analysis of diverse eukaryotes suggests the existence of an ancestral mitochondrial apparatus derived from the bacterial type II secretion system.
  32. Retinal Damage in Amyotrophic Lateral Sclerosis: Underlying Mechanisms.
  33. Drosophila MICOS knockdown impairs mitochondrial structure and function and promotes mitophagy in muscle tissue.
  34. The cGAS-STING Pathway: Novel Perspectives in Liver Diseases.
  35. BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages.
  36. Hepatic AKT orchestrates adipose tissue thermogenesis via FGF21-dependent and -independent mechanisms.
  37. Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover.
  38. WEVar: a novel statistical learning framework for predicting noncoding regulatory variants.
  39. Cardiolipin is required for membrane docking of mitochondrial ribosomes and protein synthesis.
  40. Dynein and muskelin control myosin VI delivery towards the neuronal nucleus.
  41. Filament formation by the translation factor eIF2B regulates protein synthesis in starved cells.
  42. Perinuclear mitochondrial clustering, increased ROS levels, and HIF1 are required for the activation of HSF1 by heat stress.
  1. EMBO Mol Med. 2021 May 20. e13579
    High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts.
    Emma Cretin, Priscilla Lopes, Elodie Vimont, Takashi Tatsuta, Thomas Langer, Anastasia Gazi, Martin Sachse, Patrick Yu-Wai-Man, Pascal Reynier, Timothy Wai.
      Mutations in OPA1 cause autosomal dominant optic atrophy (DOA) as well as DOA+, a phenotype characterized by more severe neurological deficits. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae, respiration, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. We screened the entire known mitochondrial proteome (1,531 genes) to identify genes that control mitochondrial morphology using a first-in-kind imaging pipeline. We identified 145 known and novel candidate genes whose depletion promoted elongation or fragmentation of the mitochondrial network in control fibroblasts and 91 in DOA+ patient fibroblasts that prevented mitochondrial fragmentation, including phosphatidyl glycerophosphate synthase (PGS1). PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1-deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology, or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation.
    Keywords:  OPA1; genetic modifiers; high-throughput screening; mitochondrial dynamics; phospholipid metabolism
    DOI:  https://doi.org/10.15252/emmm.202013579
  2. Commun Biol. 2021 May 21. 4(1): 615
    Genome-wide CRISPR/Cas9 deletion screen defines mitochondrial gene essentiality and identifies routes for tumour cell viability in hypoxia.
    Luke W Thomas, Cinzia Esposito, Rachel E Morgan, Stacey Price, Jamie Young, Steven P Williams, Lucas A Maddalena, Ultan McDermott, Margaret Ashcroft.
      Mitochondria are typically essential for the viability of eukaryotic cells, and utilize oxygen and nutrients (e.g. glucose) to perform key metabolic functions that maintain energetic homeostasis and support proliferation. Here we provide a comprehensive functional annotation of mitochondrial genes that are essential for the viability of a large panel (625) of tumour cell lines. We perform genome-wide CRISPR/Cas9 deletion screening in normoxia-glucose, hypoxia-glucose and normoxia-galactose conditions, and identify both unique and overlapping genes whose loss influences tumour cell viability under these different metabolic conditions. We discover that loss of certain oxidative phosphorylation (OXPHOS) genes (e.g. SDHC) improves tumour cell growth in hypoxia-glucose, but reduces growth in normoxia, indicating a metabolic switch in OXPHOS gene function. Moreover, compared to normoxia-glucose, loss of genes involved in energy-consuming processes that are energetically demanding, such as translation and actin polymerization, improve cell viability under both hypoxia-glucose and normoxia-galactose. Collectively, our study defines mitochondrial gene essentiality in tumour cells, highlighting that essentiality is dependent on the metabolic environment, and identifies routes for regulating tumour cell viability in hypoxia.
    DOI:  https://doi.org/10.1038/s42003-021-02098-x
  3. Eur J Hum Genet. 2021 May 20.
    Consolidating biallelic SDHD variants as a cause of mitochondrial complex II deficiency.
    Siying Lin, James Fasham, Fida' Al-Hijawi, Nouar Qutob, Adam Gunning, Joseph S Leslie, Lucy McGavin, Nishanka Ubeyratna, Wisam Baker, Ramez Zeid, Peter D Turnpenny, Andrew H Crosby, Emma L Baple, Reham Khalaf-Nazzal.
      Isolated mitochondrial complex II deficiency is a rare cause of mitochondrial respiratory chain disease. To date biallelic variants in three genes encoding mitochondrial complex II molecular components have been unequivocally associated with mitochondrial disease (SDHA/SDHB/SDHAF1). Additionally, variants in one further complex II component (SDHD) have been identified as a candidate cause of isolated mitochondrial complex II deficiency in just two unrelated affected individuals with clinical features consistent with mitochondrial disease, including progressive encephalomyopathy and lethal infantile cardiomyopathy. We present clinical and genomic investigations in four individuals from an extended Palestinian family with clinical features consistent with an autosomal recessive mitochondrial complex II deficiency, in which our genomic studies identified a homozygous NM_003002.3:c.[205 G > A];[205 G > A];p.[(Glu69Lys)];[(Glu69Lys)] SDHD variant as the likely cause. Reviewing previously published cases, these findings consolidate disruption of SDHD function as a cause of mitochondrial complex II deficiency and further define the phenotypic spectrum associated with SDHD gene variants.
    DOI:  https://doi.org/10.1038/s41431-021-00887-w
  4. Front Physiol. 2021 ;12 669497
    Metabolic Complications in Cardiac Aging.
    Thomas Sithara, Konstantinos Drosatos.
      Aging is a process that can be accompanied by molecular and cellular alterations that compromise cardiac function. Although other metabolic disorders with increased prevalence in aged populations, such as diabetes mellitus, dyslipidemia, and hypertension, are associated with cardiovascular complications; aging-related cardiomyopathy has some unique features. Healthy hearts oxidize fatty acids, glucose, lactate, ketone bodies, and amino acids for producing energy. Under physiological conditions, cardiac mitochondria use fatty acids and carbohydrate mainly to generate ATP, 70% of which is derived from fatty acid oxidation (FAO). However, relative contribution of nutrients in ATP synthesis is altered in the aging heart with glucose oxidation increasing at the expense of FAO. Cardiac aging is also associated with impairment of mitochondrial abundance and function, resulting in accumulation of reactive oxygen species (ROS) and activation of oxidant signaling that eventually leads to further mitochondrial damage and aggravation of cardiac function. This review summarizes the main components of pathophysiology of cardiac aging, which pertain to cardiac metabolism, mitochondrial function, and systemic metabolic changes that affect cardiac function.
    Keywords:  autophagy; carbohydrate metabolism; cardiac aging; fatty acid oxidation; ketone bodies; mitochondria
    DOI:  https://doi.org/10.3389/fphys.2021.669497
  5. Hum Mol Genet. 2021 May 17. pii: ddab128. [Epub ahead of print]
    Mutant TMEM230 induced neurodegeneration and impaired axonal mitochondrial transport.
    Xiaobo Wang, Gongbo Guo, Jinru Zhang, Nicolas Aebez, Zhaohui Liu, Chun-Feng Liu, Christopher A Ross, Wanli W Smith.
      Parkinson's disease (PD) is a neurodegenerative disease with movement disorders including resting tremor, rigidity, bradykinesia, and postural instability. Recent studies have identified a new PD associated gene, TMEM230 (transmembrane protein 230). However, the pathological roles of TMEM230 and its variants are not fully understood. TMEM230 gene encodes two protein isoforms. Isoform2 is the major protein form (~95%) in human. In this study, we overexpress isoform2 TMEM230 variants (WT or PD-linked *184Wext*5 mutant) or knockdown endogenous protein in cultured SH-5Y5Y cells and mouse primary hippocampus neurons to study their pathological roles. We found that overexpression of WT and mutant TMEM230 or knockdown of endogenous TMEM230 induced neurodegeneration and impaired mitochondria transport at the retrograde direction in axons. Mutant TMEM230 caused more severe neurotoxicity and mitochondrial transport impairment than WT-TMEM230 did. Our results demonstrate that maintaining TMEM230 protein levels is critical for neuron survival and axon transport. These findings suggest that mutant-TMEM230-induced mitochondrial transport impairment could be the early event leading to neurite injury and neurodegeneration in PD development.
    DOI:  https://doi.org/10.1093/hmg/ddab128
  6. Nat Genet. 2021 May 17.
    An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank.
    Ekaterina Yonova-Doing, Claudia Calabrese, Aurora Gomez-Duran, Katherine Schon, Wei Wei, Savita Karthikeyan, Patrick F Chinnery, Joanna M M Howson.
      Mitochondrial DNA (mtDNA) variation in common diseases has been underexplored, partly due to a lack of genotype calling and quality-control procedures. Developing an at-scale workflow for mtDNA variant analyses, we show correlations between nuclear and mitochondrial genomic structures within subpopulations of Great Britain and establish a UK Biobank reference atlas of mtDNA-phenotype associations. A total of 260 mtDNA-phenotype associations were new (P < 1 × 10-5), including rs2853822 /m.8655 C>T (MT-ATP6) with type 2 diabetes, rs878966690 /m.13117 A>G (MT-ND5) with multiple sclerosis, 6 mtDNA associations with adult height, 24 mtDNA associations with 2 liver biomarkers and 16 mtDNA associations with parameters of renal function. Rare-variant gene-based tests implicated complex I genes modulating mean corpuscular volume and mean corpuscular hemoglobin. Seven traits had both rare and common mtDNA associations, where rare variants tended to have larger effects than common variants. Our work illustrates the value of studying mtDNA variants in common complex diseases and lays foundations for future large-scale mtDNA association studies.
    DOI:  https://doi.org/10.1038/s41588-021-00868-1
  7. Chembiochem. 2021 May 19.
    Modulation of cellular fate of vinyl triarylamines through structural fine tuning: to stay or not to stay in the mitochondria?
    Laura Fourmois, Florent Poyer, Aude Sourdon, Delphine Naud-Martin, Sounderya Nagarajan, Rahima Chennoufi, Eric Deprez, Marie-Paule Teulade-Fichou, Florence Mahuteau-Betzer.
      Mitochondria is involved in many cellular pathways and dysfunctional mitochondria are linked to various diseases. Hence efforts have been driven to design mitochondria-targeted fluorophores for monitoring the mitochondria status. However, the factors that govern the mitochondria-targeted potential of dyes are not well-understood. In this context, we synthesized analogues of the TP-2Bzim probe belonging to the vinyltriphenylamine (TPA) class and already described for its capacity to bind nuclear DNA in fixed cells and mitochondria in live cells. These analogues ( TP-1Bzim, TP n -2Bzim, TP 1+ -2Bzim, TN-2Bzim ) differ by the cationic charge, the number of vinylbenzimidazolium branches and the nature of the triaryl core. Using microscopy, we demonstrated that the cationic derivatives accumulate in mitochondria but do not reach mtDNA. Under depolarisation of the mitochondrial membrane, TP-2Bzim and TP 1+ -2Bzim translocate to the nucleus in direct correlation with their strong DNA affinity. This reversible phenomenon emphasizes that these probes can be used to monitor ΔΨ m variations.
    Keywords:  Fluorescent probes * Chemical Biology * Organelle imaging probes * Mitochondria *
    DOI:  https://doi.org/10.1002/cbic.202100168
  8. Curr Biol. 2021 May 14. pii: S0960-9822(21)00609-6. [Epub ahead of print]
    Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development and disease.
    James L Shen, Tina M Fortier, Yan G Zhao, Ruoxi Wang, Margit Burmeister, Eric H Baehrecke.
      Mutations in Vps13D cause defects in autophagy, clearance of mitochondria, and human movement disorders. Here, we discover that Vps13D functions in a pathway downstream of Vmp1 and upstream of Marf/Mfn2. Like vps13d, vmp1 mutant cells exhibit defects in autophagy, mitochondrial size, and clearance. Through the relationship between vmp1 and vps13d, we reveal a novel role for Vps13D in the regulation of mitochondria and endoplasmic reticulum (ER) contact. Significantly, the function of Vps13D in mitochondria and ER contact is conserved between fly and human cells, including fibroblasts derived from patients suffering from VPS13D mutation-associated neurological symptoms. vps13d mutants have increased levels of Marf/MFN2, a regulator of mitochondrial fusion. Importantly, loss of marf/MFN2 suppresses vps13d mutant phenotypes, including mitochondria and ER contact. These findings indicate that Vps13d functions at a regulatory point between mitochondria and ER contact, mitochondrial fusion and autophagy, and help to explain how Vps13D contributes to disease.
    Keywords:  Drosophila; Vmp1; Vps13D; autophagy; membrane contact; mitochondria
    DOI:  https://doi.org/10.1016/j.cub.2021.04.062
  9. MicroPubl Biol. 2021 May 17. 2021
    Recombination and biased segregation of mitochondrial genomes during crossing and meiosis of different Schizosaccharomyces pombe strains.
    Stephan Kamrad, María Rodríguez-López, Shoumit Dey, Mimoza Hoti, Henry Wallace, Markus Ralser, Jürg Bähler.
      During meiosis, tethering of parental mitochondria to opposite cell poles inhibits the mixing of mitochondria with different genomes and ensures uniparental inheritance in thestandard laboratory strain of fission yeast. We here investigate mitochondrial inheritance in crosses between natural isolates using tetrad dissection and next-generation sequencing. We find that colonies grown from single spores can sometimes carry a mix of mitochondrial genotypes, that mitochondrial genomes can recombine during meiosis, that in some cases tetrads do not follow the 2:2 segregation pattern, and that certain crosses may feature a weak bias towards one of the parents. Together, these findings paint a more nuanced picture of mitochondrial inheritance in the wild.
    DOI:  https://doi.org/10.17912/micropub.biology.000390
  10. Biol Open. 2020 Jan 01. pii: bio.048629. [Epub ahead of print]
    Drp1-mediated mitochondrial fission regulates calcium and F-actin dynamics during wound healing.
    Susana Ponte, Lara Carvalho, Maria Gagliardi, Isabel Campos, Paulo J Oliveira, António Jacinto.
      Mitochondria adapt to cellular needs by changes in morphology through fusion and fission events, referred to as mitochondrial dynamics. Mitochondrial function and morphology are intimately connected and the dysregulation of mitochondrial dynamics is linked to several human diseases. In this work, we investigated the role of mitochondrial dynamics in wound healing in the Drosophila embryonic epidermis. Mutants for mitochondrial fusion and fission proteins fail to close their wounds, indicating that the regulation of mitochondrial dynamics is required for wound healing. By live-imaging, we found that loss of function of the mitochondrial fission protein Dynamin-related protein 1 (Drp1) compromises the increase of cytosolic and mitochondrial calcium upon wounding and leads to reduced ROS production and F-actin defects at the wound edge, culminating in wound healing impairment. Our results highlight a new role for mitochondrial dynamics in the regulation of calcium, ROS and F-actin during epithelial repair.
    Keywords:  Calcium; Drp1; F-actin; Mitochondria; Mitochondrial dynamics; Wound healing
    DOI:  https://doi.org/10.1242/bio.048629
  11. Sci Transl Med. 2021 May 19. pii: eabd1869. [Epub ahead of print]13(594):
    ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity.
    Michael Shum, Chitra A Shintre, Thorsten Althoff, Vincent Gutierrez, Mayuko Segawa, Alexandra D Saxberg, Melissa Martinez, Roslin Adamson, Margaret R Young, Belinda Faust, Raffi Gharakhanian, Shi Su, Karthickeyan Chella Krishnan, Kiana Mahdaviani, Michaela Veliova, Dane M Wolf, Jennifer Ngo, Laura Nocito, Linsey Stiles, Jeff Abramson, Aldons J Lusis, Andrea L Hevener, Maria E Zoghbi, Elisabeth P Carpenter, Marc Liesa.
      Although the role of hydrophilic antioxidants in the development of hepatic insulin resistance and nonalcoholic fatty liver disease has been well studied, the role of lipophilic antioxidants remains poorly characterized. A known lipophilic hydrogen peroxide scavenger is bilirubin, which can be oxidized to biliverdin and then reduced back to bilirubin by cytosolic biliverdin reductase. Oxidation of bilirubin to biliverdin inside mitochondria must be followed by the export of biliverdin to the cytosol, where biliverdin is reduced back to bilirubin. Thus, the putative mitochondrial exporter of biliverdin is expected to be a major determinant of bilirubin regeneration and intracellular hydrogen peroxide scavenging. Here, we identified ABCB10 as a mitochondrial biliverdin exporter. ABCB10 reconstituted into liposomes transported biliverdin, and ABCB10 deletion caused accumulation of biliverdin inside mitochondria. Obesity with insulin resistance up-regulated hepatic ABCB10 expression in mice and elevated cytosolic and mitochondrial bilirubin content in an ABCB10-dependent manner. Revealing a maladaptive role of ABCB10-driven bilirubin synthesis, hepatic ABCB10 deletion protected diet-induced obese mice from steatosis and hyperglycemia, improving insulin-mediated suppression of glucose production and decreasing lipogenic SREBP-1c expression. Protection was concurrent with enhanced mitochondrial function and increased inactivation of PTP1B, a phosphatase disrupting insulin signaling and elevating SREBP-1c expression. Restoration of cellular bilirubin content in ABCB10 KO hepatocytes reversed the improvements in mitochondrial function and PTP1B inactivation, demonstrating that bilirubin was the maladaptive effector linked to ABCB10 function. Thus, we identified a fundamental transport process that amplifies intracellular bilirubin redox actions, which can exacerbate insulin resistance and steatosis in obesity.
    DOI:  https://doi.org/10.1126/scitranslmed.abd1869
  12. Cell Metab. 2021 May 17. pii: S1550-4131(21)00223-0. [Epub ahead of print]
    TMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis.
    Dong Huang, Bolin Xu, Lu Liu, Lingzhi Wu, Yuangang Zhu, Alireza Ghanbarpour, Yawei Wang, Feng-Jung Chen, Jia Lyu, Yating Hu, Yunlu Kang, Wenjing Zhou, Xiao Wang, Wanqiu Ding, Xin Li, Zhaodi Jiang, Jizheng Chen, Xu Zhang, Hongwen Zhou, John Zhong Li, Chunguang Guo, Wen Zheng, Xiuqin Zhang, Peng Li, Thomas Melia, Karin Reinisch, Xiao-Wei Chen.
      How amphipathic phospholipids are shuttled between the membrane bilayer remains an essential but elusive process, particularly at the endoplasmic reticulum (ER). One prominent phospholipid shuttling process concerns the biogenesis of APOB-containing lipoproteins within the ER lumen, which may require bulk trans-bilayer movement of phospholipids from the cytoplasmic leaflet of the ER bilayer. Here, we show that TMEM41B, present in the lipoprotein export machinery, encodes a previously conceptualized ER lipid scramblase mediating trans-bilayer shuttling of bulk phospholipids. Loss of hepatic TMEM41B eliminates plasma lipids, due to complete absence of mature lipoproteins within the ER, but paradoxically also activates lipid production. Mechanistically, scramblase deficiency triggers unique ER morphological changes and unsuppressed activation of SREBPs, which potently promotes lipid synthesis despite stalled secretion. Together, this response induces full-blown nonalcoholic hepatosteatosis in the TMEM41B-deficient mice within weeks. Collectively, our data uncovered a fundamental mechanism safe-guarding ER function and integrity, dysfunction of which disrupts lipid homeostasis.
    Keywords:  SREBP; endoplasmic reticulum; fatty liver disease; lipid scramblase; lipoprotein metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2021.05.006
  13. Am J Med Genet A. 2021 May 19.
    COXPD9 in an individual from Puerto Rico and literature review.
    Hind Alsharhan, Colleen Muraresku, Rebecca D Ganetzky.
      Defects of mitoribosome assembly with destabilization of mitochondrial ribosomal proteins and subsequent aberrant mitochondrial translation machinery are one of the emerging categories of human mitochondrial disease. Mitochondrial translation deficiency constitutes a growing cause of combined oxidative phosphorylation deficiency and overall causes a set of clinically heterogeneous multi-systemic diseases. We present here the sixth individual with combined oxidative phosphorylation deficiency-9 (COXPD9) secondary to a likely pathogenic homozygous MRPL3 variant c.571A > C; p.(Thr191Pro). MRPL3 encodes a large mitochondrial ribosome subunit protein, impairing the mitochondrial translation and resulting in multisystem disease. Similar to previously reported individuals, this reported female proband presented with psychomotor retardation, sensorineural hearing loss, hypertrophic cardiomyopathy, failure to thrive, and lactic acidosis. Further, she has additional, previously unreported, features including Leigh syndrome, cataracts, hypotonia, scoliosis, myopathy, exercise intolerance, childhood-onset cardiomyopathy, and microcephaly. This subject is the oldest reported individual with COXPD9. This report also summarizes the clinical and molecular data of the previously reported individuals with COXPD9 to describe the full phenotypic spectrum.
    Keywords:  MRPL3; cardiomyopathy; lactic acidosis; mitoribosome; translation
    DOI:  https://doi.org/10.1002/ajmg.a.62344
  14. Fly (Austin). 2021 Dec;15(1): 60-72
    In vivo assay and modelling of protein and mitochondrial turnover during aging.
    Hans S Bell, John Tower.
      To maintain homoeostasis, cells must degrade damaged or misfolded proteins and synthesize functional replacements. Maintaining a balance between these processes, known as protein turnover, is necessary for stress response and cellular adaptation to a changing environment. Damaged mitochondria must also be removed and replaced. Changes in protein and mitochondrial turnover are associated with aging and neurodegenerative disease, making it important to understand how these processes occur and are regulated in cells. To achieve this, reliable assays of turnover must be developed. Several methods exist, including pulse-labelling with radioactive or stable isotopes and strategies making use of fluorescent proteins, each with their own advantages and limitations. Both cell culture and live animals have been used for these studies, in systems ranging from yeast to mammals. In vivo assays are especially useful for connecting turnover to aging and disease. With its short life cycle, suitability for fluorescent imaging, and availability of genetic tools, Drosophila melanogaster is particularly well suited for this kind of analysis.
    Keywords:  Drosophila; aging; fluorescence microscopy; isotope labelling; mitophagy; protein turnover; video tracking
    DOI:  https://doi.org/10.1080/19336934.2021.1911286
  15. Antioxid Redox Signal. 2021 May 20.
    Mitochondrial DNA instability in mammalian cells.
    Gustavo Carvalho, Bruno Marçal Repolês, Isabela Mendes, Paulina H Wanrooij.
       SIGNIFICANCE: The small, multicopy mitochondrial genome (mtDNA) is essential for efficient energy production, as alterations in its coding information or a decrease in its copy number disrupt mitochondrial ATP synthesis. However, the mitochondrial replication machinery encounters numerous challenges that may limit its ability to duplicate this important genome and that jeopardize mtDNA stability, including various lesions in the DNA template, topological stress and an insufficient nucleotide supply. Recent Advances: An ever-growing array of DNA repair or maintenance factors are being reported to localize to the mitochondria. We review current knowledge regarding the mitochondrial factors that may contribute to the tolerance or repair of various types of changes in the mitochondrial genome, such as base damage, incorporated ribonucleotides and strand breaks. We also discuss the newly-discovered link between mtDNA instability and activation of the innate immune response.
    CRITICAL ISSUES: By which mechanisms do mitochondria respond to challenges that threaten mtDNA maintenance? What types of mtDNA damage are repaired, and when are the affected molecules degraded instead? And, finally, which forms of mtDNA instability trigger an immune response, and how?
    FUTURE DIRECTIONS: Further work is required to understand the contribution of the DNA repair and damage-tolerance factors present in the mitochondrial compartment, as well as the balance between mtDNA repair and degradation. Finally, efforts to understand the events underlying mtDNA release into the cytosol are warranted. Pursuing these and many related avenues can improve our understanding of what goes wrong in mitochondrial disease.
    DOI:  https://doi.org/10.1089/ars.2021.0091
  16. Dis Model Mech. 2020 Jan 01. pii: dmm.047134. [Epub ahead of print]
    Ammonia inhibits energy metabolism in astrocytes in a rapid and glutamate dehydrogenase 2-dependent manner.
    Leonie Drews, Marcel Zimmermann, Philipp Westhoff, Dominik Brilhaus, Rebecca E Poss, Laura Bergmann, Constanze Wiek, Peter Brenneisen, Roland P Piekorz, Tabea Mettler-Altmann, Andreas P M Weber, Andreas S Reichert.
      Astrocyte dysfunction is a primary factor in hepatic encephalopathy (HE) impairing neuronal activity under hyperammonemia. In particular the early events causing ammonia-induced toxicity to astrocytes are not well understood. Using established cellular HE models, we show that mitochondria rapidly undergo fragmentation in a reversible manner upon hyperammonemia. Further, within a timescale of minutes mitochondrial respiration and glycolysis were hampered which occurred in a pH-independent manner. Using metabolomics an accumulation of numerous amino acids, including branched chain amino acids and glucose was observed. Metabolomic tracking of 15N-labeled ammonia showed rapid incorporation of 15N into glutamate and glutamate-derived amino acids. Downregulating human GLUD2, encoding mitochondrial glutamate dehydrogenase 2 (GDH2), inhibiting GDH2 activity by SIRT4 overexpression, and supplementing cells with glutamate or glutamine alleviated ammonia-induced inhibition of mitochondrial respiration. Metabolomic tracking of 13C-glutamine showed that hyperammonemia can inhibit anaplerosis of TCA-cycle intermediates. Contrary to its classical anaplerotic role, we show that under hyperammonemia GDH2 rather catalyzes the removal of ammonia by reductive amination of α-ketoglutarate which efficiently and rapidly inhibits the TCA-cycle. Overall, we propose a critical GDH2-dependent mechanism in HE models that on the one hand helps to remove ammonia but on the other hand impairs energy metabolism in mitochondria rapidly.
    Keywords:  Brain energy metabolism; Glutamate dehydrogenase; Hepatic encephalopathy; Hyperammonemia; Mitochondria; TCA-cycle
    DOI:  https://doi.org/10.1242/dmm.047134
  17. J Cell Sci. 2020 Jan 01. pii: jcs.237917. [Epub ahead of print]
    Mitochondrial-nuclear heme trafficking is regulated by GTPases in control of mitochondrial dynamics and ER contact sites.
    Osiris Martinez-Guzman, Mathilda M Willoughby, Arushi Saini, Jonathan V Dietz, Iryna Bohovych, Amy E Medlock, Oleh Khalimonchuk, Amit R Reddi.
      Heme is a cofactor and signaling molecule that is essential for much of aerobic life. All heme-dependent processes in eukaryotes require that heme is trafficked from its site of synthesis in the mitochondria to hemoproteins located throughout the cell. However, the mechanisms governing the mobilization of heme out of the mitochondria, and the spatio-temporal dynamics of these processes, are poorly understood. Herein, using genetically encoded fluorescent heme sensors, we developed a live cell assay to monitor heme distribution dynamics between the mitochondrial inner-membrane, where heme is synthesized, and the mitochondrial matrix, cytosol, and nucleus. Surprisingly, heme trafficking to the nucleus is ∼25% faster than to the cytosol or mitochondrial matrix, which are nearly identical, potentially supporting a role for heme as a mitochondrial-nuclear retrograde signal. Moreover, we discovered that the heme synthetic enzyme, 5-aminolevulinic acid synthase (ALAS), and GTPases in control of the mitochondrial dynamics machinery, Mgm1 and Dnm1, and ER contact sites, Gem1, regulate the flow of heme between the mitochondria and nucleus. Overall, our results indicate that there are parallel pathways for the distribution of bioavailable heme.
    Keywords:  Heme; Heme transport; Mitochondrial dynamics; Yeast
    DOI:  https://doi.org/10.1242/jcs.237917
  18. Am J Med Genet A. 2021 May 18.
    Mitochondrial cardiomyopathy and ventricular arrhythmias associated with biallelic variants in C1QBP.
    Gregory Webster, Meredith Reynolds, Nicoleta C Arva, Lisa M Dellefave-Castillo, Hilary S McElligott, Amber Kofman, Aleksandra Laboski, Defne Magnetta, Alfred L George, Elizabeth M McNally, Megan J Puckelwartz.
      Patients with biallelic mutations in the nuclear-encoded mitochondrial gene C1QBP/p32 have been described with syndromic features and autosomal recessive cardiomyopathy. We describe the clinical course in two siblings who developed cardiomyopathy and ventricular fibrillation in infancy. We provide genomic analysis and clinical-pathologic correlation. Both siblings had profound cardiac failure with ventricular arrhythmia. One child died suddenly. The second sibling survived resuscitation but required extracorporeal cardiopulmonary support and died shortly afterward. On cardiac autopsy, the left ventricle was hypertrophied in both children. Histological examination revealed prominent cardiomyocyte cytoplasmic clearing, and electron microscopy confirmed abnormal mitochondrial structure within cardiomyocytes. DNA sequencing revealed compound heterozygous variants in C1QBP (p.Thr40Asnfs*45 and p.Phe204Leu) in both children. Family segregation analysis demonstrated each variant was inherited from an unaffected, heterozygous parent. Inherited loss of C1QBP/p32 is associated with recessive cardiomyopathy, ventricular fibrillation, and sudden death in early life. Ultrastructural mitochondrial evaluation in the second child was similar to findings in engineered C1qbp-deficient mice. Rapid trio analysis can define rare biallelic variants in genes that may be implicated in sudden death and facilitate medical management and family planning. (184/200).
    Keywords:  C1QBP; mitochondrial cardiomyopathy; p32; pediatrics; sudden death; ventricular fibrillation
    DOI:  https://doi.org/10.1002/ajmg.a.62262
  19. Cell Metab. 2021 May 17. pii: S1550-4131(21)00183-2. [Epub ahead of print]
    Adhesion-mediated mechanosignaling forces mitohormesis.
    Kevin M Tharp, Ryo Higuchi-Sanabria, Greg A Timblin, Breanna Ford, Carlos Garzon-Coral, Catherine Schneider, Jonathon M Muncie, Connor Stashko, Joseph R Daniele, Andrew S Moore, Phillip A Frankino, Stefan Homentcovschi, Sagar S Manoli, Hao Shao, Alicia L Richards, Kuei-Ho Chen, Johanna Ten Hoeve, Gregory M Ku, Marc Hellerstein, Daniel K Nomura, Karou Saijo, Jason Gestwicki, Alexander R Dunn, Nevan J Krogan, Danielle L Swaney, Andrew Dillin, Valerie M Weaver.
      Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programed cell death. The biochemical milieu is known to affect mitochondrial function and contribute to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of aging. However, the physical characteristics of the extracellular matrix are also altered in cancerous and aging tissues. Here, we demonstrate that cells sense the physical properties of the extracellular matrix and activate a mitochondrial stress response that adaptively tunes mitochondrial function via solute carrier family 9 member A1-dependent ion exchange and heat shock factor 1-dependent transcription. Overall, our data indicate that adhesion-mediated mechanosignaling may play an unappreciated role in the altered mitochondrial functions observed in aging and cancer.
    Keywords:  UPRmt; adhesion; aging; cancer; extracellular matrix; mechanical stress; mechanotabolism; metabolism; oxidative stress; tension
    DOI:  https://doi.org/10.1016/j.cmet.2021.04.017
  20. Nature. 2021 May 14.
    Actin mixes up mitochondria for inheritance.
    Andrew S Moore, Erika L F Holzbaur.
      
    Keywords:  Cell biology; Microscopy
    DOI:  https://doi.org/10.1038/d41586-021-01115-7
  21. J Cell Sci. 2020 Jan 01. pii: jcs.250241. [Epub ahead of print]
    Mitochondria Control mTORC1 Activity Linked Compartmentalization of eIF4E to Regulate Extracellular Export of microRNAs.
    Susanta Chatterjee, Yogaditya Chakrabarty, Saikat Banerjee, Souvik Ghosh, Suvendra N Bhattacharyya.
      Defective intracellular trafficking and export of microRNAs have been observed in growth retarded mammalian cells having impaired mitochondrial potential and dynamics. Uncoupling Protein 2 mediated depolarization of mitochondrial membrane also results in progressive sequestration of microRNAs with polysomes and lowered their release via extracellular vesicles. Interestingly, impaired miRNA-trafficking process in growth retarded human cells could be reversed in presence of Genipin an inhibitor of Uncoupling Protein 2. Mitochondrial detethering of endoplasmic reticulum, observed in mitochondria depolarized cells, found to be responsible for defective compartmentalization of translation initiation factor eIF4E to endoplasmic reticulum attached polysomes. It causes retarded translation process accompanied by enhanced retention of miRNAs and target mRNAs with endoplasmic reticulum attached polysomes to restrict extracellular export of miRNAs. Reduced compartment specific activity of mTORC1 complex, the master regulator of protein synthesis, in mitochondria defective or ER- detethered cells, causes reduced phosphorylation of eIF4E-BP1 to prevent eIF-4E targeting to ER attached polysome and microRNA export. These data suggest how mitochondrial membrane potential and dynamics, by affecting mTORC1 activity and compartmentalization, determine sub-cellular localization and export of microRNAs.
    Keywords:  EIF4E and mTORC1; Exosomes; Extracellular vesicles; MiRNA; Mitochondria; P-body; Polysome; Processing bodies
    DOI:  https://doi.org/10.1242/jcs.250241
  22. Trends Pharmacol Sci. 2021 May 12. pii: S0165-6147(21)00072-9. [Epub ahead of print]
    Targeting the mitochondrial chaperone TRAP1: strategies and therapeutic perspectives.
    Stefano A Serapian, Carlos Sanchez-Martín, Elisabetta Moroni, Andrea Rasola, Giorgio Colombo.
      TRAP1, the mitochondrial isoform of heat shock protein (Hsp)90 chaperones, is a key regulator of metabolism and organelle homeostasis in diverse pathological states. While selective TRAP1 targeting is an attractive goal, classical active-site-directed strategies have proved difficult, due to high active site conservation among Hsp90 paralogs. Here, we discuss advances in developing TRAP1-directed strategies, from lead modification with mitochondria delivery groups to the computational discovery of allosteric sites and ligands. Specifically, we address the unique opportunities that targeting TRAP1 opens up in tackling fundamental questions on its biology and in unveiling new therapeutic approaches. Finally, we show how crucial to this endeavor is our ability to predict the activities of TRAP1-selective allosteric ligands and to optimize target engagement to avoid side effects.
    Keywords:  drug design; mitochondrial proteostasis; molecular chaperones; molecular dynamics
    DOI:  https://doi.org/10.1016/j.tips.2021.04.003
  23. Mol Genet Metab. 2021 Apr 28. pii: S1096-7192(21)00696-X. [Epub ahead of print]
    Successful orthotopic heart transplantation in CPTII deficiency.
    Georgianne L Arnold, Jessie Yester, Elizabeth McCracken, Brian D Feingold, Jerry Vockley.
      Carnitine palmitoyl transferase II (CPT II) catalyzes the release of activated long-chain fatty acids from acylcarnitines into mitochondria for subsequent fatty acid oxidation. Depending on residual enzyme activity, deficiency of this enzyme leads to a spectrum of symptoms from early onset hypoglycemia, hyperammonemia, cardiomyopathy and death to onset of recurrent rhabdomyolysis in adolescents and young adults. We present a case of successful orthotopic heart transplantation in a patient with severe infantile onset cardiomyopathy due to CPT II deficiency identified through newborn screening. Excellent cardiac function is preserved 12 years post-transplantation; however, the patient has developed intermittent episodes of hyperammonemia and rhabdomyolysis later in childhood and early adolescence readily resolved with intravenous glucose. Successful heart transplant in this patient demonstrates the feasibility of this management option in patients with even severe forms of long chain fatty acid oxidation disorders.
    Keywords:  CPT2 deficiency; Cardiomyopathy; Carnitine palmitoyl transferase deficiency; Fatty acid oxidation disorder; Heart transplantation
    DOI:  https://doi.org/10.1016/j.ymgme.2021.04.005
  24. Nat Metab. 2021 May 17.
    UCP1 governs liver extracellular succinate and inflammatory pathogenesis.
    Evanna L Mills, Cathal Harmon, Mark P Jedrychowski, Haopeng Xiao, Ryan Garrity, Nhien V Tran, Gary A Bradshaw, Accalia Fu, John Szpyt, Anita Reddy, Hannah Prendeville, Nika N Danial, Steven P Gygi, Lydia Lynch, Edward T Chouchani.
      Non-alcoholic fatty liver disease (NAFLD), the most prevalent liver pathology worldwide, is intimately linked with obesity and type 2 diabetes. Liver inflammation is a hallmark of NAFLD and is thought to contribute to tissue fibrosis and disease pathogenesis. Uncoupling protein 1 (UCP1) is exclusively expressed in brown and beige adipocytes, and has been extensively studied for its capacity to elevate thermogenesis and reverse obesity. Here we identify an endocrine pathway regulated by UCP1 that antagonizes liver inflammation and pathology, independent of effects on obesity. We show that, without UCP1, brown and beige fat exhibit a diminished capacity to clear succinate from the circulation. Moreover, UCP1KO mice exhibit elevated extracellular succinate in liver tissue that drives inflammation through ligation of its cognate receptor succinate receptor 1 (SUCNR1) in liver-resident stellate cell and macrophage populations. Conversely, increasing brown and beige adipocyte content in mice antagonizes SUCNR1-dependent inflammatory signalling in the liver. We show that this UCP1-succinate-SUCNR1 axis is necessary to regulate liver immune cell infiltration and pathology, and systemic glucose intolerance in an obesogenic environment. As such, the therapeutic use of brown and beige adipocytes and UCP1 extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.
    DOI:  https://doi.org/10.1038/s42255-021-00389-5
  25. Sci Rep. 2021 May 21. 11(1): 10676
    Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability.
    Jeong-Su Do, Daniel Zwick, Jonathan D Kenyon, Fei Zhong, David Askew, Alex Y Huang, Wouter Van't Hof, Marcie Finney, Mary J Laughlin.
      The key obstacle to clinical application of human inducible regulatory T cells (iTreg) as an adoptive cell therapy in autoimmune disorders is loss of FOXP3 expression in an inflammatory milieu. Here we report human iTreg co-cultured with bone marrow-derived mesenchymal stromal cells (MSCs) during short-term ex vivo expansion enhances the stability of iTreg FOXP3 expression and suppressive function in vitro and in vivo, and further that a key mechanism of action is MSC mitochondrial (mt) transfer via tunneling nanotubules (TNT). MSC mt transfer is driven by mitochondrial metabolic function (CD39/CD73 signaling) in proliferating iTreg and promotes iTreg expression of FOXP3 stabilizing factors BACH2 and SENP3. These results elucidate cellular and molecular mechanisms underlying human MSC mt transfer to proliferating cells. MSC mt transfer stabilizes FOXP3 expression in iTregs, thereby enhancing and sustaining their suppressive function in inflammatory conditions in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s41598-021-90115-8
  26. Brief Bioinform. 2021 May 19. pii: bbab170. [Epub ahead of print]
    ARAMIS: From systematic errors of NGS long reads to accurate assemblies.
    E Sacristán-Horcajada, S González-de la Fuente, R Peiró-Pastor, F Carrasco-Ramiro, R Amils, J M Requena, J Berenguer, B Aguado.
      NGS long-reads sequencing technologies (or third generation) such as Pacific BioSciences (PacBio) have revolutionized the sequencing field over the last decade improving multiple genomic applications like de novo genome assemblies. However, their error rate, mostly involving insertions and deletions (indels), is currently an important concern that requires special attention to be solved. Multiple algorithms are available to fix these sequencing errors using short reads (such as Illumina), although they require long processing times and some errors may persist. Here, we present Accurate long-Reads Assembly correction Method for Indel errorS (ARAMIS), the first NGS long-reads indels correction pipeline that combines several correction software in just one step using accurate short reads. As a proof OF concept, six organisms were selected based on their different GC content, size and genome complexity, and their PacBio-assembled genomes were corrected thoroughly by this pipeline. We found that the presence of systematic sequencing errors in long-reads PacBio sequences affecting homopolymeric regions, and that the type of indel error introduced during PacBio sequencing are related to the GC content of the organism. The lack of knowledge of this fact leads to the existence of numerous published studies where such errors have been found and should be resolved since they may contain incorrect biological information. ARAMIS yields better results with less computational resources needed than other correction tools and gives the possibility of detecting the nature of the found indel errors found and its distribution along the genome. The source code of ARAMIS is available at https://github.com/genomics-ngsCBMSO/ARAMIS.git.
    Keywords:  error correction; genome assembly; homopolymer; long read; next-generation sequencing
    DOI:  https://doi.org/10.1093/bib/bbab170
  27. EMBO Mol Med. 2021 May 16. e13074
    Impairment of the ER/mitochondria compartment in human cardiomyocytes with PLN p.Arg14del mutation.
    Friederike Cuello, Anika E Knaust, Umber Saleem, Malte Loos, Janice Raabe, Diogo Mosqueira, Sandra Laufer, Michaela Schweizer, Petra van der Kraak, Frederik Flenner, Bärbel M Ulmer, Ingke Braren, Xiaoke Yin, Konstantinos Theofilatos, Jorge Ruiz-Orera, Giannino Patone, Birgit Klampe, Thomas Schulze, Angelika Piasecki, Yigal Pinto, Aryan Vink, Norbert Hübner, Sian Harding, Manuel Mayr, Chris Denning, Thomas Eschenhagen, Arne Hansen.
      The phospholamban (PLN) p.Arg14del mutation causes dilated cardiomyopathy, with the molecular disease mechanisms incompletely understood. Patient dermal fibroblasts were reprogrammed to hiPSC, isogenic controls were established by CRISPR/Cas9, and cardiomyocytes were differentiated. Mutant cardiomyocytes revealed significantly prolonged Ca2+ transient decay time, Ca2+ -load dependent irregular beating pattern, and lower force. Proteomic analysis revealed less endoplasmic reticulum (ER) and ribosomal and mitochondrial proteins. Electron microscopy showed dilation of the ER and large lipid droplets in close association with mitochondria. Follow-up experiments confirmed impairment of the ER/mitochondria compartment. PLN p.Arg14del end-stage heart failure samples revealed perinuclear aggregates positive for ER marker proteins and oxidative stress in comparison with ischemic heart failure and non-failing donor heart samples. Transduction of PLN p.Arg14del EHTs with the Ca2+ -binding proteins GCaMP6f or parvalbumin improved the disease phenotype. This study identified impairment of the ER/mitochondria compartment without SR dysfunction as a novel disease mechanism underlying PLN p.Arg14del cardiomyopathy. The pathology was improved by Ca2+ -scavenging, suggesting impaired local Ca2+ cycling as an important disease culprit.
    Keywords:  endoplasmic reticulum; engineered heart tissue; human-induced pluripotent stem cells; mitochondria; phospholamban p.Arg14del
    DOI:  https://doi.org/10.15252/emmm.202013074
  28. J Exp Biol. 2020 Jan 01. pii: jeb.215558. [Epub ahead of print]
    Improved mitochondrial coupling as a response to high mass-specific metabolic rate in extremely small mammals.
    Boël Mélanie, Romestaing Caroline, Duchamp Claude, Veyrunes Frédéric, Renaud Sabrina, Roussel Damien, Voituron Yann.
      Mass-specific metabolic rate negatively co-varies with body mass from the whole-animal to the mitochondrial levels. Mitochondria are the mainly consumers of oxygen inspired by mammals to generate ATP or compensate energetic losses dissipated as the form of heat (proton leak) during oxidative phosphorylation. Consequently, ATP synthesis and proton leak thus compete for the same electrochemical gradient. Because proton leak co-varies negatively with body mass, it is unknown if extremely small mammals further decouple their mitochondria to maintain their body temperature or if they implement metabolic innovations to ensure cellular homeostasis. The present study investigates the impact of body mass variation on cellular and mitochondrial functioning in small mammals, comparing the two extremely small African pygmy mice (Mus mattheyi, approx. 5 g and Mus minutoides, approx. 7 g) with the larger house mouse (Mus musculus, approx. 22 g). Oxygen consumption rates were measured from the animal to the mitochondrial levels. We also measured mitochondrial ATP synthesis in order to appreciate the mitochondrial efficiency (ATP/O). At the whole-animal scale, mass- and surface-specific metabolic rates co-varied negatively with body mass, whereas this was not necessarily the case at cellular and mitochondrial levels. M. mattheyi had generally the lowest cellular and mitochondrial fluxes, depending on the tissue considered (liver or skeletal muscle), as well as having higher efficient muscle mitochondria than the other two species. M. mattheyi presents metabolic innovations to ensure its homeostasis, by generating more ATP per oxygen consumed.
    Keywords:  Allometry; Liver; Mitochondrial efficiency; Mus; Muscles; Oxidative phosphorylation
    DOI:  https://doi.org/10.1242/jeb.215558
  29. Physiol Rep. 2021 May;9(9): e14838
    Muscle mitochondrial capacity in high- and low-fitness females using near-infrared spectroscopy.
    Bart Lagerwaard, Joëlle J E Janssen, Iris Cuijpers, Jaap Keijer, Vincent C J de Boer, Arie G Nieuwenhuizen.
      The recovery of muscle oxygen consumption (m V˙ O2 ) after exercise measured using near-infrared spectroscopy (NIRS) provides a measure of skeletal muscle mitochondrial capacity. Nevertheless, due to sex differences in factors that can influence scattering and thus penetration depth of the NIRS signal in the tissue, e.g., subcutaneous adipose tissue thickness and intramuscular myoglobin and hemoglobin, it is unknown whether results in males can be extrapolated to a female population. Therefore, the aim of this study was to measure skeletal muscle mitochondrial capacity in females at different levels of aerobic fitness to test whether NIRS can measure relevant differences in mitochondrial capacity. Mitochondrial capacity was analyzed in the gastrocnemius muscle and the wrist flexors of 32 young female adults, equally divided in relatively high ( V˙ O2 peak ≥ 47 ml/kg/min) and relatively low aerobic fitness group ( V˙ O2 peak ≤ 37 ml/kg/min). m V˙ O2 recovery was significantly faster in the high- compared to the low-fitness group in the gastrocnemius, but not in the wrist flexors (p = 0.009 and p = 0.0528, respectively). Furthermore, V˙ O2 peak was significantly correlated to m V˙ O2 recovery in both gastrocnemius (R2  = 0.27, p = 0.0051) and wrist flexors (R2  = 0.13, p = 0.0393). In conclusion, NIRS measurements can be used to assess differences in mitochondrial capacity within a female population and is correlated to V˙ O2 peak. This further supports NIRS assessment of muscle mitochondrial capacity providing additional evidence for NIRS as a promising approach to monitor mitochondrial capacity, also in an exclusively female population.
    Keywords:  V˙ O2peak; NIRS; fitness; mitochondria; oxidative metabolism
    DOI:  https://doi.org/10.14814/phy2.14838
  30. J Cell Sci. 2020 Jan 01. pii: jcs.247353. [Epub ahead of print]
    Mitochondrial dysfunction triggers catabolic response in chondrocytes via ROS mediated activation of JNK/AP1 pathway.
    Mohammad Y Ansari, Nashrah Ahmad, Sriharsha Voleti, Saima J Wase, Kimberly Novak, Tariq M Haqqi.
      Mitochondrial function is impaired in osteoarthritis (OA) but its impact on cartilage catabolism is not fully understood. Here, we investigated the molecular mechanism of mitochondrial dysfunction-induced activation of catabolic response in chondrocytes. Using cartilage slices from normal and OA cartilage, we show that mitochondrial membrane potential was lower in OA cartilage which was associated with increased production of mitochondrial superoxide and catabolic genes (IL-6, COX-2, MMP-3,-9,-13 and ADAMTS5). Pharmacological induction of mitochondrial dysfunction in chondrocytes and cartilage explants using CCCP increased the mitochondrial superoxide production and the expression of IL-6, COX-2, MMP-3,-9-13 and ADAMTS5 and cartilage matrix degradation. Mitochondrial dysfunction induced expression of catabolic genes was dependent on JNK/AP1 pathway but not the NFκB pathway. Scavenging of mitochondrial superoxide with MitoTEMPO or pharmacological inhibition of JNK or cFos/cJun blocked the mitochondrial dysfunction-induced expression of the catabolic genes in chondrocytes. We demonstrate here that mitochondrial dysfunction contributes to OA pathogenesis via JNK/AP1 mediated expression of catabolic genes. Our data shows that AP1 could be used as a therapeutic target for OA management.
    Keywords:  Chondrocytes; Inflammation; JNK; Osteoarthritis; Redox; cFos-AP1
    DOI:  https://doi.org/10.1242/jcs.247353
  31. Nat Commun. 2021 05 19. 12(1): 2947
    Analysis of diverse eukaryotes suggests the existence of an ancestral mitochondrial apparatus derived from the bacterial type II secretion system.
    Lenka Horváthová, Vojtěch Žárský, Tomáš Pánek, Romain Derelle, Jan Pyrih, Alžběta Motyčková, Veronika Klápšťová, Martina Vinopalová, Lenka Marková, Luboš Voleman, Vladimír Klimeš, Markéta Petrů, Zuzana Vaitová, Ivan Čepička, Klára Hryzáková, Karel Harant, Michael W Gray, Mohamed Chami, Ingrid Guilvout, Olivera Francetic, B Franz Lang, Čestmír Vlček, Anastasios D Tsaousis, Marek Eliáš, Pavel Doležal.
      The type 2 secretion system (T2SS) is present in some Gram-negative eubacteria and used to secrete proteins across the outer membrane. Here we report that certain representative heteroloboseans, jakobids, malawimonads and hemimastigotes unexpectedly possess homologues of core T2SS components. We show that at least some of them are present in mitochondria, and their behaviour in biochemical assays is consistent with the presence of a mitochondrial T2SS-derived system (miT2SS). We additionally identified 23 protein families co-occurring with miT2SS in eukaryotes. Seven of these proteins could be directly linked to the core miT2SS by functional data and/or sequence features, whereas others may represent different parts of a broader functional pathway, possibly also involving the peroxisome. Its distribution in eukaryotes and phylogenetic evidence together indicate that the miT2SS-centred pathway is an ancestral eukaryotic trait. Our findings thus have direct implications for the functional properties of the early mitochondrion.
    DOI:  https://doi.org/10.1038/s41467-021-23046-7
  32. Eye Brain. 2021 ;13 131-146
    Retinal Damage in Amyotrophic Lateral Sclerosis: Underlying Mechanisms.
    Vladislav O Soldatov, Michail S Kukharsky, Andrey E Belykh, Andrey M Sobolev, Alexey V Deykin.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in a gradual loss of motor neuron function. Although ophthalmic complaints are not presently considered a classic symptom of ALS, retinal changes such as thinning, axonal degeneration and inclusion bodies have been found in many patients. Retinal abnormalities observed in postmortem human tissues and animal models are similar to spinal cord changes in ALS. These findings are not dramatically unexpected because retina shares an ontogenetic relationship with the brain, and many genes are associated both with neurodegeneration and retinal diseases. Experimental studies have demonstrated that ALS affects many "vulnerable points" of the retina. Aggregate deposition, impaired nuclear protein import, endoplasmic reticulum stress, glutamate excitotoxicity, vascular regression, and mitochondrial dysfunction are factors suspected as being the main cause of motor neuron damage in ALS. Herein, we show that all of these pathways can affect retinal cells in the same way as motor neurons. Furthermore, we suppose that understanding the patterns of neuro-ophthalmic interaction in ALS can help in the diagnosis and treatment of this disease.
    Keywords:  ALS; excitotoxicity; mitochondrial dysfunction; neuro-ophthalmology; retina; retinal involvement
    DOI:  https://doi.org/10.2147/EB.S299423
  33. Biol Open. 2020 Jan 01. pii: bio.054262. [Epub ahead of print]
    Drosophila MICOS knockdown impairs mitochondrial structure and function and promotes mitophagy in muscle tissue.
    Li-Jie Wang, Tian Hsu, Hsiang-Ling Lin, Chi-Yu Fu.
      The mitochondrial contact site and cristae organizing system (MICOS) is a multi-protein interaction hub that helps define mitochondrial ultrastructure. While the functional importance of MICOS is mostly characterized in yeast and mammalian cells in culture, the contributions of MICOS to tissue homeostasis in vivo remain further elucidation. In this study, we examined how knocking down expression of Drosophila MICOS genes affects mitochondrial function and muscle tissue homeostasis. We found that CG5903/MIC26-MIC27 colocalizes and functions with Mitofilin/MIC60 and QIL1/MIC13 as a Drosophila MICOS component; knocking down expression of any of these three genes predictably altered mitochondrial morphology, causing loss of cristae junctions, and disruption of cristae packing. Furthermore, the knockdown flies exhibited low mitochondrial membrane potential, fusion/fission imbalances, increased mitophagy, and limited cell death. Reductions in climbing ability indicated deficits in muscle function. Knocking down MICOS genes also caused reduced mtDNA content and fragmented mitochondrial nucleoid structure in Drosophila. Together, our data demonstrate an essential role of Drosophila MICOS in maintaining proper homeostasis of mitochondrial structure and function to promote the function of muscle tissue.
    Keywords:  Drosophila; MICOS; Mitochondria
    DOI:  https://doi.org/10.1242/bio.054262
  34. Front Immunol. 2021 ;12 682736
    The cGAS-STING Pathway: Novel Perspectives in Liver Diseases.
    Dongwei Xu, Yizhu Tian, Qiang Xia, Bibo Ke.
      Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity via the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.
    Keywords:  DNA sensor; Innate immunity; cyclic GMPAMP synthase; inflammation; liver diseases; stimulator of interferon genes
    DOI:  https://doi.org/10.3389/fimmu.2021.682736
  35. J Cell Sci. 2020 Jan 01. pii: jcs.247957. [Epub ahead of print]
    BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages.
    Jeong-Hun Ko, Antoni Olona, Adonia E Papathanassiu, Norzawani Buang, Kwon-Sik Park, Ana S H Costa, Claudio Mauro, Christian Frezza, Jacques Behmoaras.
      In response to environmental stimuli, macrophages change their nutrient consumption and undergo an early metabolic adaptation that progressively shapes their polarization state. During the transient, early phase of pro-inflammatory macrophage activation, an increase in tricarboxylic acid (TCA) cycle activity has been reported but the relative contribution of branched chain amino acid (BCAA) leucine remain to be determined. Here we show that glucose but not glutamine is a major contributor of the increase in TCA cycle metabolites during early macrophage activation in humans. We then show that, although BCAA uptake is not altered, their transamination by BCAT1 is increased following 8h lipopolysaccharide (LPS) stimulation. Of note, leucine is not metabolized to integrate the TCA cycle in neither basal nor stimulated human macrophages. Surprisingly, the pharmacological inhibition of BCAT1 reduced glucose-derived itaconate, α-ketoglutarate, and 2-hydroxyglutarate levels, without affecting succinate and citrate levels, indicating a partial inhibition of TCA cycle. This indirect effect is associated with NRF2 activation and anti-oxidant responses. These results suggest a moonlighting role of BCAT1 through redox-mediated control of mitochondrial function during early macrophage activation.
    Keywords:  BCAT1; Immunometabolism; Macrophages; Mitochondria; Redox biology; TCA cycle
    DOI:  https://doi.org/10.1242/jcs.247957
  36. Cell Rep. 2021 May 18. pii: S2211-1247(21)00467-8. [Epub ahead of print]35(7): 109128
    Hepatic AKT orchestrates adipose tissue thermogenesis via FGF21-dependent and -independent mechanisms.
    Jaimarie Sostre-Colón, Kahealani Uehara, Anna E Garcia Whitlock, Matthew J Gavin, Jeff Ishibashi, Matthew J Potthoff, Patrick Seale, Paul M Titchenell.
      Organismal stressors such as cold exposure require a systemic response to maintain body temperature. Brown adipose tissue (BAT) is a key thermogenic tissue in mammals that protects against hypothermia in response to cold exposure. Defining the complex interplay of multiple organ systems in this response is fundamental to our understanding of adipose tissue thermogenesis. In this study, we identify a role for hepatic insulin signaling via AKT in the adaptive response to cold stress and show that liver AKT is an essential cell-nonautonomous regulator of adipocyte lipolysis and BAT function. Mechanistically, inhibition of forkhead box O1 (FOXO1) by AKT controls BAT thermogenesis by enhancing catecholamine-induced lipolysis in the white adipose tissue (WAT) and increasing circulating fibroblast growth factor 21 (FGF21). Our data identify a role for hepatic insulin signaling via the AKT-FOXO1 axis in regulating WAT lipolysis, promoting BAT thermogenic capacity, and ensuring a proper thermogenic response to acute cold exposure.
    Keywords:  FGF21; FOXO1; cold sensitivity; lipolysis; liver insulin signaling; thermogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2021.109128
  37. Nat Commun. 2021 05 19. 12(1): 2942
    Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover.
    Thomas G Martin, Valerie D Myers, Praveen Dubey, Shubham Dubey, Edith Perez, Christine S Moravec, Monte S Willis, Arthur M Feldman, Jonathan A Kirk.
      The association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show impaired Fmax arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with Fmax. We confirm this relationship using BAG3 haploinsufficient mice, which display reduced Fmax and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via chaperone-assisted selective autophagy (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA complex localization is BAG3/proteotoxic stress-dependent. Using mass spectrometry, we characterize the myofilament CASA interactome in the human heart and identify eight clients of BAG3-mediated turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/Fmax, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued Fmax and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.
    DOI:  https://doi.org/10.1038/s41467-021-23272-z
  38. Brief Bioinform. 2021 May 22. pii: bbab189. [Epub ahead of print]
    WEVar: a novel statistical learning framework for predicting noncoding regulatory variants.
    Ye Wang, Yuchao Jiang, Bing Yao, Kun Huang, Yunlong Liu, Yue Wang, Xiao Qin, Andrew J Saykin, Li Chen.
      Understanding the functional consequence of noncoding variants is of great interest. Though genome-wide association studies or quantitative trait locus analyses have identified variants associated with traits or molecular phenotypes, most of them are located in the noncoding regions, making the identification of causal variants a particular challenge. Existing computational approaches developed for prioritizing noncoding variants produce inconsistent and even conflicting results. To address these challenges, we propose a novel statistical learning framework, which directly integrates the precomputed functional scores from representative scoring methods. It will maximize the usage of integrated methods by automatically learning the relative contribution of each method and produce an ensemble score as the final prediction. The framework consists of two modes. The first 'context-free' mode is trained using curated causal regulatory variants from a wide range of context and is applicable to predict regulatory variants of unknown and diverse context. The second 'context-dependent' mode further improves the prediction when the training and testing variants are from the same context. By evaluating the framework via both simulation and empirical studies, we demonstrate that it outperforms integrated scoring methods and the ensemble score successfully prioritizes experimentally validated regulatory variants in multiple risk loci.
    Keywords:  functional score; noncoding variants; prioritization
    DOI:  https://doi.org/10.1093/bib/bbab189
  39. J Cell Sci. 2020 Jan 01. pii: jcs.240374. [Epub ahead of print]
    Cardiolipin is required for membrane docking of mitochondrial ribosomes and protein synthesis.
    Richard G Lee, Junjie Gao, Stefan J Siira, Anne-Marie Shearwood, Judith A Ermer, Vinzenz Hofferek, James C Mathews, Minghao Zheng, Gavin E Reid, Oliver Rackham, Aleksandra Filipovska.
      The mitochondrial inner membrane contains a unique phospholipid known as cardiolipin (CL), which stabilises the protein complexes embedded in the membrane and supports its overall structure. Recent evidence indicates that the mitochondrial ribosome may associate with the inner membrane to facilitate co-translational insertion of the hydrophobic oxidative phosphorylation (OXPHOS) proteins into the inner membrane. We generated three mutant knockout cell lines for the cardiolipin biosynthesis gene Crls1 to investigate the effects of cardiolipin loss on mitochondrial protein synthesis. Reduced CL levels caused altered mitochondrial morphology and transcriptome-wide changes that were accompanied by reduced uncoordinated mitochondrial translation rates and impaired respiratory supercomplex formation. Aberrant protein synthesis was caused by impaired formation and distribution of mitochondrial ribosomes. Reduction or loss of cardiolipin resulted in divergent mitochondrial and endoplasmic reticulum stress responses. We show that cardiolipin is required to stabilise the interaction of the mitochondrial ribosome with the membrane via its association with OXA1 during active translation. This interaction facilitates insertion of newly synthesised mitochondrial proteins into the inner membrane and stabilises the respiratory supercomplexes.
    Keywords:  Mitochondrial membranes; Mitochondrial ribosomes; Protein synthesis
    DOI:  https://doi.org/10.1242/jcs.240374
  40. iScience. 2021 May 21. 24(5): 102416
    Dynein and muskelin control myosin VI delivery towards the neuronal nucleus.
    Matthias Kneussel, Noelia Sánchez-Rodríguez, Michaela Mischak, Frank F Heisler.
      Protein transport toward the nucleus is important for translating molecular signals into gene expression changes. Interestingly, the unconventional motor protein myosin VI regulates RNA polymerase II-dependent gene transcription. Whether actin-filament-dependent myosins are actively transported to nuclear compartments remains unknown. Here, we report that neurons also contain myosin VI inside their nucleus. Notably, nuclear appearance of this actin-dependent motor depends on functional cytoplasmic dynein, a minus end-directed microtubule motor. We find that the trafficking factor muskelin assists in the formation of dynein-myosin VI interactions and further localizes to nuclear foci, enriched in the myosin. Impairment of dynein, but not myosin VI function, reduces nuclear muskelin levels. In turn, muskelin represents a critical determinant in regulating myosin VI nuclear targeting. Our data reveal that minus end-directed microtubule transport determines myosin VI subcellular localization. They suggest a pathway of cytoplasm-to-nucleus trafficking that requires muskelin and is based on dynein-myosin cross talk.
    Keywords:  Biological Sciences; Cell Biology; Cellular Neuroscience; Molecular Neuroscience; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2021.102416
  41. Biol Open. 2020 Jan 01. pii: bio.046391. [Epub ahead of print]
    Filament formation by the translation factor eIF2B regulates protein synthesis in starved cells.
    Elisabeth Nüske, Guendalina Marini, Doris Richter, Weihua Leng, Aliona Bogdanova, Titus M Franzmann, Gaia Pigino, Simon Alberti.
      Cells exposed to starvation have to adjust their metabolism to conserve energy and protect themselves. Protein synthesis is one of the major energy-consuming processes and as such has to be tightly controlled. Many mechanistic details about how starved cells regulate the process of protein synthesis are still unknown. Here, we report that the essential translation initiation factor eIF2B forms filaments in starved budding yeast cells. We demonstrate that filamentation is triggered by starvation-induced acidification of the cytosol, which is caused by an influx of protons from the extracellular environment. We show that filament assembly by eIF2B is necessary for rapid and efficient downregulation of translation. Importantly, this mechanism does not require the kinase Gcn2. Furthermore, analysis of site-specific variants of eIF2B suggests that eIF2B assembly results in enzymatically inactive filaments that promote stress survival and fast recovery of cells from starvation. We propose that translation regulation through filament formation is an efficient mechanism that allows yeast cells to adapt to fluctuating environments.
    Keywords:  Budding yeast; Protein assembly; Regulation of translation; Starvation; Stress response
    DOI:  https://doi.org/10.1242/bio.046391
  42. J Cell Sci. 2020 Jan 01. pii: jcs.245589. [Epub ahead of print]
    Perinuclear mitochondrial clustering, increased ROS levels, and HIF1 are required for the activation of HSF1 by heat stress.
    Saloni Agarwal, Subramaniam Ganesh.
      Heat shock response (HSR) is a conserved cellular defensive response against stresses such as temperature, oxidative stress, and heavy metals. A significant group of players in HSR is the set of molecular chaperones, known as heat shock proteins (HSPs) that assist in the refolding of unfolded proteins and prevent the accumulation of damaged proteins. HSP genes are activated by the HSF1 transcription factor-a master regulator of the HSR pathway. A variety of stressors activates HSF1, but the key molecular players and the process that directly contribute to the HSF1 activation remains unclear. In this study, we show that heat shock induces perinuclear clustering of mitochondria in mammalian cells, and this clustering is essential for the activation of HSR. We also show that this perinuclear clustering of mitochondria results in the increased levels of ROS in the nucleus, leading to the activation of hypoxia-inducible factor-1α (HIF-1α). Finally, we provide evidence to suggest that HIF-1α is one of the critical regulators of HSF1 and that HIF-1α is essential for the activation of HSR during a heat shock.
    Keywords:  Chaperones; Hypoxia response; Mitochondrial transport; Oxidative stress; Stress response; Transcriptional regulation
    DOI:  https://doi.org/10.1242/jcs.245589
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