bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2021‒12‒12
thirty-one papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico
  1. Phenotypic heterogeneity of Leigh syndrome due to NDUFA12 variants is multicausal.
  2. Identification and characterisation of novel MPC1 gene variants causing mitochondrial pyruvate carrier deficiency.
  3. Response to: Phenotypic heterogeneity of Leigh syndrome due to NDUFA12 variants is multicausal.
  4. Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases?
  5. Genotype-phenotype analysis of MT-ATP6-associated Leigh syndrome.
  6. Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission.
  7. Phenotypic spectrum and clinical course of single large-scale mitochondrial DNA deletion disease in the paediatric population: a multicentre study.
  8. 2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA.
  9. MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control.
  10. Mitochondrial Dysfunction in Advanced Liver Disease: Emerging Concepts.
  11. Role of Prohibitins in Aging and Therapeutic Potential Against Age-Related Diseases.
  12. The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites.
  13. Live-imaging of Mitochondrial System in Cultured Astrocytes.
  14. Strategies to protect against age-related mitochondrial decay: Do natural products and their derivatives help?
  15. Mitochondrial Biogenesis in Neurons: How and Where.
  16. WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.
  17. Mitochondrial Transport in Glycolysis and Gluconeogenesis: Achievements and Perspectives.
  18. Mitochondria Metabolomics Reveals a Role of β-Nicotinamide Mononucleotide Metabolism in Mitochondrial DNA Replication.
  19. Mitochondrial Quality Control in Sarcopenia: Updated Overview of Mechanisms and Interventions.
  20. Mitophagy in aging and longevity.
  21. FARS2 deficiency in Drosophila reveals the developmental delay and seizure manifested by aberrant mitochondrial tRNA metabolism.
  22. Mitochondrially-Targeted Therapeutic Strategies for Alzheimer's Disease.
  23. Deficiency of T-Cell Intracellular Antigen 1 in Murine Embryonic Fibroblasts Is Associated with Changes in Mitochondrial Morphology and Respiration.
  24. Editorial: Mitochondrial Disorders: Biochemical and Molecular Basis of Disease.
  25. MITOL-mediated DRP1 ubiquitylation and degradation promotes mitochondrial hyperfusion in CMT2A-linked MFN2 mutant.
  26. Molecular mechanisms and consequences of mitochondrial permeability transition.
  27. Emerging Role of TCA Cycle-Related Enzymes in Human Diseases.
  28. Therapeutic approaches to preserve the musculature in Duchenne Muscular Dystrophy: The importance of the secondary therapies.
  29. Supercomplex organization of the electron transfer system in marine bivalves, a model of extreme longevity.
  30. Acetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming.
  31. Mitochondria in Focus: From Function to Therapeutic Strategies in Chronic Lung Diseases.
  1. Hum Mutat. 2021 Dec 09.
    Phenotypic heterogeneity of Leigh syndrome due to NDUFA12 variants is multicausal.
    Josef Finsterer.
      
    Keywords:  Leigh syndrome; NDUFA12; complex-I; mitochondrial; respiratory chain
    DOI:  https://doi.org/10.1002/humu.24301
  2. J Inherit Metab Dis. 2021 Dec 06.
    Identification and characterisation of novel MPC1 gene variants causing mitochondrial pyruvate carrier deficiency.
    Huafang Jiang, Ahmad Alahmad, Song Fu, Xiaoling Fu, Zhimei Liu, Xiaodi Han, Lanlan Li, Tianyu Song, Manting Xu, Shanshan Liu, Junling Wang, Buthaina Albash, Ahmad Alaqeel, Vasilescu Catalina, Holger Prokisch, Robert W Taylor, Robert McFarland, Fang Fang.
      
    Keywords:  Leigh-like syndrome; MPC1; glutamine; mitochondria; mitochondrial pyruvate carrier deficiency; treatment
    DOI:  https://doi.org/10.1002/jimd.12462
  3. Hum Mutat. 2021 Dec 09.
    Response to: Phenotypic heterogeneity of Leigh syndrome due to NDUFA12 variants is multicausal.
    Alessandra Torraco, Reza Maroofian, Agnès Rötig, Enrico Bertini, Daniele Ghezzi, Rosalba Carrozzo, Daria Diodato.
      
    Keywords:  Leigh syndrome; NADH ubiquinone oxidoreductase; NDUFA12; mitochondrial disease
    DOI:  https://doi.org/10.1002/humu.24303
  4. Front Neurosci. 2021 ;15 746873
    Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases?
    Di Hu, Zunren Liu, Xin Qi.
      Many lines of evidence have indicated the therapeutic potential of rescuing mitochondrial integrity by targeting specific mitochondrial quality control pathways in neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. In addition to ATP synthesis, mitochondria are critical regulators of ROS production, lipid metabolism, calcium buffering, and cell death. The mitochondrial unfolded protein response, mitochondrial dynamics, and mitophagy are the three main quality control mechanisms responsible for maintaining mitochondrial proteostasis and bioenergetics. The proper functioning of these complex processes is necessary to surveil and restore mitochondrial homeostasis and the healthy pool of mitochondria in cells. Mitochondrial dysfunction occurs early and causally in disease pathogenesis. A significant accumulation of mitochondrial damage resulting from compromised quality control pathways leads to the development of neuropathology. Moreover, genetic or pharmaceutical manipulation targeting the mitochondrial quality control mechanisms can sufficiently rescue mitochondrial integrity and ameliorate disease progression. Thus, therapies that can improve mitochondrial quality control have great promise for the treatment of neurodegenerative diseases. In this review, we summarize recent progress in the field that underscores the essential role of impaired mitochondrial quality control pathways in the pathogenesis of neurodegenerative diseases. We also discuss the translational approaches targeting mitochondrial function, with a focus on the restoration of mitochondrial integrity, including mitochondrial dynamics, mitophagy, and mitochondrial proteostasis.
    Keywords:  mitochondrial dynamics; mitochondrial proteostasis; mitochondrial quality control; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnins.2021.746873
  5. Acta Neurol Scand. 2021 Dec 07.
    Genotype-phenotype analysis of MT-ATP6-associated Leigh syndrome.
    Ji-Hoon Na, Young-Mock Lee.
      OBJECTIVES: Mitochondrial DNA (mtDNA)-associated Leigh syndrome (LS) is characterized by maternal inheritance, and the heteroplasmic mutant load of mtDNA pathogenic variants is known to affect clinical phenotypes. Among mtDNA pathogenic variants, variants of the MT-ATP6 gene account for most of reported cases. In this report, we aimed to describe the clinical and genetic findings of MT-ATP6-associated LS patients diagnosed at a single tertiary institution in Korea.METHODS: Thirteen patients with genetically confirmed MT-ATP6-associated LS were selected. We reviewed each patient's clinical findings, including general characteristics, biochemical parameters, brain MR images, muscle biopsy results, and heteroplasmic mutant load over a long-term follow-up period.
    RESULTS: MT-ATP6-associated LS was of predominantly early onset (age <2 years), although we identified 2 late-onset (>60 months) LS patients. The heteroplasmic mutant load estimated by next-generation sequencing was 96%-100% in all nucleotide change groups. Compared with other forms of MT-ATP6-associated LS, the m.8993T>G point mutation elicited a significantly higher rate of symptom onset before 2 years of age. Brain MRI showed bilateral basal ganglia involvement in all patients, followed by cerebral atrophy, brainstem and thalamus involvement, and cerebellar atrophy. After follow-up (median 7.2 years, range 1.4 to 11.5 years), LS with m.8993T>G point mutations had a slightly more severe clinical progression compared with other forms of MT-ATP6-associated LS.
    CONCLUSIONS: MT-ATP6-associated LS patients presented with a broad spectrum of clinical diagnoses and had a very high heteroplasmic mutant load. This study provides valuable data on MT-ATP6-associated LS that will inform subsequent studies on LS.
    Keywords:   MT-ATP6 ; Leigh syndrome; heteroplasmic mutant load; mitochondrial disease; mtDNA
    DOI:  https://doi.org/10.1111/ane.13566
  6. Sci Adv. 2021 Dec 10. 7(50): eabi5657
    Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission.
    Haixin Zhang, Marco Esposito, Mikael G Pezet, Juvid Aryaman, Wei Wei, Florian Klimm, Claudia Calabrese, Stephen P Burr, Carolina H Macabelli, Carlo Viscomi, Mitinori Saitou, Marcos R Chiaratti, James B Stewart, Nick Jones, Patrick F Chinnery.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abi5657
  7. J Med Genet. 2021 Dec 06. pii: jmedgenet-2021-108006. [Epub ahead of print]
    Phenotypic spectrum and clinical course of single large-scale mitochondrial DNA deletion disease in the paediatric population: a multicentre study.
    Kristoffer Björkman, John Vissing, Elsebet Østergaard, Laurence A Bindoff, Irenaeus F M de Coo, Martin Engvall, Omar Hikmat, Pirjo Isohanni, Gittan Kollberg, Christopher Lindberg, Kari Majamaa, Karin Naess, Johanna Uusimaa, Mar Tulinius, Niklas Darin.
      BACKGROUND: Large-scale mitochondrial DNA deletions (LMD) are a common genetic cause of mitochondrial disease and give rise to a wide range of clinical features. Lack of longitudinal data means the natural history remains unclear. This study was undertaken to describe the clinical spectrum in a large cohort of patients with paediatric disease onset.METHODS: A retrospective multicentre study was performed in patients with clinical onset <16 years of age, diagnosed and followed in seven European mitochondrial disease centres.
    RESULTS: A total of 80 patients were included. The average age at disease onset and at last examination was 10 and 31 years, respectively. The median time from disease onset to death was 11.5 years. Pearson syndrome was present in 21%, Kearns-Sayre syndrome spectrum disorder in 50% and progressive external ophthalmoplegia in 29% of patients. Haematological abnormalities were the hallmark of the disease in preschool children, while the most common presentations in older patients were ptosis and external ophthalmoplegia. Skeletal muscle involvement was found in 65% and exercise intolerance in 25% of the patients. Central nervous system involvement was frequent, with variable presence of ataxia (40%), cognitive involvement (36%) and stroke-like episodes (9%). Other common features were pigmentary retinopathy (46%), short stature (42%), hearing impairment (39%), cardiac disease (39%), diabetes mellitus (25%) and renal disease (19%).
    CONCLUSION: Our study provides new insights into the phenotypic spectrum of childhood-onset, LMD-associated syndromes. We found a wider spectrum of more prevalent multisystem involvement compared with previous studies, most likely related to a longer time of follow-up.
    Keywords:  and neonatal diseases and abnormalities; congenital; hereditary; paediatrics; phenotype; prognosis; sequence deletion
    DOI:  https://doi.org/10.1136/jmedgenet-2021-108006
  8. Nat Commun. 2021 Dec 06. 12(1): 6997
    2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA.
    Boris Pantic, Daniel Ives, Mara Mennuni, Diego Perez-Rodriguez, Uxoa Fernandez-Pelayo, Amaia Lopez de Arbina, Mikel Muñoz-Oreja, Marina Villar-Fernandez, Thanh-Mai Julie Dang, Lodovica Vergani, Iain G Johnston, Robert D S Pitceathly, Robert McFarland, Michael G Hanna, Robert W Taylor, Ian J Holt, Antonella Spinazzola.
      Pathological variants of human mitochondrial DNA (mtDNA) typically co-exist with wild-type molecules, but the factors driving the selection of each are not understood. Because mitochondrial fitness does not favour the propagation of functional mtDNAs in disease states, we sought to create conditions where it would be advantageous. Glucose and glutamine consumption are increased in mtDNA dysfunction, and so we targeted the use of both in cells carrying the pathogenic m.3243A>G variant with 2-Deoxy-D-glucose (2DG), or the related 5-thioglucose. Here, we show that both compounds selected wild-type over mutant mtDNA, restoring mtDNA expression and respiration. Mechanistically, 2DG selectively inhibits the replication of mutant mtDNA; and glutamine is the key target metabolite, as its withdrawal, too, suppresses mtDNA synthesis in mutant cells. Additionally, by restricting glucose utilization, 2DG supports functional mtDNAs, as glucose-fuelled respiration is critical for mtDNA replication in control cells, when glucose and glutamine are scarce. Hence, we demonstrate that mitochondrial fitness dictates metabolite preference for mtDNA replication; consequently, interventions that restrict metabolite availability can suppress pathological mtDNAs, by coupling mitochondrial fitness and replication.
    DOI:  https://doi.org/10.1038/s41467-021-26829-0
  9. Nat Cell Biol. 2021 Dec 06.
    MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control.
    Tim König, Hendrik Nolte, Mari J Aaltonen, Takashi Tatsuta, Michiel Krols, Thomas Stroh, Thomas Langer, Heidi M McBride.
      Mitochondrial-derived vesicles (MDVs) are implicated in diverse physiological processes-for example, mitochondrial quality control-and are linked to various neurodegenerative diseases. However, their specific cargo composition and complex molecular biogenesis are still unknown. Here we report the proteome and lipidome of steady-state TOMM20+ MDVs. We identified 107 high-confidence MDV cargoes, which include all β-barrel proteins and the TOM import complex. MDV cargoes are delivered as fully assembled complexes to lysosomes, thus representing a selective mitochondrial quality control mechanism for multi-subunit complexes, including the TOM machinery. Moreover, we define key biogenesis steps of phosphatidic acid-enriched MDVs starting with the MIRO1/2-dependent formation of thin membrane protrusions pulled along microtubule filaments, followed by MID49/MID51/MFF-dependent recruitment of the dynamin family GTPase DRP1 and finally DRP1-dependent scission. In summary, we define the function of MDVs in mitochondrial quality control and present a mechanistic model for global GTPase-driven MDV biogenesis.
    DOI:  https://doi.org/10.1038/s41556-021-00798-4
  10. Front Mol Biosci. 2021 ;8 772174
    Mitochondrial Dysfunction in Advanced Liver Disease: Emerging Concepts.
    Ingrid W Zhang, Cristina López-Vicario, Marta Duran-Güell, Joan Clària.
      Mitochondria are entrusted with the challenging task of providing energy through the generation of ATP, the universal cellular currency, thereby being highly flexible to different acute and chronic nutrient demands of the cell. The fact that mitochondrial diseases (genetic disorders caused by mutations in the nuclear or mitochondrial genome) manifest through a remarkable clinical variation of symptoms in affected individuals underlines the far-reaching implications of mitochondrial dysfunction. The study of mitochondrial function in genetic or non-genetic diseases therefore requires a multi-angled approach. Taking into account that the liver is among the organs richest in mitochondria, it stands to reason that in the process of unravelling the pathogenesis of liver-related diseases, researchers give special focus to characterizing mitochondrial function. However, mitochondrial dysfunction is not a uniformly defined term. It can refer to a decline in energy production, increase in reactive oxygen species and so forth. Therefore, any study on mitochondrial dysfunction first needs to define the dysfunction to be investigated. Here, we review the alterations of mitochondrial function in liver cirrhosis with emphasis on acutely decompensated liver cirrhosis and acute-on-chronic liver failure (ACLF), the latter being a form of acute decompensation characterized by a generalized state of systemic hyperinflammation/immunosuppression and high mortality rate. The studies that we discuss were either carried out in liver tissue itself of these patients, or in circulating leukocytes, whose mitochondrial alterations might reflect tissue and organ mitochondrial dysfunction. In addition, we present different methodological approaches that can be of utility to address the diverse aspects of hepatocyte and leukocyte mitochondrial function in liver disease. They include assays to measure metabolic fluxes using the comparatively novel Biolog's MitoPlates in a 96-well format as well as assessment of mitochondrial respiration by high-resolution respirometry using Oroboros' O2k-technology and Agilent Seahorse XF technology.
    Keywords:  acute decompensation; cirrhosis; immunometabolism; mitochondrial dysfunction; organ failure; systemic inflammation
    DOI:  https://doi.org/10.3389/fmolb.2021.772174
  11. Front Genet. 2021 ;12 714228
    Role of Prohibitins in Aging and Therapeutic Potential Against Age-Related Diseases.
    Misa Belser, David W Walker.
      A decline in mitochondrial function has long been associated with age-related health decline. Several lines of evidence suggest that interventions that stimulate mitochondrial autophagy (mitophagy) can slow aging and prolong healthy lifespan. Prohibitins (PHB1 and PHB2) assemble at the mitochondrial inner membrane and are critical for mitochondrial homeostasis. In addition, prohibitins (PHBs) have diverse roles in cell and organismal biology. Here, we will discuss the role of PHBs in mitophagy, oxidative phosphorylation, cellular senescence, and apoptosis. We will also discuss the role of PHBs in modulating lifespan. In addition, we will review the links between PHBs and diseases of aging. Finally, we will discuss the emerging concept that PHBs may represent an attractive therapeutic target to counteract aging and age-onset disease.
    Keywords:  PHB1; PHB2; age-related diseases; aging; prohibitin
    DOI:  https://doi.org/10.3389/fgene.2021.714228
  12. Nat Metab. 2021 Dec 06.
    The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites.
    Camilla Bean, Matteo Audano, Tatiana Varanita, Francesca Favaretto, Marta Medaglia, Marco Gerdol, Lena Pernas, Fabio Stasi, Marta Giacomello, Stèphanie Herkenne, Maheswany Muniandy, Sini Heinonen, Emma Cazaly, Miina Ollikainen, Gabriella Milan, Alberto Pallavicini, Kirsi H Pietiläinen, Roberto Vettor, Nico Mitro, Luca Scorrano.
      White to brown/beige adipocytes conversion is a possible therapeutic strategy to tackle the current obesity epidemics. While mitochondria are key for energy dissipation in brown fat, it is unknown if they can drive adipocyte browning. Here, we show that the mitochondrial cristae biogenesis protein optic atrophy 1 (Opa1) facilitates cell-autonomous adipocyte browning. In two cohorts of patients with obesity, including weight discordant monozygotic twin pairs, adipose tissue OPA1 levels are reduced. In the mouse, Opa1 overexpression favours white adipose tissue expandability as well as browning, ultimately improving glucose tolerance and insulin sensitivity. Transcriptomics and metabolomics analyses identify the Jumanji family chromatin remodelling protein Kdm3a and urea cycle metabolites, including fumarate, as effectors of Opa1-dependent browning. Mechanistically, the higher cyclic adenosine monophosphate (cAMP) levels in Opa1 pre-adipocytes activate cAMP-responsive element binding protein (CREB), which transcribes urea cycle enzymes. Flux analyses in pre-adipocytes indicate that Opa1-dependent fumarate accumulation depends on the urea cycle. Conversely, adipocyte-specific Opa1 deletion curtails urea cycle and beige differentiation of pre-adipocytes, and is rescued by fumarate supplementation. Thus, the urea cycle links the mitochondrial dynamics protein Opa1 to white adipocyte browning.
    DOI:  https://doi.org/10.1038/s42255-021-00497-2
  13. J Vis Exp. 2021 Nov 16.
    Live-imaging of Mitochondrial System in Cultured Astrocytes.
    Jeanne Espourteille, Valentin Zufferey, Jean-Honoré Laurent, Kevin Richetin.
      While much attention has been given to mitochondrial alterations at the neuronal level, recent evidence demonstrates that mitochondrial dynamics and function in astrocytes are implicated in cognition. This article describes the method for time-lapse imaging of astrocyte cultures equipped with a mitochondrial biosensor: MitoTimer. MitoTimer is a powerful and unique tool to assess mitochondrial dynamics, mobility, morphology, biogenesis, and redox state. Here, the different procedures for culture, image acquisitions, and subsequent mitochondrial analysis are presented.
    DOI:  https://doi.org/10.3791/62957
  14. Free Radic Biol Med. 2021 Dec 07. pii: S0891-5849(21)00859-5. [Epub ahead of print]
    Strategies to protect against age-related mitochondrial decay: Do natural products and their derivatives help?
    Francesco Visioli, Avery Ingram, Joseph S Beckman, Kathy R Magnusson, Tory M Hagen.
      Mitochondria serve vital roles critical for overall cellular function outside of energy transduction. Thus, mitochondrial decay is postulated to be a key factor in aging and in age-related diseases. Mitochondria may be targets of their own decay through oxidative damage. However, treating animals with antioxidants has been met with only limited success in rejuvenating mitochondrial function or in increasing lifespan. A host of nutritional strategies outside of using traditional antioxidants have been devised to promote mitochondrial function. Dietary compounds are under study that induce gene expression, enhance mitochondrial biogenesis, and mitophagy, or replenish key metabolites that decline with age. Moreover, redox-active compounds may now be targeted to mitochondria which improve their effectiveness. Herein we review the evidence that representative dietary effectors modulate mitochondrial function by stimulating their renewal or reversing the age-related loss of key metabolites. While in vitro evidence continues to accumulate that many of these compounds benefit mitochondrial function and/or prevent their decay, the results using animal models and, in some instances human clinical trials, are more mixed and sometimes even contraindicated. Thus, further research on optimal dosage and age of intervention are warranted before recommending potential mitochondrial rejuvenating compounds for human use.
    Keywords:  (poly)phenols; Aging; Essential fatty acids; Glutathione; Mitochondria; NAD; Nrf2; Nutritional supplements; Oxidative stress; Sirtuins; Triphenylphosphonium
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.12.008
  15. Int J Mol Sci. 2021 Dec 02. pii: 13059. [Epub ahead of print]22(23):
    Mitochondrial Biogenesis in Neurons: How and Where.
    Carlos Cardanho-Ramos, Vanessa Alexandra Morais.
      Neurons rely mostly on mitochondria for the production of ATP and Ca2+ homeostasis. As sub-compartmentalized cells, they have different pools of mitochondria in each compartment that are maintained by a constant mitochondrial turnover. It is assumed that most mitochondria are generated in the cell body and then travel to the synapse to exert their functions. Once damaged, mitochondria have to travel back to the cell body for degradation. However, in long cells, like motor neurons, this constant travel back and forth is not an energetically favourable process, thus mitochondrial biogenesis must also occur at the periphery. Ca2+ and ATP levels are the main triggers for mitochondrial biogenesis in the cell body, in a mechanism dependent on the Peroxisome-proliferator-activated γ co-activator-1α-nuclear respiration factors 1 and 2-mitochondrial transcription factor A (PGC-1α-NRF-1/2-TFAM) pathway. However, even though of extreme importance, very little is known about the mechanisms promoting mitochondrial biogenesis away from the cell body. In this review, we bring forward the evoked mechanisms that are at play for mitochondrial biogenesis in the cell body and periphery. Moreover, we postulate that mitochondrial biogenesis may vary locally within the same neuron, and we build upon the hypotheses that, in the periphery, local protein synthesis is responsible for giving all the machinery required for mitochondria to replicate themselves.
    Keywords:  NRF-1/2; PGC-1α; TFAM; cell body; mitochondrial biogenesis; neurodegenerative diseases; neurons; periphery
    DOI:  https://doi.org/10.3390/ijms222313059
  16. Parkinsonism Relat Disord. 2021 Dec 02. pii: S1353-8020(21)00437-5. [Epub ahead of print]94 54-61
    WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.
    Matej Skorvanek, Irena Rektorova, Wim Mandemakers, Matias Wagner, Robert Steinfeld, Laura Orec, Vladimir Han, Petra Pavelekova, Alexandra Lackova, Kristina Kulcsarova, Miriam Ostrozovicova, Zuzana Gdovinova, Barbara Plecko, Theresa Brunet, Riccardo Berutti, Demy J S Kuipers, Valerie Boumeester, Petra Havrankova, M A J Tijssen, Rauan Kaiyrzhanov, Mie Rizig, Henry Houlden, Juliane Winkelmann, Vincenzo Bonifati, Michael Zech, Robert Jech.
      INTRODUCTION: Sixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand the spectrum to later onset phenotypes including dopa-responsive early-onset parkinsonism and progressive myoclonus-ataxia.METHODS: Six individuals from four families underwent whole-exome sequencing within research and diagnostic settings. Following the identification of a genetic defect, in-depth phenotyping and protein expression studies were performed.
    RESULTS: A relatively common (gnomAD MAF = 0.0033) pathogenic p.(Trp13Gly) missense variant in WARS2 was detected in trans in all six affected individuals in combination with different pathogenic alleles (exon 2 deletion in family 1; p.(Leu100del) in family 2; p.(Gly50Asp) in family 3; and p.(Glu208*) in family 4). Two subjects presented with action tremor around age 10-12 years and developed tremor-dominant parkinsonism with prominent neuropsychiatric features later in their 20s. Two subjects presented with a progressive myoclonus-ataxia dominant phenotype. One subject presented with spasticity, choreo-dystonia, myoclonus, and speech problems. One subject presented with speech problems, ataxia, and tremor. Western blotting analyses in patient-derived fibroblasts showed a markedly decreased expression of the full-length WARS2 protein in both subjects carrying p.(Trp13Gly) and an exon-2 deletion in compound heterozygosity.
    CONCLUSIONS: This study expands the spectrum of the disease to later onset phenotypes of early-onset tremor-dominant parkinsonism and progressive myoclonus-ataxia phenotypes.
    Keywords:  Early onset parkinsonism; Progressive myoclonus ataxia; WARS2; Whole exome sequencing
    DOI:  https://doi.org/10.1016/j.parkreldis.2021.11.030
  17. Int J Mol Sci. 2021 Nov 23. pii: 12620. [Epub ahead of print]22(23):
    Mitochondrial Transport in Glycolysis and Gluconeogenesis: Achievements and Perspectives.
    Salvatore Passarella, Avital Schurr, Piero Portincasa.
      Some metabolic pathways involve two different cell components, for instance, cytosol and mitochondria, with metabolites traffic occurring from cytosol to mitochondria and vice versa, as seen in both glycolysis and gluconeogenesis. However, the knowledge on the role of mitochondrial transport within these two glucose metabolic pathways remains poorly understood, due to controversial information available in published literature. In what follows, we discuss achievements, knowledge gaps, and perspectives on the role of mitochondrial transport in glycolysis and gluconeogenesis. We firstly describe the experimental approaches for quick and easy investigation of mitochondrial transport, with respect to cell metabolic diversity. In addition, we depict the mitochondrial shuttles by which NADH formed in glycolysis is oxidized, the mitochondrial transport of phosphoenolpyruvate in the light of the occurrence of the mitochondrial pyruvate kinase, and the mitochondrial transport and metabolism of L-lactate due to the L-lactate translocators and to the mitochondrial L-lactate dehydrogenase located in the inner mitochondrial compartment.
    Keywords:  L-lactate; gluconeogenesis; glycolysis; mitochondrial shuttles; mitochondrial transport; phosphoenolpyruvate
    DOI:  https://doi.org/10.3390/ijms222312620
  18. J Biochem. 2021 Dec 04. pii: mvab136. [Epub ahead of print]
    Mitochondria Metabolomics Reveals a Role of β-Nicotinamide Mononucleotide Metabolism in Mitochondrial DNA Replication.
    Tomoko Nomiyama, Daiki Setoyama, Takehiro Yasukawa, Dongchon Kang.
      Mitochondrial DNA (mtDNA) replication is tightly regulated and necessary for cellular homeostasis; however, its relationship with mitochondrial metabolism remains unclear. Advances in metabolomics integrated with the rapid isolation of mitochondria will allow for remarkable progress in analyzing mitochondrial metabolism. Here, we propose a novel methodology for mitochondria-targeted metabolomics, which employs a quick isolation procedure using a hemolytic toxin from Streptococcus pyogenes streptolysin O (SLO). SLO-isolation of mitochondria from cultured HEK293 cells is time- and labor-saving for simultaneous multi-sample processing and has been applied to various other cell lines in this study. Furthermore, our method can detect the time-dependent reduction in mitochondrial ATP in response to a glycolytic inhibitor 2-deoxyglucose, indicating the suitability to prepare metabolite analysis-competent mitochondria. Using this methodology, we searched for specific mitochondrial metabolites associated with mtDNA replication activation, and nucleotides and NAD+ were identified to be prominently altered. Most notably, treatment of β-Nicotinamide Mononucleotide (β-NMN), a precursor of NAD+, to HEK293 cells activated and improved the rate of mtDNA replication by increasing nucleotides in mitochondria and decreasing their degradation products: nucleosides. Our results suggest that β-NMN metabolism play a role in supporting mtDNA replication by maintaining the nucleotide pool balance in the mitochondria.
    Keywords:  beta-nicotinamide mononucleotide (β-NMN); metabolomics; mitochondrial DNA; nucleotide metabolism; streptolysin O
    DOI:  https://doi.org/10.1093/jb/mvab136
  19. Aging Dis. 2021 Dec;12(8): 2016-2030
    Mitochondrial Quality Control in Sarcopenia: Updated Overview of Mechanisms and Interventions.
    Di Liu, Yi-Bin Fan, Xiao-Hua Tao, Wei-Li Pan, Yu-Xiang Wu, Xiu-Hua Wang, Yu-Qiong He, Wen-Feng Xiao, Yu-Sheng Li.
      Sarcopenia is a common geriatric disorder characterized by decreased muscle strength, low muscle mass and poor physical performance. This aging-related skeletal muscle deterioration leads to adverse outcomes and severely impairs the quality of life of patients. The accumulation of dysfunctional mitochondria with aging is an important factor in the occurrence and progression of sarcopenia. Mitochondrial quality control (MQC) fundamentally ensures the normal mitochondrial functions and is comprised of four main parts: proteostasis, biogenesis, dynamics and autophagy. Therefore, any pathophysiologic factors compromising the quality control of homeostasis in the skeletal muscle may lead to sarcopenia. However, the specific theoretical aspects of these processes have not been fully elucidated. Current therapeutic interventions using nutritional and pharmaceutical treatments show a modest therapeutic efficacy; however, only physical exercise is recommended as the first-line therapy for sarcopenia, which can ameliorate skeletal muscle deficiency by maintaining the homeostatic MQC. In this review, we summarized the known mechanisms that contribute to the pathogenesis of sarcopenia by impairing normal mitochondrial functions and described potential interventions that mitigate sarcopenia through improving MQC.
    Keywords:  mitochondria; mitochondrial quality control; sarcopenia; therapeutic intervention
    DOI:  https://doi.org/10.14336/AD.2021.0427
  20. IUBMB Life. 2021 Dec 10.
    Mitophagy in aging and longevity.
    Jing Guo, Wei-Chung Chiang.
      The clearance of damaged or unwanted mitochondria by autophagy (also known as mitophagy) is a mitochondrial quality control mechanism postulated to play an essential role in cellular homeostasis, metabolism, and development and confers protection against a wide range of diseases. Proper removal of damaged or unwanted mitochondria is essential for organismal health. Defects in mitophagy are associated with Parkinson's, Alzheimer's disease, cancer, and other degenerative disorders. Mitochondria regulate organismal fitness and longevity via multiple pathways, including cellular senescence, stem cell function, inflammation, mitochondrial unfolded protein response (mtUPR), and bioenergetics. Thus, mitophagy is postulated to be pivotal for maintaining organismal healthspan and lifespan and the protection against aged-related degeneration. In this review, we will summarize recent understanding of the mechanism of mitophagy and aspects of mitochondrial functions. We will focus on mitochondria-related cellular processes that are linked to aging and examine current genetic evidence that supports the hypothesis that mitophagy is a pro-longevity mechanism.
    Keywords:  aging; longevity; mitophagy
    DOI:  https://doi.org/10.1002/iub.2585
  21. Nucleic Acids Res. 2021 Dec 08. pii: gkab1187. [Epub ahead of print]
    FARS2 deficiency in Drosophila reveals the developmental delay and seizure manifested by aberrant mitochondrial tRNA metabolism.
    Wenlu Fan, Xiaoye Jin, Man Xu, Yongmei Xi, Weiguo Lu, Xiaohang Yang, Min-Xin Guan, Wanzhong Ge.
      Mutations in genes encoding mitochondrial aminoacyl-tRNA synthetases are linked to diverse diseases. However, the precise mechanisms by which these mutations affect mitochondrial function and disease development are not fully understood. Here, we develop a Drosophila model to study the function of dFARS2, the Drosophila homologue of the mitochondrial phenylalanyl-tRNA synthetase, and further characterize human disease-associated FARS2 variants. Inactivation of dFARS2 in Drosophila leads to developmental delay and seizure. Biochemical studies reveal that dFARS2 is required for mitochondrial tRNA aminoacylation, mitochondrial protein stability, and assembly and enzyme activities of OXPHOS complexes. Interestingly, by modeling FARS2 mutations associated with human disease in Drosophila, we provide evidence that expression of two human FARS2 variants, p.G309S and p.D142Y, induces seizure behaviors and locomotion defects, respectively. Together, our results not only show the relationship between dysfunction of mitochondrial aminoacylation system and pathologies, but also illustrate the application of Drosophila model for functional analysis of human disease-causing variants.
    DOI:  https://doi.org/10.1093/nar/gkab1187
  22. Curr Alzheimer Res. 2021 Dec 08.
    Mitochondrially-Targeted Therapeutic Strategies for Alzheimer's Disease.
    Isaac G Onyango, James P Bennett, Gorazd B Stokin.
      Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disease and the most common cause of dementia among older adults. There are no effective treatments avail- able for the disease, and it is associated with great societal concern because of the substantial costs of providing care to its sufferers, whose numbers will increase as populations age. While multiple causes have been proposed to be significant contributors to the onset of sporadic AD, increased age is a unifying risk factor. In addition to amyloid-β (Aβ) and tau protein playing a key role in the initi- ation and progression of AD, impaired mitochondrial bioenergetics and dynamics are likely major etiological factors in AD pathogenesis and have many potential origins, including Aβ and tau. Mito- chondrial dysfunction is evident in the central nervous system (CNS) and systemically early in the disease process. Addressing these multiple mitochondrial deficiencies is a major challenge of mito- chondrial systems biology. We review evidence for mitochondrial impairments ranging from mito- chondrial DNA (mtDNA) mutations to epigenetic modification of mtDNA, altered gene expres- sion, impaired mitobiogenesis, oxidative stress, altered protein turnover and changed organelle dy- namics (fission and fusion). We also discuss therapeutic approaches, including repurposed drugs, epigenetic modifiers, and lifestyle changes that target each level of deficiency which could poten- tially alter the course of this progressive, heterogeneous Disease while being cognizant that success- ful future therapeutics may require a combinatorial approach.
    Keywords:  Alzheimer's disease; bioenergetics; epigenetic modifiers; lifestyle changes; mitochondria; mtDNA; repurposed drugs; β-amyloid
    DOI:  https://doi.org/10.2174/1567205018666211208125855
  23. Int J Mol Sci. 2021 Nov 26. pii: 12775. [Epub ahead of print]22(23):
    Deficiency of T-Cell Intracellular Antigen 1 in Murine Embryonic Fibroblasts Is Associated with Changes in Mitochondrial Morphology and Respiration.
    Isabel Carrascoso, Beatriz Ramos Velasco, José M Izquierdo.
      T-cell intracellular antigen 1 (TIA1) is a multifunctional RNA-binding protein involved in regulating gene expression and splicing during development and in response to environmental stress, to maintain cell homeostasis and promote survival. Herein, we used TIA1-deficient murine embryonic fibroblasts (MEFs) to study their role in mitochondria homeostasis. We found that the loss of TIA1 was associated with changes in mitochondrial morphology, promoting the appearance of elongated mitochondria with heterogeneous cristae density and size. The proteomic patterns of TIA1-deficient MEFs were consistent with expression changes in molecular components related to mitochondrial dynamics/organization and respiration. Bioenergetics analysis illustrated that TIA1 deficiency enhances mitochondrial respiration. Overall, our findings shed light on the role of TIA1 in mitochondrial dynamics and highlight a point of crosstalk between potential pro-survival and pro-senescence pathways.
    Keywords:  TIA1; mitochondria; mitochondrial dynamics; mitochondrial respiration; murine embryonic fibroblast
    DOI:  https://doi.org/10.3390/ijms222312775
  24. Front Genet. 2021 ;12 769770
    Editorial: Mitochondrial Disorders: Biochemical and Molecular Basis of Disease.
    Guilhian Leipnitz, Grant M Hatch, Al-Walid Mohsen, Ronald J A Wanders.
      
    Keywords:  case report; mitochondrial disorders; pathophysiology; reaction mechanism; treatment
    DOI:  https://doi.org/10.3389/fgene.2021.769770
  25. J Cell Sci. 2021 Dec 06. pii: jcs.257808. [Epub ahead of print]
    MITOL-mediated DRP1 ubiquitylation and degradation promotes mitochondrial hyperfusion in CMT2A-linked MFN2 mutant.
    Rajdeep Das, Izaz Monir Kamal, Subhrangshu Das, Saikat Chakrabarti, Oishee Chakrabarti.
      Mutations in Mitofusin2 (MFN2), associated with the pathology of the debilitating neuropathy, Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. One such abundant MFN2 mutant, R364W results in the generation of elongated, interconnected mitochondria. However, the mechanism leading to this mitochondrial aberration remains poorly understood. Here we show that mitochondrial hyperfusion in the presence of R364W-MFN2 is due to increased degradation of DRP1. The Ubiquitin E3 ligase MITOL is known to ubiquitylate both MFN2 and DRP1. Interaction with and its subsequent ubiquitylation by MITOL is stronger in presence of WT-MFN2 than R364W-MFN2. This differential interaction of MITOL with MFN2 in the presence of R364W-MFN2 renders the ligase more available for DRP1 ubiquitylation. Multimonoubiquitylation and proteasomal degradation of DRP1 in R364W-MFN2 cells in the presence of MITOL eventually leads to mitochondrial hyperfusion. Here we provide a mechanistic insight into mitochondrial hyperfusion, while also reporting that MFN2 can indirectly modulate DRP1 - an effect not shown before.
    Keywords:  CMT2A-linked MFN2 mutant; DRP1; MITOL; Mitochondrial hyperfusion; Ubiquitylation
    DOI:  https://doi.org/10.1242/jcs.257808
  26. Nat Rev Mol Cell Biol. 2021 Dec 08.
    Molecular mechanisms and consequences of mitochondrial permeability transition.
    Massimo Bonora, Carlotta Giorgi, Paolo Pinton.
      Mitochondrial permeability transition (mPT) is a phenomenon that abruptly causes the flux of low molecular weight solutes (molecular weight up to 1,500) across the generally impermeable inner mitochondrial membrane. The mPT is mediated by the so-called mitochondrial permeability transition pore (mPTP), a supramolecular entity assembled at the interface of the inner and outer mitochondrial membranes. In contrast to mitochondrial outer membrane permeabilization, which mostly activates apoptosis, mPT can trigger different cellular responses, from the physiological regulation of mitophagy to the activation of apoptosis or necrosis. Although there are several molecular candidates for the mPTP, its molecular nature remains contentious. This lack of molecular data was a significant setback that prevented mechanistic insight into the mPTP, pharmacological targeting and the generation of informative animal models. In recent years, experimental evidence has highlighted mitochondrial F1Fo ATP synthase as a participant in mPTP formation, although a molecular model for its transition to the mPTP is still lacking. Recently, the resolution of the F1Fo ATP synthase structure by cryogenic electron microscopy led to a model for mPTP gating. The elusive molecular nature of the mPTP is now being clarified, marking a turning point for understanding mitochondrial biology and its pathophysiological ramifications. This Review provides an up-to-date reference for the understanding of the mammalian mPTP and its cellular functions. We review current insights into the molecular mechanisms of mPT and validated observations - from studies in vivo or in artificial membranes - on mPTP activity and functions. We end with a discussion of the contribution of the mPTP to human disease. Throughout the Review, we highlight the multiple unanswered questions and, when applicable, we also provide alternative interpretations of the recent discoveries.
    DOI:  https://doi.org/10.1038/s41580-021-00433-y
  27. Int J Mol Sci. 2021 Dec 02. pii: 13057. [Epub ahead of print]22(23):
    Emerging Role of TCA Cycle-Related Enzymes in Human Diseases.
    Woojin Kang, Miki Suzuki, Takako Saito, Kenji Miyado.
      The tricarboxylic acid (TCA) cycle is the main source of cellular energy and participates in many metabolic pathways in cells. Recent reports indicate that dysfunction of TCA cycle-related enzymes causes human diseases, such as neurometabolic disorders and tumors, have attracted increasing interest in their unexplained roles. The diseases which develop as a consequence of loss or dysfunction of TCA cycle-related enzymes are distinct, suggesting that each enzyme has a unique function. This review aims to provide a comprehensive overview of the relationship between each TCA cycle-related enzyme and human diseases. We also discuss their functions in the context of both mitochondrial and extra-mitochondrial (or cytoplasmic) enzymes.
    Keywords:  TCA cycle; TCA cycle-related enzymes; calcium oscillations; human diseases; mitochondria
    DOI:  https://doi.org/10.3390/ijms222313057
  28. Exp Cell Res. 2021 Dec 06. pii: S0014-4827(21)00524-3. [Epub ahead of print] 112968
    Therapeutic approaches to preserve the musculature in Duchenne Muscular Dystrophy: The importance of the secondary therapies.
    Giuseppe Angelini, Giada Mura, Graziella Messina.
      Muscular dystrophies (MDs) are heterogeneous diseases, characterized by primary wasting of skeletal muscle, which in severe cases, such as Duchenne Muscular Dystrophy (DMD), leads to wheelchair dependency, respiratory failure, and premature death. Research is ongoing to develop efficacious therapies, particularly for DMD. Most of the efforts, currently focusing on correcting or restoring the primary defect of MDs, are based on gene-addition, exon-skipping, stop codon read-through, and genome-editing. Although promising, most of them revealed several practical limitations. Shared knowledge in the field is that, in order to be really successful, any therapeutic approach has to rely on spared functional muscle tissue, restricting the number of patients eligible for clinical trials to the youngest and less compromised individuals. In line with this, many therapeutic strategies aim to preserve muscle tissue and function. This Review outlines the most interesting and recent studies addressing the secondary outcomes of DMD and how to better deliver the therapeutic agents. In the future, the effective treatment of DMD will likely require combinations of therapies addressing both the primary genetic defect and its consequences.
    Keywords:  Muscle protection; Muscular Dystrophies; Nanocarriers; Nutrigenomics; Secondary therapies
    DOI:  https://doi.org/10.1016/j.yexcr.2021.112968
  29. J Gerontol A Biol Sci Med Sci. 2021 Dec 06. pii: glab363. [Epub ahead of print]
    Supercomplex organization of the electron transfer system in marine bivalves, a model of extreme longevity.
    Enrique Rodríguez, Amanda Radke, Tory M Hagen, Pierre U Blier.
      The mitochondrial oxidative stress theory of aging (MOSTA) suggests that the organelle's decay contributes to the aging phenotype via exacerbated oxidative stress, loss of organ coordination and energetics, cellular integrity and activity of the mitochondrial electron transfer system (ETS). Recent advances in understanding the structure of the ETS show that the enzymatic complexes responsible for oxidative phosphorylation are arranged in supramolecular structures called supercomplexes that lose organization during aging. Their exact role and universality among organisms are still under debate. Here, we take advantage of marine bivalves as an aging model to compare the structure of the ETS among species ranging from 28 to 507 years in maximal lifespan. Our results show that regardless of lifespan, the bivalve ETS is arrayed as a set of supercomplexes. However, bivalve species display varying degrees ETS supramolecular organization with the highest supercomplex structures found in A. islandica, the longest-lived of the bivalve species under study. We discuss this comparative model in light of differences in the nature and stoichiometry of these complexes, and highlight the potential link between the complexity of these superstructures and longer lifespans.
    Keywords:  Electron transfer system; Invertebrate; Mitochondria; Supercomplex
    DOI:  https://doi.org/10.1093/gerona/glab363
  30. Nat Commun. 2021 Dec 08. 12(1): 7115
    Acetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming.
    Clément Adam, Léa Paolini, Naïg Gueguen, Guillaume Mabilleau, Laurence Preisser, Simon Blanchard, Pascale Pignon, Florence Manero, Morgane Le Mao, Alain Morel, Pascal Reynier, Céline Beauvillain, Yves Delneste, Vincent Procaccio, Pascale Jeannin.
      Lactic acidosis, the extracellular accumulation of lactate and protons, is a consequence of increased glycolysis triggered by insufficient oxygen supply to tissues. Macrophages are able to differentiate from monocytes under such acidotic conditions, and remain active in order to resolve the underlying injury. Here we show that, in lactic acidosis, human monocytes differentiating into macrophages are characterized by depolarized mitochondria, transient reduction of mitochondrial mass due to mitophagy, and a significant decrease in nutrient absorption. These metabolic changes, resembling pseudostarvation, result from the low extracellular pH rather than from the lactosis component, and render these cells dependent on autophagy for survival. Meanwhile, acetoacetate, a natural metabolite produced by the liver, is utilized by monocytes/macrophages as an alternative fuel to mitigate lactic acidosis-induced pseudostarvation, as evidenced by retained mitochondrial integrity and function, retained nutrient uptake, and survival without the need of autophagy. Our results thus show that acetoacetate may increase tissue tolerance to sustained lactic acidosis.
    DOI:  https://doi.org/10.1038/s41467-021-27426-x
  31. Front Immunol. 2021 ;12 782074
    Mitochondria in Focus: From Function to Therapeutic Strategies in Chronic Lung Diseases.
    Dayene de Assis Fernandes Caldeira, Daniel J Weiss, Patricia Rieken Macêdo Rocco, Pedro Leme Silva, Fernanda Ferreira Cruz.
      Mitochondria are essential organelles for cell metabolism, growth, and function. Mitochondria in lung cells have important roles in regulating surfactant production, mucociliary function, mucus secretion, senescence, immunologic defense, and regeneration. Disruption in mitochondrial physiology can be the central point in several pathophysiologic pathways of chronic lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and asthma. In this review, we summarize how mitochondria morphology, dynamics, redox signaling, mitophagy, and interaction with the endoplasmic reticulum are involved in chronic lung diseases and highlight strategies focused on mitochondrial therapy (mito-therapy) that could be tested as a potential therapeutic target for lung diseases.
    Keywords:  chronic lung diseases; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial morphology; mitotherapy; reactive species of oxygen (ROS)
    DOI:  https://doi.org/10.3389/fimmu.2021.782074
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