bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒10‒09
nineteen papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico
  1. Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes.
  2. Two independent respiratory chains adapt OXPHOS performance to glycolytic switch.
  3. miR-181a/b downregulation: a mutation-independent therapeutic approach for inherited retinal diseases.
  4. Mitochondrial dynamics maintain muscle stem cell regenerative competence throughout adult life by regulating metabolism and mitophagy.
  5. Pathogenic mtDNA variants, in particular single large-scale mtDNA deletions, are strongly associated with post-lingual onset sensorineural hearing loss in primary mitochondrial disease.
  6. Cell-Free Mitochondrial DNA in Acute Brain Injury.
  7. Independent regulation of mitochondrial DNA quantity and quality in Caenorhabditis elegans primordial germ cells.
  8. Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer's disease.
  9. Microfluidic devices as model platforms of CNS injury-ischemia to study axonal regeneration by regulating mitochondrial transport and bioenergetic metabolism.
  10. A method for multiplexed full-length single-molecule sequencing of the human mitochondrial genome.
  11. Thermosensation in Caenorhabditis elegans is linked to ubiquitin-dependent protein turnover via insulin and calcineurin signalling.
  12. Miro1 regulates mitochondrial homeostasis and meiotic resumption of mouse oocyte.
  13. DNA methylation and cell fate in mouse embryos.
  14. Evaluating mitophagy in embryonic stem cells by using fluorescence-based imaging.
  15. Resveratrol: A potential therapeutic natural polyphenol for neurodegenerative diseases associated with mitochondrial dysfunction.
  16. Preparation of mitochondrial damage-associated molecular patterns from mouse liver tissue.
  17. AMPK-induced mitochondrial biogenesis decelerates retinal pigment epithelial cell degeneration under nutrient starvation.
  18. ACTB gene mutation in combined Dystonia-Deafness syndrome with parkinsonism: Expanding the phenotype and highlighting the long-term GPi DBS outcome.
  19. The genetic and molecular features of the intronic pentanucleotide repeat expansion in spinocerebellar ataxia type 10.
  1. Nature. 2022 Oct 05.
    Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes.
    Wei Wei, Katherine R Schon, Greg Elgar, Andrea Orioli, Melanie Tanguy, Adam Giess, Marc Tischkowitz, Mark J Caulfield, Patrick F Chinnery.
      DNA transfer from cytoplasmic organelles to the cell nucleus is a legacy of the endosymbiotic event-the majority of nuclear-mitochondrial segments (NUMTs) are thought to be ancient, preceding human speciation1-3. Here we analyse whole-genome sequences from 66,083 people-including 12,509 people with cancer-and demonstrate the ongoing transfer of mitochondrial DNA into the nucleus, contributing to a complex NUMT landscape. More than 99% of individuals had at least one of 1,637 different NUMTs, with 1 in 8 individuals having an ultra-rare NUMT that is present in less than 0.1% of the population. More than 90% of the extant NUMTs that we evaluated inserted into the nuclear genome after humans diverged from apes. Once embedded, the sequences were no longer under the evolutionary constraint seen within the mitochondrion, and NUMT-specific mutations had a different mutational signature to mitochondrial DNA. De novo NUMTs were observed in the germline once in every 104 births and once in every 103 cancers. NUMTs preferentially involved non-coding mitochondrial DNA, linking transcription and replication to their origin, with nuclear insertion involving multiple mechanisms including double-strand break repair associated with PR domain zinc-finger protein 9 (PRDM9) binding. The frequency of tumour-specific NUMTs differed between cancers, including a probably causal insertion in a myxoid liposarcoma. We found evidence of selection against NUMTs on the basis of size and genomic location, shaping a highly heterogenous and dynamic human NUMT landscape.
    DOI:  https://doi.org/10.1038/s41586-022-05288-7
  2. Cell Metab. 2022 Sep 28. pii: S1550-4131(22)00395-3. [Epub ahead of print]
    Two independent respiratory chains adapt OXPHOS performance to glycolytic switch.
    Erika Fernández-Vizarra, Sandra López-Calcerrada, Ana Sierra-Magro, Rafael Pérez-Pérez, Luke E Formosa, Daniella H Hock, María Illescas, Ana Peñas, Michele Brischigliaro, Shujing Ding, Ian M Fearnley, Charalampos Tzoulis, Robert D S Pitceathly, Joaquín Arenas, Miguel A Martín, David A Stroud, Massimo Zeviani, Michael T Ryan, Cristina Ugalde.
      The structural and functional organization of the mitochondrial respiratory chain (MRC) remains intensely debated. Here, we show the co-existence of two separate MRC organizations in human cells and postmitotic tissues, C-MRC and S-MRC, defined by the preferential expression of three COX7A subunit isoforms, COX7A1/2 and SCAFI (COX7A2L). COX7A isoforms promote the functional reorganization of distinct co-existing MRC structures to prevent metabolic exhaustion and MRC deficiency. Notably, prevalence of each MRC organization is reversibly regulated by the activation state of the pyruvate dehydrogenase complex (PDC). Under oxidative conditions, the C-MRC is bioenergetically more efficient, whereas the S-MRC preferentially maintains oxidative phosphorylation (OXPHOS) upon metabolic rewiring toward glycolysis. We show a link between the metabolic signatures converging at the PDC and the structural and functional organization of the MRC, challenging the widespread notion of the MRC as a single functional unit and concluding that its structural heterogeneity warrants optimal adaptation to metabolic function.
    Keywords:  COX7A1–2; SCAFI/COX7RP/COX7A2L; bioenergetics; glycolysis; metabolic switch; mitochondria; oxidative metabolism; pyruvate dehydrogenase; respiratory chain organizations; respiratory supercomplexes
    DOI:  https://doi.org/10.1016/j.cmet.2022.09.005
  3. EMBO Mol Med. 2022 Oct 04. e15941
    miR-181a/b downregulation: a mutation-independent therapeutic approach for inherited retinal diseases.
    Sabrina Carrella, Martina Di Guida, Simona Brillante, Davide Piccolo, Ludovica Ciampi, Irene Guadagnino, Jorge Garcia Piqueras, Mariateresa Pizzo, Elena Marrocco, Marta Molinari, Georgios Petrogiannakis, Sara Barbato, Yulia Ezhova, Alberto Auricchio, Brunella Franco, Elvira De Leonibus, Enrico Maria Surace, Alessia Indrieri, Sandro Banfi.
      Inherited retinal diseases (IRDs) are a group of diseases whose common landmark is progressive photoreceptor loss. The development of gene-specific therapies for IRDs is hampered by their wide genetic heterogeneity. Mitochondrial dysfunction is proving to constitute one of the key pathogenic events in IRDs; hence, approaches that enhance mitochondrial activities have a promising therapeutic potential for these conditions. We previously reported that miR-181a/b downregulation boosts mitochondrial turnover in models of primary retinal mitochondrial diseases. Here, we show that miR-181a/b silencing has a beneficial effect also in IRDs. In particular, the injection in the subretinal space of an adeno-associated viral vector (AAV) that harbors a miR-181a/b inhibitor (sponge) sequence (AAV2/8-GFP-Sponge-miR-181a/b) improves retinal morphology and visual function both in models of autosomal dominant (RHO-P347S) and of autosomal recessive (rd10) retinitis pigmentosa. Moreover, we demonstrate that miR-181a/b downregulation modulates the level of the mitochondrial fission-related protein Drp1 and rescues the mitochondrial fragmentation in RHO-P347S photoreceptors. Overall, these data support the potential use of miR-181a/b downregulation as an innovative mutation-independent therapeutic strategy for IRDs, which can be effective both to delay disease progression and to aid gene-specific therapeutic approaches.
    Keywords:  inherited retinal diseases; miR-181; mitochondria; photoreceptor; therapy
    DOI:  https://doi.org/10.15252/emmm.202215941
  4. Cell Stem Cell. 2022 Oct 06. pii: S1934-5909(22)00379-4. [Epub ahead of print]29(10): 1506-1508
    Mitochondrial dynamics maintain muscle stem cell regenerative competence throughout adult life by regulating metabolism and mitophagy.
    Xiaotong Hong, Joan Isern, Silvia Campanario, Eusebio Perdiguero, Ignacio Ramírez-Pardo, Jessica Segalés, Pablo Hernansanz-Agustín, Andrea Curtabbi, Oleg Deryagin, Angela Pollán, José A González-Reyes, José M Villalba, Marco Sandri, Antonio L Serrano, José A Enríquez, Pura Muñoz-Cánoves.
      
    DOI:  https://doi.org/10.1016/j.stem.2022.09.002
  5. Mol Genet Metab. 2022 Sep 19. pii: S1096-7192(22)00398-5. [Epub ahead of print]137(3): 230-238
    Pathogenic mtDNA variants, in particular single large-scale mtDNA deletions, are strongly associated with post-lingual onset sensorineural hearing loss in primary mitochondrial disease.
    Johanna Elander, Elizabeth M McCormick, Maria Värendh, Karin Stenfeldt, Rebecca D Ganetzky, Amy Goldstein, Zarazuela Zolkipli-Cunningham, Laura E MacMullen, Rui Xiao, Marni J Falk, Johannes K Ehinger.
      In this retrospective cohort study of 193 consecutive subjects with primary mitochondrial disease (PMD) seen at the Children's Hospital of Philadelphia Mitochondrial Medicine Frontier Program, we assessed prevalence, severity, and time of onset of sensorineural hearing loss (SNHL) for PMD cases with different genetic etiologies. Subjects were grouped by genetic diagnosis: mitochondrial DNA (mtDNA) pathogenic variants, single large-scale mtDNA deletions (SLSMD), or nuclear DNA (nDNA) pathogenic variants. SNHL was audiometrically confirmed in 27% of PMD subjects (20% in mtDNA pathogenic variants, 58% in SLSMD and 25% in nDNA pathogenic variants). SLSMD had the highest odds ratio for SNHL. SNHL onset was post-lingual in 79% of PMD cases, interestingly including all cases with mtDNA pathogenic variants and SLSMD, which was significantly different from PMD cases caused by nDNA pathogenic variants. SNHL onset during school age was predominant in this patient population. Regular audiologic assessment is important for PMD patients, and PMD of mtDNA etiology should be considered as a differential diagnosis in pediatric patients and young adults with post-lingual SNHL onset, particularly in the setting of multi-system clinical involvement. Pathogenic mtDNA variants and SLSMD are less likely etiologies in subjects with congenital, pre-lingual onset SNHL.
    Keywords:  Audiology; Mitochondria; Mitochondrial DNA; Mitochondrial disease; Primary mitochondrial disease; Sensorineural hearing loss
    DOI:  https://doi.org/10.1016/j.ymgme.2022.09.002
  6. Neurotrauma Rep. 2022 ;3(1): 415-420
    Cell-Free Mitochondrial DNA in Acute Brain Injury.
    Saeed Kayhanian, Angelos Glynos, Richard Mair, Andras Lakatos, Peter J A Hutchinson, Adel E Helmy, Patrick F Chinnery.
      Traumatic brain injury and aneurysmal subarachnoid haemorrhage are a major cause of morbidity and mortality worldwide. Treatment options remain limited and are hampered by our understanding of the cellular and molecular mechanisms, including the inflammatory response observed in the brain. Mitochondrial DNA (mtDNA) has been shown to activate an innate inflammatory response by acting as a damage-associated molecular pattern (DAMP). Here, we show raised circulating cell-free (ccf) mtDNA levels in both cerebrospinal fluid (CSF) and serum within 48 h of brain injury. CSF ccf-mtDNA levels correlated with clinical severity and the interleukin-6 cytokine response. These findings support the use of ccf-mtDNA as a biomarker after acute brain injury linked to the inflammatory disease mechanism.
    Keywords:  DAMP; acute brain injury; brain inflammation; mitochondrial DNA; subarachnoid hemorrhage; traumatic brain injury
    DOI:  https://doi.org/10.1089/neur.2022.0032
  7. Elife. 2022 Oct 06. pii: e80396. [Epub ahead of print]11
    Independent regulation of mitochondrial DNA quantity and quality in Caenorhabditis elegans primordial germ cells.
    Aaron Z A Schwartz, Nikita Tsyba, Yusuff Abdu, Maulik R Patel, Jeremy Nance.
      Mitochondria harbor an independent genome, called mitochondrial DNA (mtDNA), which contains essential metabolic genes. Although mtDNA mutations occur at high frequency, they are inherited infrequently, indicating that germline mechanisms limit their accumulation. To determine how germline mtDNA is regulated, we examined the control of mtDNA quantity and quality in C. elegans primordial germ cells (PGCs). We show that PGCs combine strategies to generate a low point in mtDNA number by segregating mitochondria into lobe-like protrusions that are cannibalized by adjacent cells, and by concurrently eliminating mitochondria through autophagy, reducing overall mtDNA content twofold. As PGCs exit quiescence and divide, mtDNAs replicate to maintain a set point of ~200 mtDNAs per germline stem cell. Whereas cannibalism and autophagy eliminate mtDNAs stochastically, we show that the kinase PTEN-induced kinase 1 (PINK1), operating independently of Parkin and autophagy, preferentially reduces the fraction of mutant mtDNAs. Thus, PGCs employ parallel mechanisms to control both the quantity and quality of the founding population of germline mtDNAs.
    Keywords:  C. elegans; PINK1; autophagy; bottleneck; cell biology; developmental biology; mitochondrial DNA; primordial germ cells; purifying selection
    DOI:  https://doi.org/10.7554/eLife.80396
  8. J Neuroinflammation. 2022 Oct 06. 19(1): 248
    Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer's disease.
    Yun Li, Xiaohuan Xia, Yi Wang, Jialin C Zheng.
      Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly globally. Emerging evidence has demonstrated microglia-driven neuroinflammation as a key contributor to the onset and progression of AD, however, the mechanisms that mediate neuroinflammation remain largely unknown. Recent studies have suggested mitochondrial dysfunction including mitochondrial DNA (mtDNA) damage, metabolic defects, and quality control (QC) disorders precedes microglial activation and subsequent neuroinflammation. Therefore, an in-depth understanding of the relationship between mitochondrial dysfunction and microglial activation in AD is important to unveil the pathogenesis of AD and develop effective approaches for early AD diagnosis and treatment. In this review, we summarized current progress in the roles of mtDNA, mitochondrial metabolism, mitochondrial QC changes in microglial activation in AD, and provide comprehensive thoughts for targeting microglial mitochondria as potential therapeutic strategies of AD.
    Keywords:  Alzheimer’s disease; Metabolism; Microglia; Mitochondria; mtDNA
    DOI:  https://doi.org/10.1186/s12974-022-02613-9
  9. Cell Regen. 2022 Oct 03. 11(1): 33
    Microfluidic devices as model platforms of CNS injury-ischemia to study axonal regeneration by regulating mitochondrial transport and bioenergetic metabolism.
    Ning Huang, Zu-Hang Sheng.
      Central nervous system (CNS) neurons typically fail to regenerate their axons after injury leading to neurological impairment. Axonal regeneration is a highly energy-demanding cellular program that requires local mitochondria to supply most energy within injured axons. Recent emerging lines of evidence have started to reveal that injury-triggered acute mitochondrial damage and local energy crisis contribute to the intrinsic energetic restriction that accounts for axon regeneration failure in the CNS. Characterizing and reprogramming bioenergetic signaling and mitochondrial maintenance after axon injury-ischemia is fundamental for developing therapeutic strategies that can restore local energy metabolism and thus facilitate axon regeneration. Therefore, establishing reliable and reproducible neuronal model platforms is critical for assessing axonal energetic metabolism and regeneration capacity after injury-ischemia. In this focused methodology article, we discuss recent advances in applying cutting-edge microfluidic chamber devices in combination with state-of-the-art live-neuron imaging tools to monitor axonal regeneration, mitochondrial transport, bioenergetic metabolism, and local protein synthesis in response to injury-ischemic stress in mature CNS neurons.
    Keywords:  Axon injury; Axon regeneration; Axonal bioenergetics; Axonal protein synthesis; Ischemia; Microfluidic device; Mitochondrial transport
    DOI:  https://doi.org/10.1186/s13619-022-00138-3
  10. Nat Commun. 2022 Oct 06. 13(1): 5902
    A method for multiplexed full-length single-molecule sequencing of the human mitochondrial genome.
    Ieva Keraite, Philipp Becker, Davide Canevazzi, Cristina Frias-López, Marc Dabad, Raúl Tonda-Hernandez, Ida Paramonov, Matthew John Ingham, Isabelle Brun-Heath, Jordi Leno, Anna Abulí, Elena Garcia-Arumí, Simon Charles Heath, Marta Gut, Ivo Glynne Gut.
      Methods to reconstruct the mitochondrial DNA (mtDNA) sequence using short-read sequencing come with an inherent bias due to amplification and mapping. They can fail to determine the phase of variants, to capture multiple deletions and to cover the mitochondrial genome evenly. Here we describe a method to target, multiplex and sequence at high coverage full-length human mitochondrial genomes as native single-molecules, utilizing the RNA-guided DNA endonuclease Cas9. Combining Cas9 induced breaks, that define the mtDNA beginning and end of the sequencing reads, as barcodes, we achieve high demultiplexing specificity and delineation of the full-length of the mtDNA, regardless of the structural variant pattern. The long-read sequencing data is analysed with a pipeline where our custom-developed software, baldur, efficiently detects single nucleotide heteroplasmy to below 1%, physically determines phase and can accurately disentangle complex deletions. Our workflow is a tool for studying mtDNA variation and will accelerate mitochondrial research.
    DOI:  https://doi.org/10.1038/s41467-022-33530-3
  11. Nat Commun. 2022 Oct 05. 13(1): 5874
    Thermosensation in Caenorhabditis elegans is linked to ubiquitin-dependent protein turnover via insulin and calcineurin signalling.
    Alexandra Segref, Kavya L Vakkayil, Tsimafei Padvitski, Qiaochu Li, Virginia Kroef, Jakob Lormann, Lioba Körner, Fabian Finger, Thorsten Hoppe.
      Organismal physiology and survival are influenced by environmental conditions and linked to protein quality control. Proteome integrity is achieved by maintaining an intricate balance between protein folding and degradation. In Caenorhabditis elegans, acute heat stress determines cell non-autonomous regulation of chaperone levels. However, how the perception of environmental changes, including physiological temperature, affects protein degradation remains largely unexplored. Here, we show that loss-of-function of dyf-1 in Caenorhabditis elegans associated with dysfunctional sensory neurons leads to defects in both temperature perception and thermal adaptation of the ubiquitin/proteasome system centered on thermosensory AFD neurons. Impaired perception of moderate temperature changes worsens ubiquitin-dependent proteolysis in intestinal cells. Brain-gut communication regulating protein turnover is mediated by upregulation of the insulin-like peptide INS-5 and inhibition of the calcineurin-regulated forkhead-box transcription factor DAF-16/FOXO. Our data indicate that perception of ambient temperature and its neuronal integration is important for the control of proteome integrity in complex organisms.
    DOI:  https://doi.org/10.1038/s41467-022-33467-7
  12. J Cell Physiol. 2022 Oct 02.
    Miro1 regulates mitochondrial homeostasis and meiotic resumption of mouse oocyte.
    Yue Xue, Tie-Gang Meng, Ying-Chun Ouyang, Sai-Li Liu, Jia-Ni Guo, Zhen-Bo Wang, Heide Schatten, Chun-Ying Song, Xing-Ping Guo, Qing-Yuan Sun.
      Miro1, a mitochondrial Rho GTPase1, is a kind of mitochondrial outer membrane protein involved in the regulation of mitochondrial anterograde transport and its subcellular distribution. Mitochondria influence reproductive processes of mammals in some aspects. Mitochondria are important for oocyte maturation, fertilization and embryonic development. The purpose of this study was to evaluate whether Miro1 regulates mouse oocyte maturation by altering mitochondrial homeostasis. We showed that Miro1 was expressed in mouse oocyte at different maturation stages. Miro1 mainly distributed in the cytoplasm and around the spindle during oocyte maturation. Small interference RNA-mediated Miro1 depletion caused significantly abnormal distribution of mitochondria and endoplasmic reticulum as well as mitochondrial dysfunction, resulting in severely impaired germinal vesicle breakdown (GVBD) of mouse oocytes. For those oocytes which went through GVBD in the Miro1-depleted group, part of them were inhibited in meiotic prophase I stage with abnormal chromosome arrangement and scattered spindle length. Our results suggest that Miro1 is essential for maintaining the maturation potential of mouse oocyte.
    Keywords:  Miro1; Mitochondria; meiosis; oocyte
    DOI:  https://doi.org/10.1002/jcp.30890
  13. Nat Rev Genet. 2022 Oct 07.
    DNA methylation and cell fate in mouse embryos.
    Dorothy Clyde.
      
    DOI:  https://doi.org/10.1038/s41576-022-00542-0
  14. Front Cell Dev Biol. 2022 ;10 910464
    Evaluating mitophagy in embryonic stem cells by using fluorescence-based imaging.
    Kun Liu, Xing Li, Zheng Li, Jiani Cao, Xiaoyan Li, Youqing Xu, Lei Liu, Tongbiao Zhao.
      Embryonic stem cells (ESCs), which are characterized by the capacity for self-renewal and pluripotency, hold great promise for regenerative medicine. Increasing evidence points to the essential role of mitophagy in pluripotency regulation. Our recent work showed that PINK1/OPTN take part in guarding ESC mitochondrial homeostasis and pluripotency. Evaluating mitophagy in ESCs is important for exploring the relationships between mitochondrial homeostasis and pluripotency. ESCs are smaller in size than adult somatic cells and the mitophagosomes in ESCs are difficult to observe. Many methods have been employed-for example, detecting colocalization of LC3-II and mitochondria-to evaluate mitophagy in ESCs. However, it is important to define an objective way to detect mitophagy in ESCs. Here, we evaluated two commonly used fluorescence-based imaging methods to detect mitophagy in ESCs. By using autophagy- or mitophagy-defective ESC lines, we showed that the mito-Keima (mt-Keima) system is a suitable and effective way for detecting and quantifying mitophagy in ESCs. Our study provides evidence that mt-Keima is an effective tool to study mitophagy function in ESCs.
    Keywords:  ATG3; LC3; PINK1; mitophagy; mt-keima
    DOI:  https://doi.org/10.3389/fcell.2022.910464
  15. Front Pharmacol. 2022 ;13 922232
    Resveratrol: A potential therapeutic natural polyphenol for neurodegenerative diseases associated with mitochondrial dysfunction.
    Ekta Yadav, Pankajkumar Yadav, Mohd Masih Uzzaman Khan, HariOm Singh, Amita Verma.
      Most polyphenols can cross blood-brain barrier, therefore, they are widely utilized in the treatment of various neurodegenerative diseases (ND). Resveratrol, a natural polyphenol contained in blueberry, grapes, mulberry, etc., is well documented to exhibit potent neuroprotective activity against different ND by mitochondria modulation approach. Mitochondrial function impairment is the most common etiology and pathological process in various neurodegenerative disorders, viz. Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Nowadays these ND associated with mitochondrial dysfunction have become a major threat to public health as well as health care systems in terms of financial burden. Currently available therapies for ND are limited to symptomatic cures and have inevitable toxic effects. Therefore, there is a strict requirement for a safe and highly effective drug treatment developed from natural compounds. The current review provides updated information about the potential of resveratrol to target mitochondria in the treatment of ND.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; neurodegenerative diseases; polyphenol; resveratrol
    DOI:  https://doi.org/10.3389/fphar.2022.922232
  16. STAR Protoc. 2022 Sep 30. pii: S2666-1667(22)00618-9. [Epub ahead of print]3(4): 101738
    Preparation of mitochondrial damage-associated molecular patterns from mouse liver tissue.
    Lauren P Westhaver, Sarah Nersesian, Adam Nelson, Leah K MacLean, Emily B Carter, Jeanette E Boudreau.
      Mitochondrial damage-associated molecular patterns (mitoDAMPs) are released from cells dying uncontrolled, non-apoptotic deaths, usually secondary to disease or trauma. Here, we describe preparation of mitoDAMPs from mouse liver, but this protocol can be adapted for preparation of mitoDAMPs from other species and tissues. Tissues are dissociated and then processed to isolate mitochondria. Mitochondria are then sonicated and mitoDAMPs are collected by ultracentrifugation. This procedure produces μg quantities of mitoDAMPs and facilitates research to understand their impacts in health and disease. For complete details on the use and execution of this protocol, please refer to Westhaver et al. (2022).
    Keywords:  Cell Biology; Cell isolation; Cell separation/fractionation; Cell-based Assays; Immunology; Metabolomics
    DOI:  https://doi.org/10.1016/j.xpro.2022.101738
  17. BMB Rep. 2022 Oct 05. pii: 5694. [Epub ahead of print]
    AMPK-induced mitochondrial biogenesis decelerates retinal pigment epithelial cell degeneration under nutrient starvation.
    Yujin Park, Yeeun Jeong, Sumin Son, Dong-Eun Kim.
      The implications of nutrient starvation due to aging on the degeneration of the retinal pigment epithelium (RPE) is yet to be fully explored. We examined the involvement of AMPK activation in mitochondrial homeostasis and its relationship with the maintenance of a healthy mitochondrial population and epithelial characteristics of RPE cells under nutrient starvation. Nutrient starvation induced mitochondrial senescence, which led to the accumulation of reactive oxygen species (ROS) in RPE cells. As nutrient starvation persisted, RPE cells underwent pathological epithelial-mesenchymal transition (EMT) via the upregulation of TWIST1, a transcription regulator which is activated by ROS-induced NF-κB signaling. Enhanced activation of AMPK with metformin decelerated mitochondrial senescence and EMT progression through mitochondrial biogenesis, primed by activation of PGC1-α. Thus, by facilitating mitochondrial biogenesis, AMPK protects RPE cells from the loss of epithelial integrity due to the accumulation of ROS in senescent mitochondria under nutrient starvation.
  18. Parkinsonism Relat Disord. 2022 Sep 24. pii: S1353-8020(22)00314-5. [Epub ahead of print]104 3-6
    ACTB gene mutation in combined Dystonia-Deafness syndrome with parkinsonism: Expanding the phenotype and highlighting the long-term GPi DBS outcome.
    Giulia Straccia, Chiara Reale, Massimo Castellani, Isabel Colangelo, Eva Orunesu, Sara Meoni, Elena Moro, Paul Krack, Holger Prokisch, Michael Zech, Luigi Michele Romito, Barbara Garavaglia.
      We report a Dystonia-Deafness syndrome patient treated by pallidal Deep Brain Stimulation with significant long-term benefits. Our study expands and confirms the complex phenotypic spectrum of ACTB gene-related disorders and supports the effectiveness of pallidal stimulation on motor outcomes and quality of life in dystonia due to ACTB p.Arg183Trp heterozygosity.
    DOI:  https://doi.org/10.1016/j.parkreldis.2022.09.012
  19. Front Genet. 2022 ;13 936869
    The genetic and molecular features of the intronic pentanucleotide repeat expansion in spinocerebellar ataxia type 10.
    Tatsuaki Kurosaki, Tetsuo Ashizawa.
      Spinocerebellar ataxia type 10 (SCA10) is characterized by progressive cerebellar neurodegeneration and, in many patients, epilepsy. This disease mainly occurs in individuals with Indigenous American or East Asian ancestry, with strong evidence supporting a founder effect. The mutation causing SCA10 is a large expansion in an ATTCT pentanucleotide repeat in intron 9 of the ATXN10 gene. The ATTCT repeat is highly unstable, expanding to 280-4,500 repeats in affected patients compared with the 9-32 repeats in normal individuals, one of the largest repeat expansions causing neurological disorders identified to date. However, the underlying molecular basis of how this huge repeat expansion evolves and contributes to the SCA10 phenotype remains largely unknown. Recent progress in next-generation DNA sequencing technologies has established that the SCA10 repeat sequence has a highly heterogeneous structure. Here we summarize what is known about the structure and origin of SCA10 repeats, discuss the potential contribution of variant repeats to the SCA10 disease phenotype, and explore how this information can be exploited for therapeutic benefit.
    Keywords:  RNA-gain-of-function mechanism; intronic repeat expansion; pentanucleotide repeat; repeat interruption; spinocerebellar ataxia type 10
    DOI:  https://doi.org/10.3389/fgene.2022.936869
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