bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2021–12–12
forty-five papers selected by
Catalina Vasilescu, University of Helsinki
  1. Mitochondrial Transport in Glycolysis and Gluconeogenesis: Achievements and Perspectives.
  2. Mitochondria Metabolomics Reveals a Role of β-Nicotinamide Mononucleotide Metabolism in Mitochondrial DNA Replication.
  3. Phenotypic spectrum and clinical course of single large-scale mitochondrial DNA deletion disease in the paediatric population: a multicentre study.
  4. 2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA.
  5. Identification and characterisation of novel MPC1 gene variants causing mitochondrial pyruvate carrier deficiency.
  6. Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission.
  7. MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control.
  8. Genotype-phenotype analysis of MT-ATP6-associated Leigh syndrome.
  9. Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases?
  10. Editorial: Mitochondrial Disorders: Biochemical and Molecular Basis of Disease.
  11. Response to: Phenotypic heterogeneity of Leigh syndrome due to NDUFA12 variants is multicausal.
  12. Quantitative assays to measure the transport activity of the mitochondrial calcium uniporter in cell lines or Xenopus oocytes.
  13. Strategies to protect against age-related mitochondrial decay: Do natural products and their derivatives help?
  14. Role of Prohibitins in Aging and Therapeutic Potential Against Age-Related Diseases.
  15. FARS2 deficiency in Drosophila reveals the developmental delay and seizure manifested by aberrant mitochondrial tRNA metabolism.
  16. The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites.
  17. Surveying the mitochondrial proteome.
  18. Mechanism of PINK1 activation by autophosphorylation and insights into assembly on the TOM complex.
  19. Live-imaging of Mitochondrial System in Cultured Astrocytes.
  20. Phenotypic heterogeneity of Leigh syndrome due to NDUFA12 variants is multicausal.
  21. Mitochondrial Biogenesis in Neurons: How and Where.
  22. Mitochondrial Dysfunction in Advanced Liver Disease: Emerging Concepts.
  23. Acute RyR1 Ca2+ leak enhances NADH-linked mitochondrial respiratory capacity.
  24. Co-Exposure of Cardiomyocytes to IFN-γ and TNF-α Induces Mitochondrial Dysfunction and Nitro-Oxidative Stress: Implications for the Pathogenesis of Chronic Chagas Disease Cardiomyopathy.
  25. Acetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming.
  26. Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function.
  27. The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance.
  28. WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.
  29. Mitochondrial ribosomal stress in lung diseases.
  30. Neurotoxin-mediated --potent activation of the axon degeneration regulator SARM1.
  31. Mitophagy in aging and longevity.
  32. Molecular species selectivity of lipid transport creates a mitochondrial sink for di-unsaturated phospholipids.
  33. MITOL-mediated DRP1 ubiquitylation and degradation promotes mitochondrial hyperfusion in CMT2A-linked MFN2 mutant.
  34. Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates development and early survival of retinal neurons.
  35. Molecular mechanisms and consequences of mitochondrial permeability transition.
  36. Emerging Role of TCA Cycle-Related Enzymes in Human Diseases.
  37. Chromatin Profiling of Human Naïve Pluripotent Stem Cells.
  38. Somatic mitochondrial DNA mutations in different grades of glioma.
  39. Mitochondrial Quality Control in Sarcopenia: Updated Overview of Mechanisms and Interventions.
  40. Position 34 of tRNA is a discriminative element for m5C38 modification by human DNMT2.
  41. Analysis of a family with mitochondrial trifunctional protein deficiency caused by HADHA gene mutations.
  42. Mitochondrial uncoupling protein 1 antagonizes atherosclerosis by blocking NLRP3 inflammasome-dependent interleukin-1β production.
  43. Novel imaging findings in pyruvate dehydrogenase complex (PDHc) deficiency- results from a nation-wide population-based study.
  44. A genetically encoded fluorescent biosensor for extracellular L-lactate.
  45. VPS13C-associated Parkinson's disease: Two novel cases and review of the literature.
  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  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. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. STAR Protoc. 2021 Dec 17. 2(4): 100979
    Quantitative assays to measure the transport activity of the mitochondrial calcium uniporter in cell lines or Xenopus oocytes.
    Madison X Rodriguez, Anna M Van Keuren, Ming-Feng Tsai.
      The mitochondrial calcium uniporter, which mediates mitochondrial Ca2+ uptake, regulates key cellular functions, including intracellular Ca2+ signaling, cell-fate determination, and mitochondrial bioenergetics. Here, we describe two complementary strategies to quantify the uniporter's transport activity. First, we detail a mitochondrial Ca2+ radionuclide uptake assay in cultured cell lines. Second, we describe electrophysiological recordings of the uniporter expressed in Xenopus oocytes. These approaches enable a detailed kinetic analysis of the uniporter to link its molecular properties to physiological functions. For complete details on the use and execution of this protocol, please refer to Tsai and Tsai (2018) and Phillips et al. (2019).
    Keywords:  Biophysics; Cell Biology; Cell-based Assays; Molecular Biology
    DOI:  https://doi.org/10.1016/j.xpro.2021.100979
  13. 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
  14. 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
  15. 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
  16. 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
  17. Nat Cell Biol. 2021 Dec 06.
    Surveying the mitochondrial proteome.
    Dominic Winter, Thomas Becker.
      
    DOI:  https://doi.org/10.1038/s41556-021-00801-y
  18. Mol Cell. 2021 Nov 26. pii: S1097-2765(21)00991-6. [Epub ahead of print]
    Mechanism of PINK1 activation by autophosphorylation and insights into assembly on the TOM complex.
    Shafqat Rasool, Simon Veyron, Naoto Soya, Mohamed A Eldeeb, Gergely L Lukacs, Edward A Fon, Jean-François Trempe.
      Mutations in PINK1 cause autosomal-recessive Parkinson's disease. Mitochondrial damage results in PINK1 import arrest on the translocase of the outer mitochondrial membrane (TOM) complex, resulting in the activation of its ubiquitin kinase activity by autophosphorylation and initiation of Parkin-dependent mitochondrial clearance. Herein, we report crystal structures of the entire cytosolic domain of insect PINK1. Our structures reveal a dimeric autophosphorylation complex targeting phosphorylation at the invariant Ser205 (human Ser228). The dimer interface requires insert 2, which is unique to PINK1. The structures also reveal how an N-terminal helix binds to the C-terminal extension and provide insights into stabilization of PINK1 on the core TOM complex.
    Keywords:  PINK1; Parkin; Parkinson; TOM; X-ray crystallography; kinase; mass spectrometry; mitochondria; phosphorylation; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2021.11.012
  19. 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
  20. 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
  21. 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
  22. 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
  23. Nat Commun. 2021 Dec 10. 12(1): 7219
    Acute RyR1 Ca2+ leak enhances NADH-linked mitochondrial respiratory capacity.
    Nadège Zanou, Haikel Dridi, Steven Reiken, Tanes Imamura de Lima, Chris Donnelly, Umberto De Marchi, Manuele Ferrini, Jeremy Vidal, Leah Sittenfeld, Jerome N Feige, Pablo M Garcia-Roves, Isabel C Lopez-Mejia, Andrew R Marks, Johan Auwerx, Bengt Kayser, Nicolas Place.
      Sustained ryanodine receptor (RyR) Ca2+ leak is associated with pathological conditions such as heart failure or skeletal muscle weakness. We report that a single session of sprint interval training (SIT), but not of moderate intensity continuous training (MICT), triggers RyR1 protein oxidation and nitrosylation leading to calstabin1 dissociation in healthy human muscle and in in vitro SIT models (simulated SIT or S-SIT). This is accompanied by decreased sarcoplasmic reticulum Ca2+ content, increased levels of mitochondrial oxidative phosphorylation proteins, supercomplex formation and enhanced NADH-linked mitochondrial respiratory capacity. Mechanistically, (S-)SIT increases mitochondrial Ca2+ uptake in mouse myotubes and muscle fibres, and decreases pyruvate dehydrogenase phosphorylation in human muscle and mouse myotubes. Countering Ca2+ leak or preventing mitochondrial Ca2+ uptake blunts S-SIT-induced adaptations, a result supported by proteomic analyses. Here we show that triggering acute transient Ca2+ leak through RyR1 in healthy muscle may contribute to the multiple health promoting benefits of exercise.
    DOI:  https://doi.org/10.1038/s41467-021-27422-1
  24. Front Immunol. 2021 ;12 755862
    Co-Exposure of Cardiomyocytes to IFN-γ and TNF-α Induces Mitochondrial Dysfunction and Nitro-Oxidative Stress: Implications for the Pathogenesis of Chronic Chagas Disease Cardiomyopathy.
    João Paulo Silva Nunes, Pauline Andrieux, Pauline Brochet, Rafael Ribeiro Almeida, Eduardo Kitano, André Kenji Honda, Leo Kei Iwai, Débora Andrade-Silva, David Goudenège, Karla Deysiree Alcântara Silva, Raquel de Souza Vieira, Débora Levy, Sergio Paulo Bydlowski, Frédéric Gallardo, Magali Torres, Edimar Alcides Bocchi, Miguel Mano, Ronaldo Honorato Barros Santos, Fernando Bacal, Pablo Pomerantzeff, Francisco Rafael Martins Laurindo, Priscila Camillo Teixeira, Helder I Nakaya, Jorge Kalil, Vincent Procaccio, Christophe Chevillard, Edecio Cunha-Neto.
      Infection by the protozoan Trypanosoma cruzi causes Chagas disease cardiomyopathy (CCC) and can lead to arrhythmia, heart failure and death. Chagas disease affects 8 million people worldwide, and chronic production of the cytokines IFN-γ and TNF-α by T cells together with mitochondrial dysfunction are important players for the poor prognosis of the disease. Mitochondria occupy 40% of the cardiomyocytes volume and produce 95% of cellular ATP that sustain the life-long cycles of heart contraction. As IFN-γ and TNF-α have been described to affect mitochondrial function, we hypothesized that IFN-γ and TNF-α are involved in the myocardial mitochondrial dysfunction observed in CCC patients. In this study, we quantified markers of mitochondrial dysfunction and nitro-oxidative stress in CCC heart tissue and in IFN-γ/TNF-α-stimulated AC-16 human cardiomyocytes. We found that CCC myocardium displayed increased levels of nitro-oxidative stress and reduced mitochondrial DNA as compared with myocardial tissue from patients with dilated cardiomyopathy (DCM). IFN-γ/TNF-α treatment of AC-16 cardiomyocytes induced increased nitro-oxidative stress and decreased the mitochondrial membrane potential (ΔΨm). We found that the STAT1/NF-κB/NOS2 axis is involved in the IFN-γ/TNF-α-induced decrease of ΔΨm in AC-16 cardiomyocytes. Furthermore, treatment with mitochondria-sparing agonists of AMPK, NRF2 and SIRT1 rescues ΔΨm in IFN-γ/TNF-α-stimulated cells. Proteomic and gene expression analyses revealed that IFN-γ/TNF-α-treated cells corroborate mitochondrial dysfunction, transmembrane potential of mitochondria, altered fatty acid metabolism and cardiac necrosis/cell death. Functional assays conducted on Seahorse respirometer showed that cytokine-stimulated cells display decreased glycolytic and mitochondrial ATP production, dependency of fatty acid oxidation as well as increased proton leak and non-mitochondrial oxygen consumption. Together, our results suggest that IFN-γ and TNF-α cause direct damage to cardiomyocytes' mitochondria by promoting oxidative and nitrosative stress and impairing energy production pathways. We hypothesize that treatment with agonists of AMPK, NRF2 and SIRT1 might be an approach to ameliorate the progression of Chagas disease cardiomyopathy.
    Keywords:  chronic Chagas disease cardiomyopathy; energy metabolism; interferon gamma; mitochondria ; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fimmu.2021.755862
  25. 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
  26. iScience. 2021 Dec 17. 24(12): 103460
    Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function.
    Karen Rosier, Molly T McDevitt, Joél Smet, Brendan J Floyd, Maxime Verschoore, Maria J Marcaida, Craig A Bingman, Irma Lemmens, Matteo Dal Peraro, Jan Tavernier, Benjamin F Cravatt, Natalia V Gounko, Katlijn Vints, Yenthe Monnens, Kritika Bhalla, Laetitia Aerts, Edrees H Rashan, Arnaud V Vanlander, Rudy Van Coster, Luc Régal, David J Pagliarini, John W M Creemers.
      Deficiency of the serine hydrolase prolyl endopeptidase-like (PREPL) causes a recessive metabolic disorder characterized by neonatal hypotonia, feeding difficulties, and growth hormone deficiency. The pathophysiology of PREPL deficiency and the physiological substrates of PREPL remain largely unknown. In this study, we connect PREPL with mitochondrial gene expression and oxidative phosphorylation by analyzing its protein interactors. We demonstrate that the long PREPLL isoform localizes to mitochondria, whereas PREPLS remains cytosolic. Prepl KO mice showed reduced mitochondrial complex activities and disrupted mitochondrial gene expression. Furthermore, mitochondrial ultrastructure was abnormal in a PREPL-deficient patient and Prepl KO mice. In addition, we reveal that PREPL has (thio)esterase activity and inhibition of PREPL by Palmostatin M suggests a depalmitoylating function. We subsequently determined the crystal structure of PREPL, thereby providing insight into the mechanism of action. Taken together, PREPL is a (thio)esterase rather than a peptidase and PREPLL is involved in mitochondrial homeostasis.
    Keywords:  Molecular biology; Molecular medicine; Structural biology
    DOI:  https://doi.org/10.1016/j.isci.2021.103460
  27. Front Neurosci. 2021 ;15 784987
    The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance.
    Elin L Strachan, Delphi Mac White-Begg, John Crean, Alison L Reynolds, Breandán N Kennedy, Niamh C O'Sullivan.
      Optic atrophy (OA) with autosomal inheritance is a form of optic neuropathy characterized by the progressive and irreversible loss of vision. In some cases, this is accompanied by additional, typically neurological, extra-ocular symptoms. Underlying the loss of vision is the specific degeneration of the retinal ganglion cells (RGCs) which form the optic nerve. Whilst autosomal OA is genetically heterogenous, all currently identified causative genes appear to be associated with mitochondrial organization and function. However, it is unclear why RGCs are particularly vulnerable to mitochondrial aberration. Despite the relatively high prevalence of this disorder, there are currently no approved treatments. Combined with the lack of knowledge concerning the mechanisms through which aberrant mitochondrial function leads to RGC death, there remains a clear need for further research to identify the underlying mechanisms and develop treatments for this condition. This review summarizes the genes known to be causative of autosomal OA and the mitochondrial dysfunction caused by pathogenic mutations. Furthermore, we discuss the suitability of available in vivo models for autosomal OA with regards to both treatment development and furthering the understanding of autosomal OA pathology.
    Keywords:  in vivo models; mitochondria; optic atrophy; retinal ganglion cells (RGC); retinal organoids
    DOI:  https://doi.org/10.3389/fnins.2021.784987
  28. 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
  29. Am J Physiol Lung Cell Mol Physiol. 2021 Dec 07.
    Mitochondrial ribosomal stress in lung diseases.
    Loukmane Karim, Beata Kosmider, Karim Bahmed.
      Mitochondria are involved in a variety of critical cellular functions, and their impairment drives cell injury. The mitochondrial ribosome (mitoribosome) is responsible for the protein synthesis of mitochondrial DNA encoded genes. These proteins are involved in oxidative phosphorylation, respiration, and ATP production required in the cell. Mitoribosome components originate from both mitochondrial and nuclear genomes. Their dysfunction can be caused by impaired mitochondrial protein synthesis or mitoribosome misassembly, leading to a decline in mitochondrial translation. This decrease can trigger mitochondrial ribosomal stress and contribute to pulmonary cell injury, death, and diseases. This review focuses on the contribution of the impaired mitoribosome structural components and function to respiratory disease pathophysiology. We present recent findings in the fields of lung cancer, chronic obstructive pulmonary disease, interstitial lung disease, and asthma. We also include reports on the mitoribosome dysfunction in pulmonary hypertension, high altitude pulmonary edema, bacterial and viral infections. Studies of the mitoribosome alterations in respiratory diseases can lead to novel therapeutic targets.
    Keywords:  disease; lung; mitochondria; mitoribosome
    DOI:  https://doi.org/10.1152/ajplung.00078.2021
  30. Elife. 2021 Dec 06. pii: e72823. [Epub ahead of print]10
    Neurotoxin-mediated --potent activation of the axon degeneration regulator SARM1.
    Andrea Loreto, Carlo Angeletti, Weixi Gu, Andrew Osborne, Bart Nieuwenhuis, Jonathan Gilley, Peter Arthur-Farraj, Elisa Merlini, Adolfo Amici, Zhenyao Luo, Lauren Hartley-Tassell, Thomas Ve, Laura M Desrochers, Qi Wang, Bostjan Kobe, Giuseppe Orsomando, Michael P Coleman.
      Axon loss underlies symptom onset and progression in many neurodegenerative disorders. Axon degeneration in injury and disease is promoted by activation of the nicotinamide adenine dinucleotide (NAD)-consuming enzyme SARM1. Here, we report a novel activator of SARM1, a metabolite of the pesticide and neurotoxin vacor. Removal of SARM1 completely rescues mouse neurons from vacor-induced neuron and axon death in vitro and in vivo. We present the crystal structure the Drosophila SARM1 regulatory domain complexed with this activator, the vacor metabolite VMN, which as the most potent activator yet know is likely to support drug development for human SARM1 and NMNAT2 disorders. This study indicates the mechanism of neurotoxicity and pesticide action by vacor, raises important questions about other pyridines in wider use today, provides important new tools for drug discovery, and demonstrates that removing SARM1 can robustly block programmed axon death induced by toxicity as well as genetic mutation.
    Keywords:  biochemistry; chemical biology; mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.72823
  31. 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
  32. EMBO J. 2021 Dec 07. e106837
    Molecular species selectivity of lipid transport creates a mitochondrial sink for di-unsaturated phospholipids.
    Mike F Renne, Xue Bao, Margriet Wj Hokken, Adolf S Bierhuizen, Martin Hermansson, Richard R Sprenger, Tom A Ewing, Xiao Ma, Ruud C Cox, Jos F Brouwers, Cedric H De Smet, Christer S Ejsing, Anton Ipm de Kroon.
      Mitochondria depend on the import of phospholipid precursors for the biosynthesis of phosphatidylethanolamine (PE) and cardiolipin, yet the mechanism of their transport remains elusive. A dynamic lipidomics approach revealed that mitochondria preferentially import di-unsaturated phosphatidylserine (PS) for subsequent conversion to PE by the mitochondrial PS decarboxylase Psd1p. Several protein complexes tethering mitochondria to the endomembrane system have been implicated in lipid transport in yeast, including the endoplasmic reticulum (ER)-mitochondrial encounter structure (ERMES), ER-membrane complex (EMC), and the vacuole and mitochondria patch (vCLAMP). By limiting the availability of unsaturated phospholipids, we created conditions to investigate the mechanism of lipid transfer and the contributions of the tethering complexes in vivo. Under these conditions, inactivation of ERMES components or of the vCLAMP component Vps39p exacerbated accumulation of saturated lipid acyl chains, indicating that ERMES and Vps39p contribute to the mitochondrial sink for unsaturated acyl chains by mediating transfer of di-unsaturated phospholipids. These results support the concept that intermembrane lipid flow is rate-limited by molecular species-dependent lipid efflux from the donor membrane and driven by the lipid species' concentration gradient between donor and acceptor membrane.
    Keywords:  lipid transport; membrane contact sites; membrane lipid homeostasis; membrane lipid unsaturation; mitochondria
    DOI:  https://doi.org/10.15252/embj.2020106837
  33. 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
  34. Elife. 2021 Dec 08. pii: e71185. [Epub ahead of print]10
    Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates development and early survival of retinal neurons.
    David Sokolov, Emily R Sechrest, Yekai Wang, Connor Nevin, Jianhai Du, Saravanan Kolandaivelu.
      Despite mounting evidence that the mammalian retina is exceptionally reliant on proper NAD+ homeostasis for health and function, the specific roles of subcellular NAD+ pools in retinal development, maintenance, and disease remain obscure. Here, we show that deletion of the nuclear-localized NAD+ synthase nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1) in the developing murine retina causes early and severe degeneration of photoreceptors and select inner retinal neurons via multiple distinct cell death pathways. This severe phenotype is associated with disruptions to retinal central carbon metabolism, purine nucleotide synthesis, and amino acid pathways. Furthermore, transcriptomic and immunostaining approaches reveal dysregulation of a collection of photoreceptor and synapse-specific genes in NMNAT1 knockout retinas prior to detectable morphological or metabolic alterations. Collectively, our study reveals previously unrecognized complexity in NMNAT1-associated retinal degeneration and suggests a yet-undescribed role for NMNAT1 in gene regulation during photoreceptor terminal differentiation.
    Keywords:  developmental biology; mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.71185
  35. 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
  36. 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
  37. Methods Mol Biol. 2022 ;2416 181-200
    Chromatin Profiling of Human Naïve Pluripotent Stem Cells.
    Adam Bendall, Claudia I Semprich.
      Chromatin immunoprecipitation combined with high-throughput sequencing (ChIP-sequencing) facilitates the genome-wide mapping of DNA sequences that are enriched for specific chromatin-binding proteins or histone post-translational modifications. More recently developed chromatin profiling methods called Cleavage Under Targets and Release Using Nuclease (CUT&RUN) and Cleavage Under Targets and Tagmentation (CUT&Tag) have adapted the ChIP-sequencing approach to produce similar data from a smaller amount of starting material, and while overcoming many of the conventional drawbacks of ChIP-sequencing. Here, we present detailed protocols for ChIP-seq, CUT&RUN, and CUT&Tag to profile genome-wide protein-DNA interactions in naïve human pluripotent stem cells.
    Keywords:  CUT&RUN; CUT&Tag; ChIP-seq; Chromatin immunoprecipitation
    DOI:  https://doi.org/10.1007/978-1-0716-1908-7_12
  38. Per Med. 2021 Dec 07.
    Somatic mitochondrial DNA mutations in different grades of glioma.
    Bee Hong Soon, Nadiah Abu, Nor Azian Abdul Murad, Sue-Mian Then, Azizi Abu Bakar, Farizal Fadzil, Jegan Thanabalan, Mohd Saffari Mohd Haspani, Charng Jeng Toh, Ramesh Kumar, Ainul Syahrilfazli Jaafar, Anis Nabillah Mohd Azli, Mohd Syakir Mohd Azahar, Sanmugarajah Paramasvaran, Kamalanathan Palaniandy, Azmi Mohd Tamil, Rahman Jamal.
      Aim: Mitochondrial DNA (mtDNA) alterations play an important role in the multistep processes of cancer development. Gliomas are among the most diagnosed brain cancer. The relationship between mtDNA alterations and different grades of gliomas are still elusive. This study aimed to elucidate the profile of somatic mtDNA mutations in different grades of gliomas and correlate it with clinical phenotype. Materials & methods: Forty histopathologically confirmed glioma tissue samples and their matched blood were collected and subjected for mtDNA sequencing. Results & conclusion: About 75% of the gliomas harbored at least one somatic mutation in the mtDNA gene, and 45% of these mutations were pathogenic. Mutations were scattered across the mtDNA genome, and the commonest nonsynonymous mutations were located at complex I and IV of the mitochondrial respiratory chain. These findings may have implication for future research to determine the mitochondrial energetics and its downstream metabolomics on gliomas.
    Keywords:  Malaysia; cancer; genome; glioblastoma; gliomas; microarray; mitochondria; mtDNA; mutation; somatic mutation
    DOI:  https://doi.org/10.2217/pme-2021-0033
  39. 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
  40. Nucleic Acids Res. 2021 Dec 06. pii: gkab1148. [Epub ahead of print]
    Position 34 of tRNA is a discriminative element for m5C38 modification by human DNMT2.
    Zhi-Xuan Huang, Jing Li, Qing-Ping Xiong, Hao Li, En-Duo Wang, Ru-Juan Liu.
      Dnmt2, a member of the DNA methyltransferase superfamily, catalyzes the formation of 5-methylcytosine at position 38 in the anticodon loop of tRNAs. Dnmt2 regulates many cellular biological processes, especially the production of tRNA-derived fragments and intergenerational transmission of paternal metabolic disorders to offspring. Moreover, Dnmt2 is closely related to human cancers. The tRNA substrates of mammalian Dnmt2s are mainly detected using bisulfite sequencing; however, we lack supporting biochemical data concerning their substrate specificity or recognition mechanism. Here, we deciphered the tRNA substrates of human DNMT2 (hDNMT2) as tRNAAsp(GUC), tRNAGly(GCC) and tRNAVal(AAC). Intriguingly, for tRNAAsp(GUC) and tRNAGly(GCC), G34 is the discriminator element; whereas for tRNAVal(AAC), the inosine modification at position 34 (I34), which is formed by the ADAT2/3 complex, is the prerequisite for hDNMT2 recognition. We showed that the C32U33(G/I)34N35 (C/U)36A37C38 motif in the anticodon loop, U11:A24 in the D stem, and the correct size of the variable loop are required for Dnmt2 recognition of substrate tRNAs. Furthermore, mammalian Dnmt2s possess a conserved tRNA recognition mechanism.
    DOI:  https://doi.org/10.1093/nar/gkab1148
  41. Mol Med Rep. 2022 Feb;pii: 47. [Epub ahead of print]25(2):
    Analysis of a family with mitochondrial trifunctional protein deficiency caused by HADHA gene mutations.
    Jinling Yang, Dejian Yuan, Xiaohui Tan, Yexi Zeng, Ning Tang, Dayu Chen, Jianqiang Tan, Ren Cai, Jun Huang, Tizhen Yan.
      Mitochondrial trifunctional protein (MTP) deficiency (MTPD; MIM 609015) is a metabolic disease of fatty acid oxidation. MTPD is an autosomal recessive disorder caused by mutations in the HADHA gene, encoding the α‑subunit of a trifunctional protease, or in the HADHB gene, encoding the β‑subunit of a trifunctional protease. To the best of our knowledge, only two cases of families with MTPD due to HADHB gene mutations have been reported in China, and the HADHA gene mutation has not been reported in a Chinese family with MTPD. The present study reported the clinical characteristics and compound heterozygous HADHA gene mutations of two patients with MTPD in the Chinese population. The medical history, routine examination data, blood acyl‑carnitine analysis results, results of pathological examination after autopsy and family pedigree map were collected for patients with MTPD. The HADHA gene was analyzed by Sanger sequencing or high‑throughput sequencing, the pathogenicity of the newly discovered variant was interpreted by bioinformatics analysis, and the function of the mutated protein was modeled and analyzed according to 3D structure. The two patients with MTPD experienced metabolic crises and died following an infectious disease. Lactate dehydrogenase, creatine kinase (CK), CK‑MB and liver enzyme abnormalities were observed in routine examinations. Tandem mass spectrometry revealed that long‑chain acyl‑carnitine was markedly elevated in blood samples from the patients with MTPD. The autopsy results for one child revealed fat accumulation in the liver and heart. Next‑generation sequencing detected compound heterozygous c.703C>T (p.R235W) and c.2107G>A (p.G703R) mutations in the HADHA gene. The mother did not have acute fatty liver during pregnancy with the two patients. Using amniotic fluid prenatal diagnostic testing, the unborn child was confirmed to carry only c.2107G>A (p.G703R). Molecular mechanistic analysis indicated that the two variants affected the conformation of the α‑subunit of the MTP enzyme complex, and consequently affected the stability and function of the enzyme complex. The present study comprehensively analyzed the cases, including exome sequencing and protein structure analysis and, to the best of our knowledge, describes the first observation of compound heterozygous mutations in the HADHA gene underlying this disorder in China. The clinical phenotypes of the two heterozygous variants of the HADHA gene are non‑lethal. The present study may improve understanding of the HADHA gene mutation spectrum and clinical phenotype in the Chinese population.
    Keywords:  HADHA; metabolic crisis; mitochondrial trifunctional protein deficiency; structural analysis
    DOI:  https://doi.org/10.3892/mmr.2021.12563
  42. Sci Adv. 2021 Dec 10. 7(50): eabl4024
    Mitochondrial uncoupling protein 1 antagonizes atherosclerosis by blocking NLRP3 inflammasome-dependent interleukin-1β production.
    Ping Gu, Xiaoyan Hui, Qiantao Zheng, Yuan Gao, Leigang Jin, Weimin Jiang, Changsheng Zhou, Tianxia Liu, Yu Huang, Qing Liu, Tao Nie, Yanfang Wang, Yu Wang, Jianguo Zhao, Aimin Xu.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abl4024
  43. J Inherit Metab Dis. 2021 Dec 06.
    Novel imaging findings in pyruvate dehydrogenase complex (PDHc) deficiency- results from a nation-wide population-based study.
    Antri Savvidou, Liz Ivarsson, Karin Naess, Erik A Eklund, Johan Lundgren, Maria Dahlin, Deborah Frithiof, Kalliopi Sofou, Niklas Darin.
       BACKGROUND AND OBJECTIVES: The vast clinical and radiological spectrum of pyruvate dehydrogenase complex (PDHc) deficiency continue to pose challenges both in diagnostics and disease monitoring. Prompt diagnosis is important to enable early initiation of ketogenic diet.
    METHODS: The patients were recruited from an ongoing population-based study in Sweden. All patients with a genetically confirmed diagnosis that had been investigated with an MRI of the brain were included. Repeated investigations were assessed to study the evolution of the MRI changes.
    RESULTS: Sixty-two MRI investigations had been performed in 34 patients (23 females). The genetic cause were mutations in PDHA1 in 29, PDHX and DLAT in two each and PDHB in one. The lesions were prenatal developmental in 16, prenatal clastic in 18 and postnatal clastic in 15 individuals. Leigh-like lesions with predominant involvement of globus pallidus were present in 12, while leukoencephalopathy was present in six and stroke-like lesions in three individuals. A combination of prenatal developmental and clastic lesions was present in 15 individuals. In addition, one male with PDHA1 also had postnatal clastic lesions.
    DISCUSSION: The most common lesions found in our study were agenesis or hypoplasia of corpus callosum, ventriculomegaly or Leigh-like lesions. Furthermore, we describe a broad spectrum of other MRI changes that include leukoencephalopathy and stroke-like lesions. We argue that a novel important clue, suggesting the possibility of PDHc deficiency on MRI scans, is the simultaneous presence of multiple lesions on MRI that have occurred during different phases of brain development. This article is protected by copyright. All rights reserved.
    Keywords:  Leigh-like lesions; leukoencephalopathy; magnetic resonance imaging; pyruvate dehydrogenase complex deficiency; stroke-like lesions
    DOI:  https://doi.org/10.1002/jimd.12463
  44. Nat Commun. 2021 Dec 06. 12(1): 7058
    A genetically encoded fluorescent biosensor for extracellular L-lactate.
    Yusuke Nasu, Ciaran Murphy-Royal, Yurong Wen, Jordan N Haidey, Rosana S Molina, Abhi Aggarwal, Shuce Zhang, Yuki Kamijo, Marie-Eve Paquet, Kaspar Podgorski, Mikhail Drobizhev, Jaideep S Bains, M Joanne Lemieux, Grant R Gordon, Robert E Campbell.
      L-Lactate, traditionally considered a metabolic waste product, is increasingly recognized as an important intercellular energy currency in mammals. To enable investigations of the emerging roles of intercellular shuttling of L-lactate, we now report an intensiometric green fluorescent genetically encoded biosensor for extracellular L-lactate. This biosensor, designated eLACCO1.1, enables cellular resolution imaging of extracellular L-lactate in cultured mammalian cells and brain tissue.
    DOI:  https://doi.org/10.1038/s41467-021-27332-2
  45. Parkinsonism Relat Disord. 2021 Dec 01. pii: S1353-8020(21)00438-7. [Epub ahead of print]94 37-39
    VPS13C-associated Parkinson's disease: Two novel cases and review of the literature.
    Edoardo Monfrini, Francesca Spagnolo, Margherita Canesi, Agostino Seresini, Bruno Passarella, Marco Percetti, Manuela Seia, Stefano Goldwurm, Viviana Cereda, Giacomo P Comi, Gianni Pezzoli, Alessio Di Fonzo.
      VPS13C is a protein-coding gene involved in the regulation of mitochondrial function through the endolysosomal pathway in neurons. Homozygous and compound heterozygous VPS13C mutations are etiologically associated with early-onset Parkinson's disease (PD). Moreover, recent studies linked biallelic VPS13C mutations with the development of dementia with Lewy bodies (DLB). Neuropathological studies on two mutated subjects showed diffuse Lewy body disease. In this article, we report the clinical and genetic findings of two subjects affected by early-onset PD carrying three novel VPS13C mutations (i.e., one homozygous and one compound heterozygous), and review the previous literature on the genetic and clinical findings of VPS13C-mutated patients, contributing to the knowledge of this rare genetic alpha-synucleinopathy.
    Keywords:  Dementia with lewy bodies; Genetics; Parkinson's disease; Review; VPS13C
    DOI:  https://doi.org/10.1016/j.parkreldis.2021.11.031
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