bims-midneu Biomed News
on Mitochondrial dysfunction in neurodegeneration
Issue of 2021–06–06
thirty-two papers selected by
Radha Desai, Merck Sharp & Dohme Corp.
  1. PINK1 and parkin shape the organism-wide distribution of a deleterious mitochondrial genome.
  2. Single-Cell Approaches for Studying the Role of Mitochondrial DNA in Neurodegenerative Disease.
  3. The parkinsonian LRRK2 R1441G mutation shows macroautophagy-mitophagy dysregulation concomitant with endoplasmic reticulum stress.
  4. Mitochondrial Alterations in Fibroblasts of Early Stage Bipolar Disorder Patients.
  5. Early Dysfunction of Substantia Nigra Dopamine Neurons in the ParkinQ311X Mouse.
  6. The dysregulated Pink1- drosophila mitochondrial proteome is partially corrected with exercise.
  7. Rapamycin Ameliorates Defects in Mitochondrial Fission and Mitophagy in Glioblastoma Cells.
  8. A Biochemical and Structural Understanding of TOM Complex Interactions and Implications for Human Health and Disease.
  9. Melatonin reshapes the mitochondrial network and promotes intercellular mitochondrial transfer via tunneling nanotubes (TNTs) after ischemic-like injury in hippocampal HT22 cells.
  10. Mitochondria in neurogenesis: Implications for mitochondrial diseases.
  11. Isolation of Mitochondria-Associated ER Membranes (MAMs), Synaptic MAMs, and Glycosphingolipid Enriched Microdomains (GEMs) from Brain Tissues and Neuronal Cells.
  12. Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration.
  13. Impact of Fatty Acid-Binding Proteins in α-Synuclein-Induced Mitochondrial Injury in Synucleinopathy.
  14. The Role of PGC1α in Alzheimer's Disease and Therapeutic Interventions.
  15. Systems Biology Reveals S-Nitrosylation-Dependent Regulation of Mitochondrial Functions in Mice with Shank3 Mutation Associated with Autism Spectrum Disorder.
  16. p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death.
  17. Ang(1-7) exerts Nrf2-mediated neuroprotection against amyloid beta-induced cognitive deficits in rodents.
  18. Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer's Disease.
  19. Patch-Clamp Recording of the Activity of Ion Channels in the Inner Mitochondrial Membrane.
  20. Assessment of Mitochondrial Membrane Potential and NADH Redox State in Acute Brain Slices.
  21. The NDUFS4 Knockout Mouse: A Dual Threat Model of Childhood Mitochondrial Disease and Normative Aging.
  22. Dystonia Responsive to Dopamine: POLG Mutations Should Be Considered If Sensory Neuropathy Is Present.
  23. Studying Mitochondrial Network Formation by In Vivo and In Vitro Reconstitution Assay.
  24. Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
  25. Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation.
  26. The Combination of Paraformaldehyde and Glutaraldehyde Is a Potential Fixative for Mitochondria.
  27. A near-infrared fluorescent probe reveals decreased mitochondrial polarity during mitophagy.
  28. Abnormal brain cholesterol homeostasis in Alzheimer's disease-a targeted metabolomic and transcriptomic study.
  29. Allotopic Expression of ATP6 in Mouse as a Transgenic Model of Mitochondrial Disease.
  30. Respiratory Dysfunctions in Parkinson's Disease Patients.
  31. Suborganellar Localization of Mitochondrial Proteins and Transcripts in Human Cells.
  32. Sprinkling salt on mitochondria: The metabolic and pathophysiological roles of mitochondrial Na+ signaling mediated by NCLX.
  1. Cell Rep. 2021 Jun 01. pii: S2211-1247(21)00552-0. [Epub ahead of print]35(9): 109203
    PINK1 and parkin shape the organism-wide distribution of a deleterious mitochondrial genome.
    Arnaud Ahier, Chuan-Yang Dai, Ina Kirmes, Nadia Cummins, Grace Ching Ching Hung, Jürgen Götz, Steven Zuryn.
      In multiple species, certain tissue types are prone to acquiring greater loads of mitochondrial genome (mtDNA) mutations relative to others, but the mechanisms that drive these heteroplasmy differences are unknown. We find that the conserved PTEN-induced putative kinase (PINK1/PINK-1) and the E3 ubiquitin-protein ligase parkin (PDR-1), which are required for mitochondrial autophagy (mitophagy), underlie stereotyped differences in heteroplasmy of a deleterious mitochondrial genome mutation (ΔmtDNA) between major somatic tissues types in Caenorhabditis elegans. We demonstrate that tissues prone to accumulating ΔmtDNA have lower mitophagy responses than those with low mutation levels. Moreover, we show that ΔmtDNA heteroplasmy increases when proteotoxic species that are associated with neurodegenerative disease and mitophagy inhibition are overexpressed in the nervous system. These results suggest that PINK1 and parkin drive organism-wide patterns of heteroplasmy and provide evidence of a causal link between proteotoxicity, mitophagy, and mtDNA mutation levels in neurons.
    Keywords:  Alzheimer's disease; PINK1; heteroplasmy; mitochondria; mitophagy; mtDNA; parkin; polyglutamate; proteotoxicity; tau
    DOI:  https://doi.org/10.1016/j.celrep.2021.109203
  2. Methods Mol Biol. 2021 ;2277 299-329
    Single-Cell Approaches for Studying the Role of Mitochondrial DNA in Neurodegenerative Disease.
    Laura J Bailey, Joanna L Elson, Ilse S Pienaar.
      In light of accumulating evidence suggestive of cell type-specific vulnerabilities as a result of normal aging processes that adversely affect the brain, as well as age-related neurodegenerative disorders such as Parkinson's disease (PD), the current chapter highlights how we study mitochondrial DNA (mtDNA) changes at a single-cell level. In particular, we comment on increasing questioning of the narrow neurocentric view of such pathologies, where microglia and astrocytes have traditionally been considered bystanders rather than players in related pathological processes. Here we review the contribution made by single-cell mtDNA alterations towards neuronal vulnerability seen in neurodegenerative disorders, focusing on PD as a prominent example. In addition, we give an overview of methodologies that support such experimental investigations. In considering the significant advances that have been made in recent times for developing mitochondria-specific therapies, investigations to account for cell type-specific mitochondrial patterns and how these are altered by disease hold promise for delivering more effective disease-modifying therapeutics.
    Keywords:  Age-related disorders; Cell specificity; Mitochondria; Mitochondrial DNA; Neurodegeneration; Parkinson’s disease; Single-cell analyses
    DOI:  https://doi.org/10.1007/978-1-0716-1270-5_19
  3. Cell Biol Toxicol. 2021 May 31.
    The parkinsonian LRRK2 R1441G mutation shows macroautophagy-mitophagy dysregulation concomitant with endoplasmic reticulum stress.
    Sokhna M S Yakhine-Diop, Mario Rodríguez-Arribas, Saray Canales-Cortés, Guadalupe Martínez-Chacón, Elisabet Uribe-Carretero, Mercedes Blanco-Benítez, Gema Duque-González, Marta Paredes-Barquero, Eva Alegre-Cortés, Vicente Climent, Ana Aiastui, Adolfo López de Munain, José M Bravo-San Pedro, Mireia Niso-Santano, José M Fuentes, Rosa A González-Polo.
      Autophagy is a mechanism responsible for the degradation of cellular components to maintain their homeostasis. However, autophagy is commonly altered and compromised in several diseases, including neurodegenerative disorders. Parkinson's disease (PD) can be considered a multifactorial disease because environmental factors, genetic factors, and aging are involved. Several genes are involved in PD pathology, among which the LRRK2 gene and its mutations, inherited in an autosomal dominant manner, are responsible for most genetic PD cases. The R1441G LRRK2 mutation is, after G2019S, the most important in PD pathogenesis. Our results demonstrate a relationship between the R1441G LRRK2 mutation and a mechanistic dysregulation of autophagy that compromises cell viability. This altered autophagy mechanism is associated with organellar stress including mitochondrial (which induces mitophagy) and endoplasmic reticulum (ER) stress, consistent with the fact that patients with this mutation are more vulnerable to toxins related to PD, such as MPP+.
    Keywords:  Autophagy; MAMs; Mitochondrial dysfunction; Neurodegeneration; Parkinson disease
    DOI:  https://doi.org/10.1007/s10565-021-09617-w
  4. Biomedicines. 2021 May 07. pii: 522. [Epub ahead of print]9(5):
    Mitochondrial Alterations in Fibroblasts of Early Stage Bipolar Disorder Patients.
    Ana P Marques, Rosa Resende, Diana F Silva, Mariana Batista, Daniela Pereira, Brigite Wildenberg, Sofia Morais, António Macedo, Cláudia Pais, Joana B Melo, Nuno Madeira, Cláudia F Pereira.
      This study aims to evaluate whether mitochondrial changes occur in the early stages of bipolar disorder (BD). Using fibroblasts derived from BD patients and matched controls, the levels of proteins involved in mitochondrial biogenesis and dynamics (fission and fusion) were evaluated by Western Blot analysis. Mitochondrial membrane potential (MMP) was studied using the fluorescent probe TMRE. Mitochondrial morphology was analyzed with the probe Mitotracker Green and mitophagy was evaluated by quantifying the co-localization of HSP60 (mitochondria marker) and LC3B (autophagosome marker) by immunofluorescence. Furthermore, the activity of the mitochondrial respiratory chain and the glycolytic capacity of controls and BD patients-derived cells were also studied using the Seahorse technology. BD patient-derived fibroblasts exhibit fragmented mitochondria concomitantly with changes in mitochondrial dynamics and biogenesis in comparison with controls. Moreover, a decrease in the MMP and increased mitophagy was observed in fibroblasts obtained from BD patients when compared with control cells. Impaired energetic metabolism due to inhibition of the mitochondrial electron transport chain (ETC) and subsequent ATP depletion, associated with glycolysis stimulation, was also a feature of BD fibroblasts. Overall, these results support the fact that mitochondrial disturbance is an early event implicated in BD pathophysiology that might trigger neuronal changes and modification of brain circuitry.
    Keywords:  bioenergetics; bipolar disorder; fibroblasts; mitochondrial biogenesis; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.3390/biomedicines9050522
  5. Biomedicines. 2021 May 05. pii: 514. [Epub ahead of print]9(5):
    Early Dysfunction of Substantia Nigra Dopamine Neurons in the ParkinQ311X Mouse.
    Maria Regoni, Letizia Zanetti, Stefano Comai, Daniela Mercatelli, Salvatore Novello, Federica Albanese, Laura Croci, Gian Giacomo Consalez, Andrea Ciammola, Flavia Valtorta, Michele Morari, Jenny Sassone.
      Mutations in the PARK2 gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP), a neurodegenerative disease characterized by early dysfunction and loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). No therapy is currently available to prevent or slow down the neurodegeneration in ARJP patients. Preclinical models are key to clarifying the early events that lead to neurodegeneration and reveal the potential of novel neuroprotective strategies. ParkinQ311X is a transgenic mouse model expressing in DA neurons a mutant parkin variant found in ARJP patients. This model was previously reported to show the neuropathological hallmark of the disease, i.e., the progressive loss of DA neurons. However, the early dysfunctions that precede neurodegeneration have never been investigated. Here, we analyzed SNc DA neurons in parkinQ311X mice and found early features of mitochondrial dysfunction, extensive cytoplasmic vacuolization, and dysregulation of spontaneous in vivo firing activity. These data suggest that the parkinQ311X mouse recapitulates key features of ARJP and provides a useful tool for studying the neurodegenerative mechanisms underlying the human disease and for screening potential neuroprotective drugs.
    Keywords:  Parkinson’s disease; cytoplasmic vacuolization; dopaminergic neurons; early dysfunction; firing activity; mitochondria; parkinQ311X mouse
    DOI:  https://doi.org/10.3390/biomedicines9050514
  6. Aging (Albany NY). 2021 Jun 01. 13
    The dysregulated Pink1- drosophila mitochondrial proteome is partially corrected with exercise.
    Brad Ebanks, Thomas L Ingram, Gunjan Katyal, John R Ingram, Nicoleta Moisoi, Lisa Chakrabarti.
      One of the genes which has been linked to the onset of juvenile/early onset Parkinson's disease (PD) is PINK1. There is evidence that supports the therapeutic potential of exercise in the alleviation of PD symptoms. It is possible that exercise may enhance synaptic plasticity, protect against neuro-inflammation and modulate L-Dopa regulated signalling pathways. We explored the effects of exercise on Pink1 deficient Drosophila melanogaster which undergo neurodegeneration and muscle degeneration. We used a 'power-tower' type exercise platform to deliver exercise activity to Pink1- and age matched wild-type Drosophila. Mitochondrial proteomic profiles responding to exercise were obtained. Of the 516 proteins identified, 105 proteins had different levels between Pink1- and wild-type non-exercised Drosophila. Gene ontology enrichment analysis and STRING network analysis highlighted proteins and pathways with altered expression within the mitochondrial proteome. Comparison of the Pink1- exercised proteome to wild-type proteomes showed that exercising the Pink1- Drosophila caused their proteomic profile to return towards wild-type levels.
    Keywords:  PINK1; drosophila; exercise; mitochondria; proteomics
    DOI:  https://doi.org/10.18632/aging.203128
  7. Int J Mol Sci. 2021 May 20. pii: 5379. [Epub ahead of print]22(10):
    Rapamycin Ameliorates Defects in Mitochondrial Fission and Mitophagy in Glioblastoma Cells.
    Paola Lenzi, Rosangela Ferese, Francesca Biagioni, Federica Fulceri, Carla L Busceti, Alessandra Falleni, Stefano Gambardella, Alessandro Frati, Francesco Fornai.
      Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of the present study consists of detailing an mTOR-dependent mitophagy occlusion, along with suppression of mitochondrial fission. These phenomena contribute to explain the increase in altered mitochondria reported here. Administration of the mTOR inhibitor rapamycin rescues mitochondrial alterations. In detail, rapamycin induces the expression of genes promoting mitophagy (PINK1, PARKIN, ULK1, AMBRA1) and mitochondrial fission (FIS1, DRP1). This occurs along with over-expression of VPS34, an early gene placed upstream in the autophagy pathway. The topographic stoichiometry of proteins coded by these genes within mitochondria indicates that, a remarkable polarization of proteins involved in fission and mitophagy within mitochondria including LC3 takes place. Co-localization of these proteins within mitochondria, persists for weeks following rapamycin, which produces long-lasting mitochondrial plasticity. Thus, rapamycin restores mitochondrial status in GBM cells. These findings add novel evidence about mitochondria and GBM, while fostering a novel therapeutic approach to restore healthy mitochondria through mTOR inhibition.
    Keywords:  AMBRA1; DRP1; FIS1; OPA1; PARKIN; PINK1; ULK1; VPS34; autophagy; mitochondria
    DOI:  https://doi.org/10.3390/ijms22105379
  8. Cells. 2021 May 11. pii: 1164. [Epub ahead of print]10(5):
    A Biochemical and Structural Understanding of TOM Complex Interactions and Implications for Human Health and Disease.
    Ashley S Pitt, Susan K Buchanan.
      The central role mitochondria play in cellular homeostasis has made its study critical to our understanding of various aspects of human health and disease. Mitochondria rely on the translocase of the outer membrane (TOM) complex for the bulk of mitochondrial protein import. In addition to its role as the major entry point for mitochondrial proteins, the TOM complex serves as an entry pathway for viral proteins. TOM complex subunits also participate in a host of interactions that have been studied extensively for their function in neurodegenerative diseases, cardiovascular diseases, innate immunity, cancer, metabolism, mitophagy and autophagy. Recent advances in our structural understanding of the TOM complex and the protein import machinery of the outer mitochondrial membrane have made structure-based therapeutics targeting outer mitochondrial membrane proteins during mitochondrial dysfunction an exciting prospect. Here, we describe advances in understanding the TOM complex, the interactome of the TOM complex subunits, the implications for the development of therapeutics, and our understanding of the structure/function relationship between components of the TOM complex and mitochondrial homeostasis.
    Keywords:  TOM complex; TOM complex interactions; TOM subunits; mitochondrial cell signaling; mitochondrial quality control
    DOI:  https://doi.org/10.3390/cells10051164
  9. J Pineal Res. 2021 Jun 04. e12747
    Melatonin reshapes the mitochondrial network and promotes intercellular mitochondrial transfer via tunneling nanotubes (TNTs) after ischemic-like injury in hippocampal HT22 cells.
    Maria Gemma Nasoni, Silvia Carloni, Barbara Canonico, Sabrina Burattini, Erica Cesarini, Stefano Papa, Marica Pagliarini, Patrizia Ambrogini, Walter Balduini, Francesca Luchetti.
      Mitochondrial dysfunction is considered one of the hallmarks of ischemia/reperfusion injury. Mitochondria are plastic organelles that undergo continuous biogenesis, fusion and fission. They can be transferred between cells through tunneling nanotubes (TNTs), dynamic structures that allow the exchange of proteins, soluble molecules and organelles. Maintaining mitochondrial dynamics is crucial to cell function and survival. The present study aimed to assess the effects of melatonin on mitochondrial dynamics, TNT formation and mitochondria transfer in HT22 cells exposed to oxygen/glucose deprivation followed by reoxygenation (OGD/R). The results showed that melatonin treatment during the reoxygenation phase reduced mitochondrial reactive oxygen species (ROS) production, improved cell viability and increased the expression of PGC1α and SIRT3. Melatonin also preserved the expression of the membrane translocase proteins TOM20 and TIM23, and of the matrix protein HSP60, which are involved in mitochondrial biogenesis. Moreover, it promoted mitochondrial fusion and enhanced the expression of MFN2 and OPA1. Remarkably, melatonin also fostered mitochondrial transfer between injured HT22 cells through TNT connections. These results provide new insights into the effect of melatonin on mitochondrial network reshaping and cell survival. Fostering TNTs formation represents a novel mechanism mediating the protective effect of melatonin in ischemia/reperfusion injury.
    Keywords:  HT22; Melatonin; mitochondrial network; oxygen-glucose deprivation; tunneling nanotubes
    DOI:  https://doi.org/10.1111/jpi.12747
  10. Stem Cells. 2021 Jun 05.
    Mitochondria in neurogenesis: Implications for mitochondrial diseases.
    Dario Brunetti, Werner Dykstra, Stephanie Le, Annika Zink, Alessandro Prigione.
      Mitochondria are organelles with recognized key roles in cellular homeostasis, including bioenergetics, redox, calcium signaling, and cell death. Mitochondria are essential for neuronal function, given the high energy demands of the human brain. Consequently, mitochondrial diseases affecting oxidative phosphorylation (OXPHOS) commonly exhibit neurological impairment. Emerging evidence suggests that mitochondria are important not only for mature postmitotic neurons but also for the regulation of neural progenitor cells (NPCs) during the process of neurogenesis. These recent findings put mitochondria as central regulator of cell fate decisions during brain development. OXPHOS mutations may disrupt the function of NPCs and thereby impair the metabolic programming required for neural fate commitment. Promoting the mitochondrial function of NPCs could therefore represent a novel interventional approach against incurable mitochondrial diseases.
    Keywords:  NPCs; iPSCs; mitochondria; mitochondrial diseases; neurogenesis
    DOI:  https://doi.org/10.1002/stem.3425
  11. Methods Mol Biol. 2021 ;2277 357-370
    Isolation of Mitochondria-Associated ER Membranes (MAMs), Synaptic MAMs, and Glycosphingolipid Enriched Microdomains (GEMs) from Brain Tissues and Neuronal Cells.
    Ida Annunziata, Jason Andrew Weesner, Alessandra d'Azzo.
      Subcellular fractionation is a valuable procedure in cell biology to separate and purify various subcellular constituents from one another, i.e., nucleus, cytosol, membranes/organelles, and cytoskeleton. The procedure relies on the use of differential centrifugation of cell and tissue homogenates. Fractionated subcellular organelles may be subjected to additional purification steps that enable the isolation of specific cellular sub-compartments, including interorganellar membrane contact sites. Here we outline a protocol tailored to the isolation of mitochondria, mitochondria-associated ER membranes (MAMs), and glycosphingolipid enriched microdomains (GEMs) from the adult mouse brain, primary neurospheres, and murine embryonic fibroblasts (MEFs). We also provide a detailed protocol for the purification of synaptosomes and their corresponding MAMs .
    Keywords:  Brain; Centrifugation; ER; GEMs; MAMs; Mitochondria; Neuronal cells; Synaptosomes
    DOI:  https://doi.org/10.1007/978-1-0716-1270-5_22
  12. Life (Basel). 2021 May 11. pii: 432. [Epub ahead of print]11(5):
    Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration.
    Hope I Needs, Margherita Protasoni, Jeremy M Henley, Julien Prudent, Ian Collinson, Gonçalo C Pereira.
      The fact that >99% of mitochondrial proteins are encoded by the nuclear genome and synthesised in the cytosol renders the process of mitochondrial protein import fundamental for normal organelle physiology. In addition to this, the nuclear genome comprises most of the proteins required for respiratory complex assembly and function. This means that without fully functional protein import, mitochondrial respiration will be defective, and the major cellular ATP source depleted. When mitochondrial protein import is impaired, a number of stress response pathways are activated in order to overcome the dysfunction and restore mitochondrial and cellular proteostasis. However, prolonged impaired mitochondrial protein import and subsequent defective respiratory chain function contributes to a number of diseases including primary mitochondrial diseases and neurodegeneration. This review focuses on how the processes of mitochondrial protein translocation and respiratory complex assembly and function are interlinked, how they are regulated, and their importance in health and disease.
    Keywords:  mitochondrial dysfunction; mitochondrial proteostasis; neurodegeneration; protein import; respiratory complex assembly; supercomplexes
    DOI:  https://doi.org/10.3390/life11050432
  13. Biomedicines. 2021 May 17. pii: 560. [Epub ahead of print]9(5):
    Impact of Fatty Acid-Binding Proteins in α-Synuclein-Induced Mitochondrial Injury in Synucleinopathy.
    An Cheng, Wenbin Jia, Ichiro Kawahata, Kohji Fukunaga.
      Synucleinopathies are diverse diseases with motor and cognitive dysfunction due to progressive neuronal loss or demyelination, due to oligodendrocyte loss in the brain. While the etiology of neurodegenerative disorders (NDDs) is likely multifactorial, mitochondrial injury is one of the most vital factors in neuronal loss and oligodendrocyte dysfunction, especially in Parkinson's disease, dementia with Lewy body, multiple system atrophy, and Krabbe disease. In recent years, the abnormal accumulation of highly neurotoxic α-synuclein in the mitochondrial membrane, which leads to mitochondrial dysfunction, was well studied. Furthermore, fatty acid-binding proteins (FABPs), which are members of a superfamily and are essential in fatty acid trafficking, were reported to trigger α-synuclein oligomerization in neurons and glial cells and to target the mitochondrial outer membrane, thereby causing mitochondrial loss. Here, we provide an updated overview of recent findings on FABP and α-synuclein interactions and mitochondrial injury in NDDs.
    Keywords:  fatty acid-binding proteins; mitochondria; neurodegenerative disorders; α-synuclein
    DOI:  https://doi.org/10.3390/biomedicines9050560
  14. Int J Mol Sci. 2021 May 28. pii: 5769. [Epub ahead of print]22(11):
    The Role of PGC1α in Alzheimer's Disease and Therapeutic Interventions.
    Bibiana C Mota, Magdalena Sastre.
      The peroxisome proliferator-activated receptor co-activator-1α (PGC1α) belongs to a family of transcriptional regulators, which act as co-activators for a number of transcription factors, including PPARs, NRFs, oestrogen receptors, etc. PGC1α has been implicated in the control of mitochondrial biogenesis, the regulation of the synthesis of ROS and inflammatory cytokines, as well as genes controlling metabolic processes. The levels of PGC1α have been shown to be altered in neurodegenerative disorders. In the brains of Alzheimer's disease (AD) patients and animal models of amyloidosis, PGC1α expression was reduced compared with healthy individuals. Recently, it was shown that overexpression of PGC1α resulted in reduced amyloid-β (Aβ) generation, particularly by regulating the expression of BACE1, the rate-limiting enzyme involved in the production of Aβ. These results provide evidence pointing toward PGC1α activation as a new therapeutic avenue for AD, which has been supported by the promising observations of treatments with drugs that enhance the expression of PGC1α and gene therapy studies in animal models of AD. This review summarizes the different ways and mechanisms whereby PGC1α can be neuroprotective in AD and the pre-clinical treatments that have been explored so far.
    Keywords:  Alzheimer’s disease; PGC1α; amyloid-β
    DOI:  https://doi.org/10.3390/ijms22115769
  15. Brain Sci. 2021 May 21. pii: 677. [Epub ahead of print]11(6):
    Systems Biology Reveals S-Nitrosylation-Dependent Regulation of Mitochondrial Functions in Mice with Shank3 Mutation Associated with Autism Spectrum Disorder.
    Maryam Kartawy, Igor Khaliulin, Haitham Amal.
      Autism spectrum disorder (ASD) is a neurodevelopmental disorder manifested in repetitive behavior, abnormalities in social interactions, and communication. The pathogenesis of this disorder is not clear, and no effective treatment is currently available. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the ASD mouse model based on the Shank3 mutation. The energy supply to the brain mostly relies on oxidative phosphorylation in the mitochondria. Recent studies show that mitochondrial dysfunction and oxidative stress are involved in ASD pathology. In this work, we performed SNO proteomics analysis of cortical tissues of the Shank3 mouse model of ASD with the focus on mitochondrial proteins and processes. The study was based on the SNOTRAP technology followed by systems biology analysis. This work revealed that 63 mitochondrial proteins were S-nitrosylated and that several mitochondria-related processes, including those associated with oxidative phosphorylation, oxidative stress, and apoptosis, were enriched. This study implies that aberrant SNO signaling induced by the Shank3 mutation can target a wide range of mitochondria-related proteins and processes that may contribute to the ASD pathology. It is the first study to investigate the role of NO-dependent mitochondrial functions in ASD.
    Keywords:  S-nitrosylation; autism spectrum disorder; nitric oxide; proteomics mitochondria; systems biology
    DOI:  https://doi.org/10.3390/brainsci11060677
  16. Sci Rep. 2021 Jun 01. 11(1): 11474
    p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death.
    A D Foster, L L Flynn, C Cluning, F Cheng, J M Davidson, A Lee, N Polain, R Mejzini, N Farrawell, J J Yerbury, R Layfield, P A Akkari, S L Rea.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) that exist on a spectrum of neurodegenerative disease. A hallmark of pathology is cytoplasmic TDP-43 aggregates within neurons, observed in 97% of ALS cases and ~ 50% of FTLD cases. This mislocalisation from the nucleus into the cytoplasm and TDP-43 cleavage are associated with pathology, however, the drivers of these changes are unknown. p62 is invariably also present within these aggregates. We show that p62 overexpression causes TDP-43 mislocalisation into cytoplasmic aggregates, and aberrant TDP-43 cleavage that was dependent on both the PB1 and ubiquitin-associated (UBA) domains of p62. We further show that p62 overexpression induces neuron death. We found that stressors (proteasome inhibition and arsenic) increased p62 expression and that this shifted the nuclear:cytoplasmic TDP-43 ratio. Overall, our study suggests that environmental factors that increase p62 may thereby contribute to TDP-43 pathology in ALS and FTLD.
    DOI:  https://doi.org/10.1038/s41598-021-90822-2
  17. Mol Biol Rep. 2021 Jun 01.
    Ang(1-7) exerts Nrf2-mediated neuroprotection against amyloid beta-induced cognitive deficits in rodents.
    Vibhav Varshney, Debapriya Garabadu.
      Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive deficits in an individual. Ang(1-7) exhibits neuroprotection against amyloid beta (Aβ)-induced mitochondrial dysfunction and neurotoxicity in experimental conditions. Further, Ang(1-7) also exhibits nrf2-mediated antioxidant activity in experimental conditions. However, its therapeutic role on nrf2-mediated mitochondrial function is yet to be established in the Aβ-induced neurotoxicity. The experimental dementia was induced in the male rats by intracerebroventricular administration of Aβ(1-42) on day-1 (D-1) of the experimental schedule of 14 days. Ang(1-7) was administered once daily from D-1 toD-14 to the Aβ-challenged rodents. Ang(1-7) attenuated Aβ-induced increase in escape latency and decrease in the time spent in the target quadrant during Morris water maze and percentage of spontaneous alteration behavior during Y-maze tests in the rats. Further, Ang(1-7) attenuated Aβ-induced cholinergic dysfunction in terms of decrease in the level of acetylcholine and activity of choline acetyltransferase, and increase in the activity of acetylcholinesterase, and increase in the level of Aβ in rat hippocampus, pre-frontal cortex and amygdala. Furthermore, Ang(1-7) reversed Aβ-induced decrease in the mitochondrial function, integrity and bioenergetics in all brain regions. Additionally, Ang(1-7) attenuated Aβ-induced increase in the extent of apoptosis and decrease in the level of heme oxygenase-1 in all selected brain regions. Trigonelline significantly abolished the therapeutic effectiveness of Ang(1-7) on Aβ-induced alterations in the behavioral, neurochemicals and molecular observations in the animals. Ang(1-7) may exhibit nrf2-mediated neuroprotection in these rodents. Hence, Ang(1-7) could be a potential therapeutic option in the pharmacotherapy of AD.
    Keywords:  Alzheimer’s disease; Amygdala; Hippocampus; Mitochondrial functions; Nrf2; Prefrontal cortex
    DOI:  https://doi.org/10.1007/s11033-021-06447-1
  18. Int J Mol Sci. 2021 May 03. pii: 4850. [Epub ahead of print]22(9):
    Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer's Disease.
    Chanchal Sharma, Sehwan Kim, Youngpyo Nam, Un Ju Jung, Sang Ryong Kim.
      Alzheimer's disease (AD) is the most frequent cause of age-related neurodegeneration and cognitive impairment, and there are currently no broadly effective therapies. The underlying pathogenesis is complex, but a growing body of evidence implicates mitochondrial dysfunction as a common pathomechanism involved in many of the hallmark features of the AD brain, such as formation of amyloid-beta (Aβ) aggregates (amyloid plaques), neurofibrillary tangles, cholinergic system dysfunction, impaired synaptic transmission and plasticity, oxidative stress, and neuroinflammation, that lead to neurodegeneration and cognitive dysfunction. Indeed, mitochondrial dysfunction concomitant with progressive accumulation of mitochondrial Aβ is an early event in AD pathogenesis. Healthy mitochondria are critical for providing sufficient energy to maintain endogenous neuroprotective and reparative mechanisms, while disturbances in mitochondrial function, motility, fission, and fusion lead to neuronal malfunction and degeneration associated with excess free radical production and reduced intracellular calcium buffering. In addition, mitochondrial dysfunction can contribute to amyloid-β precursor protein (APP) expression and misprocessing to produce pathogenic fragments (e.g., Aβ1-40). Given this background, we present an overview of the importance of mitochondria for maintenance of neuronal function and how mitochondrial dysfunction acts as a driver of cognitive impairment in AD. Additionally, we provide a brief summary of possible treatments targeting mitochondrial dysfunction as therapeutic approaches for AD.
    Keywords:  Alzheimer’s disease; calcium buffering; free radical; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/ijms22094850
  19. Methods Mol Biol. 2021 ;2276 235-248
    Patch-Clamp Recording of the Activity of Ion Channels in the Inner Mitochondrial Membrane.
    Piotr Bednarczyk, Rafał P Kampa, Shur Gałecka, Aleksandra Sęk, Agnieszka Walewska, Piotr Koprowski.
      Mitochondria are intracellular organelles, which play a crucial role in the generation of ATP. Mitochondria are surrounded by a double membrane, consisting of a smooth outer membrane (OMM) and a markedly folded inner mitochondrial membrane (IMM). Mitochondrion that has been stripped of its outer membrane, leaving the inner membrane intact is called mitoplast. There is a number of different transport proteins located in the inner mitochondrial membrane including ion channels that mediate fluxes of potassium, calcium, and chloride ions. These channels regulate the mitochondrial membrane potential, respiration, and production of reactive oxygen species. The stability of mitoplasts offers the possibility of measuring the activity of ion channels from IMM using the patch-clamp technique. Electrophysiological measurements of currents through ion channels in the IMM permit discovery of unique properties of these channels with the aim of new specific pharmacological therapies. In this chapter, we describe the isolation of mitochondria, preparation of mitoplast for patch-clamp recordings and single-mitoplast PCR experiments, which can be helpful in mastering the technique of recording the activity of mitochondrial ion channels.
    Keywords:  Inner mitochondrial membrane; Ion channel; Mitochondria; Mitoplast; PCR; Patch-clamp technique
    DOI:  https://doi.org/10.1007/978-1-0716-1266-8_18
  20. Methods Mol Biol. 2021 ;2276 193-202
    Assessment of Mitochondrial Membrane Potential and NADH Redox State in Acute Brain Slices.
    Andrey Y Vinokurov, Viktor V Dremin, Gennadii A Piavchenko, Olga A Stelmashchuk, Plamena R Angelova, Andrey Y Abramov.
      Brain is one of the most energy-demanding organs. Energy in the form of ATP is produced in brain cells predominantly in oxidative phosphorylation coupled to mitochondrial respiration. Any alteration of the mitochondrial metabolism or prolonged ischemic or anoxic conditions can lead to serious neurological conditions, including neurodegenerative disorders. Assessment of mitochondrial metabolism is important for understanding physiological and pathological processes in the brain. Bioenergetics in central nervous system is dependent on multiple parameters including neuron-glia interactions and considering this, in vivo or ex vivo, the measurements of mitochondrial metabolism should also be complimenting the experiments on isolated mitochondria or cell cultures. To assess the mitochondrial function, there are several key bioenergetic parameters which indicate mitochondrial health. One of the major characteristics of mitochondria is the mitochondrial membrane potential (ΔΨm) which is used as a proton motive force for ATP production and generated by activity of the electron transport chain. Major donor of electrons for the mitochondrial respiratory chain is NADH. Here we demonstrate how to measure mitochondrial NADH/NAD(P)H autofluorescence and ΔΨm in acute brain slices in a time-dependent manner and provide information for the identification of NADH redox index, mitochondrial NADH pool, and the rate of NADH production in the Krebs cycle. Additionally, non-mitochondrial NADH/NADPH autofluorescence can signify the level of activity of the pentose phosphate pathway.
    Keywords:  Acute brain slices; Mitochondria; Mitochondrial membrane potential; NADH
    DOI:  https://doi.org/10.1007/978-1-0716-1266-8_14
  21. Methods Mol Biol. 2021 ;2277 143-155
    The NDUFS4 Knockout Mouse: A Dual Threat Model of Childhood Mitochondrial Disease and Normative Aging.
    Anthony S Grillo, Alessandro Bitto, Matt Kaeberlein.
      Mice missing the Complex I subunit NADH:Ubiquinone Oxidoreductase Fe-S Protein 4 (NDUFS4) of the electron transport chain are a leading model of the severe mitochondrial disease Leigh syndrome. These mice have enabled a better understanding of mitochondrial dysfunction in human disease, as well as in the discovery of interventions that can potentially suppress mitochondrial disease manifestations. In addition, increasing evidence suggests significant overlap between interventions that increase survival in NDUFS4 knockout mice and that extend life span during normative aging. This chapter discusses the practical aspects of handling and studying these mice, which can be challenging due to their severe disease phenotype. Common procedures such as breeding, genotyping, weaning, or treating these transgenic mice are also discussed.
    Keywords:  Aging; Complex I; Electron transport chain; Hypoxia; Leigh syndrome; Mitochondrial disease; Mitochondrial dysfunction; NAD; NDUFS4; Rapamycin; mTOR
    DOI:  https://doi.org/10.1007/978-1-0716-1270-5_10
  22. J Mov Disord. 2021 May;14(2): 157-160
    Dystonia Responsive to Dopamine: POLG Mutations Should Be Considered If Sensory Neuropathy Is Present.
    Jessica Qiu, Kishore Raj Kumar, Eloise Watson, Kate Ahmad, Carolyn M Sue, Michael W Hayes.
      The POLG gene encodes mitochondrial DNA polymerase, and mutations in this gene cause a spectrum of disorders related to mitochondrial DNA depletion or deletion. Dystonia has only rarely been reported as an early and prominent manifestation of POLG mutations. We report a case of a 30-year-old male presenting with lower limb dystonia with peripheral neuropathy and demonstrate that the dystonia was levodopa responsive (with video findings). Whole-genome sequencing revealed biallelic variants in the POLG gene: a known pathogenic variant [NM_001126131.2:c.2209G>C (p.Gly737Arg)] and a novel likely pathogenic variant [NM_001126131.2:c.3305A>C (p.Gln1102Pro)]. A genetic diagnosis was made before the appearance of more readily recognizable features of mitochondrial disease, allowing us to avoid invasive tissue biopsies or potentially deleterious treatments, such as sodium valproate. A POLG-related disorder should be suspected in cases of dystonia with peripheral neuropathy, and this diagnosis may have implications for further investigations and management.
    Keywords:  Dystonia; Genetics; POLG; Parkinsonism; Peripheral Neuropathies
    DOI:  https://doi.org/10.14802/jmd.20159
  23. Methods Mol Biol. 2021 ;2276 333-341
    Studying Mitochondrial Network Formation by In Vivo and In Vitro Reconstitution Assay.
    Wanqing Du, Xiangjun Di, Qian Peter Su.
      Mitochondria change their morphologies from small isolated vesicles to large continuous networks across the cell cycles. The mitochondrial network formation (MNF) plays an important role in maintaining mitochondrial DNA integrity and interchanging mitochondrial materials. The disruption of the mitochondrial network affects mitochondrial functions, such as ATP production, integration of metabolism, calcium homeostasis, and regulation of apoptosis, leading to the abnormal development and several human diseases including neurodegenerative disease. In this unit, we describe the method of studying MNF, which is driven by microtubule-dependent motor protein, by in vivo imaging and single-molecule in vitro reconstitution assays.
    Keywords:  In vitro reconstitution system; KIF5B; Mitochondrial network formation (MNF); Single-molecule
    DOI:  https://doi.org/10.1007/978-1-0716-1266-8_25
  24. Nat Med. 2021 May 31.
    Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
    Payam Mohassel, Sandra Donkervoort, Museer A Lone, Matthew Nalls, Kenneth Gable, Sita D Gupta, A Reghan Foley, Ying Hu, Jonas Alex Morales Saute, Ana Lucila Moreira, Fernando Kok, Alessandro Introna, Giancarlo Logroscino, Christopher Grunseich, Alec R Nickolls, Naemeh Pourshafie, Sarah B Neuhaus, Dimah Saade, Andrea Gangfuß, Heike Kölbel, Zoe Piccus, Claire E Le Pichon, Chiara Fiorillo, Cindy V Ly, Ana Töpf, Lauren Brady, Sabine Specht, Aliza Zidell, Helio Pedro, Eric Mittelmann, Florian P Thomas, Katherine R Chao, Chamindra G Konersman, Megan T Cho, Tracy Brandt, Volker Straub, Anne M Connolly, Ulrike Schara, Andreas Roos, Mark Tarnopolsky, Ahmet Höke, Robert H Brown, Chia-Hsueh Lee, Thorsten Hornemann, Teresa M Dunn, Carsten G Bönnemann.
      Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease.
    DOI:  https://doi.org/10.1038/s41591-021-01346-1
  25. Commun Biol. 2021 Jun 02. 4(1): 666
    Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation.
    Alexandra Stavsky, Ohad Stoler, Marko Kostic, Tomer Katoshevsky, Essam A Assali, Ivana Savic, Yael Amitai, Holger Prokisch, Steffen Leiz, Cornelia Daumer-Haas, Ilya Fleidervish, Fabiana Perrochi, Daniel Gitler, Israel Sekler.
      Calcium dynamics control synaptic transmission. Calcium triggers synaptic vesicle fusion, determines release probability, modulates vesicle recycling, participates in long-term plasticity and regulates cellular metabolism. Mitochondria, the main source of cellular energy, serve as calcium signaling hubs. Mitochondrial calcium transients are primarily determined by the balance between calcium influx, mediated by the mitochondrial calcium uniporter (MCU), and calcium efflux through the sodium/lithium/calcium exchanger (NCLX). We identified a human recessive missense SLC8B1 variant that impairs NCLX activity and is associated with severe mental retardation. On this basis, we examined the effect of deleting NCLX in mice on mitochondrial and synaptic calcium homeostasis, synaptic activity, and plasticity. Neuronal mitochondria exhibited basal calcium overload, membrane depolarization, and a reduction in the amplitude and rate of calcium influx and efflux. We observed smaller cytoplasmic calcium transients in the presynaptic terminals of NCLX-KO neurons, leading to a lower probability of release and weaker transmission. In agreement, synaptic facilitation in NCLX-KO hippocampal slices was enhanced. Importantly, deletion of NCLX abolished long term potentiation of Schaffer collateral synapses. Our results show that NCLX controls presynaptic calcium transients that are crucial for defining synaptic strength as well as short- and long-term plasticity, key elements of learning and memory processes.
    DOI:  https://doi.org/10.1038/s42003-021-02114-0
  26. Biomolecules. 2021 May 10. pii: 711. [Epub ahead of print]11(5):
    The Combination of Paraformaldehyde and Glutaraldehyde Is a Potential Fixative for Mitochondria.
    Yuan Qin, Wenting Jiang, Anqi Li, Meng Gao, Hanyu Liu, Yufei Gao, Xiangang Tian, Guohua Gong.
      Mitochondria are highly dynamic organelles, constantly undergoing shape changes, which are controlled by mitochondrial movement, fusion, and fission. Mitochondria play a pivotal role in various cellular processes under physiological and pathological conditions, including metabolism, superoxide generation, calcium homeostasis, and apoptosis. Abnormal mitochondrial morphology and mitochondrial protein expression are always closely related to the health status of cells. Analysis of mitochondrial morphology and mitochondrial protein expression in situ is widely used to reflect the abnormality of cell function in the chemical fixed sample. Paraformaldehyde (PFA), the most commonly used fixative in cellular immunostaining, still has disadvantages, including loss of antigenicity and disruption of morphology during fixation. We tested the effect of ethanol (ETHO), PFA, and glutaraldehyde (GA) fixation on cellular mitochondria. The results showed that 3% PFA and 1.5% GA (PFA-GA) combination reserved mitochondrial morphology better than them alone in situ in cells. Mitochondrial network and protein antigenicity were well maintained, indicated by preserved MitoTracker and mitochondrial immunostaining after PFA-GA fixation. Our results suggest that the PFA-GA combination is a valuable fixative for the study of mitochondria in situ.
    Keywords:  fixative; glutaraldehyde; mitochondria; mitochondrial morphology; paraformaldehyde
    DOI:  https://doi.org/10.3390/biom11050711
  27. Chem Sci. 2019 Dec 18. 11(6): 1617-1622
    A near-infrared fluorescent probe reveals decreased mitochondrial polarity during mitophagy.
    Xiaoyi Li, Xiaohua Li, Huimin Ma.
      Mitophagy is a selective form of autophagy by which dysfunctional and damaged mitochondria are degraded in autolysosomes. Since defective mitophagy is closely related to various pathological processes, investigation on the detailed mitophagy process is of great importance. In this respect, disclosing the alterations of mitochondrial microenvironments is expected to be a promising way. However, an appropriate method for monitoring the fluctuations of mitochondrial polarity during mitophagy is still lacking. Here, we report a near-infrared hydroxyl-hemicyanine fluorescent probe that responds to polarity exclusively. Both the shift of emission maxima and the fluorescence intensity ratios at two different wavelengths of the probe can be applied to quantifying the polarity accurately. With ratiometric fluorescence imaging, the polarity differences of normal and cancer cells are clearly discriminated. Most importantly, the mitochondrial polarity variations during starvation and drug-induced mitophagy are determined for the first time. The observed decrease of mitochondrial polarity during mitophagy, together with the rationally designed probe, may facilitate the study on the vital role of mitophagy in physiological and pathological bioprocesses.
    DOI:  https://doi.org/10.1039/c9sc05505c
  28. NPJ Aging Mech Dis. 2021 Jun 01. 7(1): 11
    Abnormal brain cholesterol homeostasis in Alzheimer's disease-a targeted metabolomic and transcriptomic study.
    Vijay R Varma, H Büşra Lüleci, Anup M Oommen, Sudhir Varma, Chad T Blackshear, Michael E Griswold, Yang An, Jackson A Roberts, Richard O'Brien, Olga Pletnikova, Juan C Troncoso, David A Bennett, Tunahan Çakır, Cristina Legido-Quigley, Madhav Thambisetty.
      The role of brain cholesterol metabolism in Alzheimer's disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson's disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.
    DOI:  https://doi.org/10.1038/s41514-021-00064-9
  29. Methods Mol Biol. 2021 ;2277 1-13
    Allotopic Expression of ATP6 in Mouse as a Transgenic Model of Mitochondrial Disease.
    David A Dunn, Carl A Pinkert.
      Progress in animal modeling of polymorphisms and mutations in mitochondrial DNA (mtDNA) is not as developed as nuclear transgenesis due to a host of cellular and physiological distinctions. mtDNA mutation modeling is of critical importance as mutations in the mitochondrial genome give rise to a variety of pathological conditions and play a contributing role in many others. Nuclear localization and transcription of mtDNA genes followed by cytoplasmic translation and transport into mitochondria (allotopic expression, AE) provide an opportunity to create in vivo modeling of a targeted mutation in mitochondrial genes. Accordingly, such technology has been suggested as a strategy for gene replacement therapy in patients harboring mitochondrial DNA mutations. Here, we use our AE approach to transgenic mouse modeling of the pathogenic human T8993G mutation in mtATP6 as a case study for designing AE animal models.
    Keywords:  ATP6; Allotopic expression; Animal modeling; Mitochondrial disease; Transgenic mouse; mtDNA
    DOI:  https://doi.org/10.1007/978-1-0716-1270-5_1
  30. Brain Sci. 2021 May 04. pii: 595. [Epub ahead of print]11(5):
    Respiratory Dysfunctions in Parkinson's Disease Patients.
    Any Docu Axelerad, Alina Zorina Stroe, Oana Cristina Arghir, Daniel Docu Axelerad, Anca Elena Gogu.
      Respiratory dysfunctions have been associated with Parkinson's disease since the first observations of the disease in 1817. Patients with Parkinson's disease frequently present respiratory disorders with obstructive ventilatory patterns and restrictive modifications, as well as limitations in respiratory volumes. In addition, respiratory impairments are observed due to the rigidity and kyphosis that Parkinson's disease patients experience. Subsidiary pulmonary complications can also appear as side effects of medication. Silent aspiration can be the cause of pneumonia in Parkinson's disease. Pulmonary dysfunction is one of the main factors that leads to the morbidity and mortality of patients with Parkinson's disease. Here, we performed a narrative review of the literature and reviewed studies on dyspnea, lung volumes, respiratory muscle function, sleep breathing disorders, and subsidiary speech and swallow impairments related to pulmonary dysfunction in patients with Parkinson's disease.
    Keywords:  Parkinson’s disease; pulmonary complications; respiratory dysfunction
    DOI:  https://doi.org/10.3390/brainsci11050595
  31. Methods Mol Biol. 2021 ;2277 157-173
    Suborganellar Localization of Mitochondrial Proteins and Transcripts in Human Cells.
    Smirnova Anna, Richert Ludovic, Smirnov Alexandre, Mély Yves, Tarassov Ivan.
      Mitochondria have complex ultrastructure which includes continuous subcompartments, such as matrix, intermembrane space, and two membranes, as well as focal structures, such as nucleoids, RNA granules, and mitoribosomes. Comprehensive studies of the spatial distribution of proteins and RNAs inside the mitochondria are necessary to understand organellar gene expression processes and macromolecule targeting pathways. Here we give examples of distribution analysis of mitochondrial proteins and transcripts by conventional microscopy and the super-resolution technique 3D STORM. We provide detailed protocols and discuss limitations of immunolabeling of mitochondrial proteins and newly synthesized mitochondrial RNAs by bromouridine incorporation and single-molecule RNA FISH in hepatocarcinoma cells.
    Keywords:  3D STORM; Colocalization analysis; Confocal microscopy; Immunolabeling; RNA in situ hybridization; Submitochondrial ultrastructure
    DOI:  https://doi.org/10.1007/978-1-0716-1270-5_11
  32. Cell Calcium. 2021 May 19. pii: S0143-4160(21)00070-1. [Epub ahead of print]97 102416
    Sprinkling salt on mitochondria: The metabolic and pathophysiological roles of mitochondrial Na+ signaling mediated by NCLX.
    Essam A Assali, Israel Sekler.
      NCLX, the mitochondrial Na+/Ca2+ transporter is a key player in Ca2+ signaling. However, its role in Na+ signaling is poorly understood. In this review we focus on Na+ signaling by NCLX, and discuss recent physiological and pathophysiological roles attributed to the Na+ influx into mitochondria.
    Keywords:  Hypoxia; Ischemia; Mitochondrial Ca(2+) efflux; NCLX; Na(+) signaling
    DOI:  https://doi.org/10.1016/j.ceca.2021.102416
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