bims-midneu Biomed News
on Mitochondrial dysfunction in neurodegeneration
Issue of 2021–05–02
forty-two papers selected by
Radha Desai, Merck Sharp & Dohme Corp.
  1. PINK1: A Bridge between Mitochondria and Parkinson's Disease.
  2. GLP-1 improves the neuronal supportive ability of astrocytes in Alzheimer's disease by regulating mitochondrial dysfunction via the cAMP/PKA pathway.
  3. Changes in Drp1 Function and Mitochondrial Morphology Are Associated with the α-Synuclein Pathology in a Transgenic Mouse Model of Parkinson's Disease.
  4. Abnormalities of mitochondrial dynamics and bioenergetics in neuronal cells from CDKL5 deficiency disorder.
  5. PINK1-mediated mitophagy maintains pluripotency through optineurin.
  6. Mitochondrial complex I abnormalities is associated with tau and clinical symptoms in mild Alzheimer's disease.
  7. Telencephalon-specific Alkbh1 conditional knockout mice display hippocampal atrophy and impaired learning.
  8. PTEN regulates mitochondrial biogenesis via the AKT/GSK-3β/PGC-1α pathway in autism.
  9. The Mia40/CHCHD4 Oxidative Folding System: Redox Regulation and Signaling in the Mitochondrial Intermembrane Space.
  10. Genes Implicated in Familial Parkinson's Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage.
  11. Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies.
  12. Treating Neurodegenerative Disease with Antioxidants: Efficacy of the Bioactive Phenol Resveratrol and Mitochondrial-Targeted MitoQ and SkQ.
  13. TRPM2 channel in oxidative stress-induced mitochondrial dysfunction and apoptotic cell death.
  14. Human Mitoribosome Biogenesis and Its Emerging Links to Disease.
  15. Homoplasmy of the m. 8993 T>G variant in a patient without MRI findings of Leigh syndrome, ataxia or retinal abnormalities.
  16. BAP31: Physiological functions and roles in disease.
  17. The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS.
  18. The human brain acetylome reveals that decreased acetylation of mitochondrial proteins associates with Alzheimer's disease.
  19. Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity.
  20. Mitophagy in Human Diseases.
  21. Clinical Insights into Mitochondrial Neurodevelopmental and Neurodegenerative Disorders: Their Biosignatures from Mass Spectrometry-Based Metabolomics.
  22. High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer's Disease Signatures.
  23. IFN-β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1.
  24. Mitochondrial Dynamics: A Key Role in Neurodegeneration and a Potential Target for Neurodegenerative Disease.
  25. Protein profiling identified mitochondrial dysfunction and synaptic abnormalities after dexamethasone intervention in rats with traumatic brain injury.
  26. A Mechanism for the Inhibition of Tau Neurotoxicity: Studies with Artificial Membranes, Isolated Mitochondria, and Intact Cells.
  27. The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer's Disease Pathology.
  28. Inducible knockout of Clec16a in mice results in sensory neurodegeneration.
  29. Mitochondria Donation by Mesenchymal Stem Cells: Current Understanding and Mitochondria Transplantation Strategies.
  30. Low neuronal metabolism during isoflurane-induced burst suppression is related to synaptic inhibition while neurovascular coupling and mitochondrial function remain intact.
  31. New Insights of the NEET Protein CISD2 Reveals Distinct Features Compared to Its Close Mitochondrial Homolog mitoNEET.
  32. Quantitative imaging of membrane contact sites for sterol transfer between endo-lysosomes and mitochondria in living cells.
  33. Brown Vialetto Van Laere syndrome: presenting with left ventricular non-compaction and mimicking mitochondrial disorders.
  34. Deletion of Mitochondrial Translocator Protein (TSPO) Gene Decreases Oxidative Retinal Pigment Epithelial Cell Death via Modulation of TRPM2 Channel.
  35. The hypoxia sensitive metal transcription factor MTF-1 activates NCX1 brain promoter and participates in remote postconditioning neuroprotection in stroke.
  36. Mitochondrial DNA Methylation and Human Diseases.
  37. Blood-Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration.
  38. Mitochondrial K+ channels and their implications for disease mechanisms.
  39. Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases.
  40. Dexmedetomidine protects SH-SY5Y cells against MPP+ -induced declining of mitochondrial membrane potential and cell cycle deficits.
  41. TFG binds LC3C to regulate ULK1 localization and autophagosome formation.
  42. Sp1 is a substrate of Keap1 and regulates the activity of CRL4AWDR23 ubiquitin ligase toward Nrf2.
  1. Life (Basel). 2021 Apr 21. pii: 371. [Epub ahead of print]11(5):
    PINK1: A Bridge between Mitochondria and Parkinson's Disease.
    Filipa Barroso Gonçalves, Vanessa Alexandra Morais.
      Mitochondria are known as highly dynamic organelles essential for energy production. Intriguingly, in the recent years, mitochondria have revealed the ability to maintain cell homeostasis and ultimately regulate cell fate. This regulation is achieved by evoking mitochondrial quality control pathways that are capable of sensing the overall status of the cellular environment. In a first instance, actions to maintain a robust pool of mitochondria take place; however, if unsuccessful, measures that lead to overall cell death occur. One of the central key players of these mitochondrial quality control pathways is PINK1 (PTEN-induce putative kinase), a mitochondrial targeted kinase. PINK1 is known to interact with several substrates to regulate mitochondrial functions, and not only is responsible for triggering mitochondrial clearance via mitophagy, but also participates in maintenance of mitochondrial functions and homeostasis, under healthy conditions. Moreover, PINK1 has been associated with the familial form of Parkinson's disease (PD). Growing evidence has strongly linked mitochondrial homeostasis to the central nervous system (CNS), a system that is replenished with high energy demanding long-lasting neuronal cells. Moreover, sporadic cases of PD have also revealed mitochondrial impairments. Thus, one could speculate that mitochondrial homeostasis is the common denominator in these two forms of the disease, and PINK1 may play a central role in maintaining mitochondrial homeostasis. In this review, we will discuss the role of PINK1 in the mitochondrial physiology and scrutinize its role in the cascade of PD pathology.
    Keywords:  PINK1; Parkinson’s disease; mitochondria homeostasis
    DOI:  https://doi.org/10.3390/life11050371
  2. Biochem Pharmacol. 2021 Apr 22. pii: S0006-2952(21)00184-2. [Epub ahead of print]188 114578
    GLP-1 improves the neuronal supportive ability of astrocytes in Alzheimer's disease by regulating mitochondrial dysfunction via the cAMP/PKA pathway.
    Yunzhen Xie, Jiaping Zheng, Shiqi Li, Huiying Li, Yu Zhou, Wenrong Zheng, Meilian Zhang, Libin Liu, Zhou Chen.
      The glucagon-like peptide-1 (GLP-1) was shown to have neuroprotective effects in Alzheimer's disease (AD). However, the underlying mechanism remains elusive. Astrocytic mitochondrial abnormalities have been revealed to constitute important pathologies. In the present study, we investigated the role of astrocytic mitochondria in the neuroprotective effect of GLP-1 in AD. To this end, 6-month-old 5 × FAD mice were subcutaneously treated with liraglutide, a GLP-1 analogue (25 nmol/kg/qd) for 8 weeks. Liraglutide ameliorated mitochondrial dysfunction and prevented neuronal loss with activation of the cyclic adenosine 3',5'-monophosphate (cAMP)/phosphorylate protein kinase A (PKA) pathway in the brain of 5 × FAD mice. Next, we exposed astrocytes to β-amyloid (Aβ) in vitro and treated them with GLP-1. By activating the cAMP/PKA pathway, GLP-1 increased the phosphorylation of DRP-1 at the s637 site and mitigated mitochondrial fragmentation in Aβ-treated astrocytes. GLP-1 further improved the Aβ-induced energy failure, mitochondrial reactive oxygen species (ROS) overproduction, mitochondrial membrane potential (MMP) collapse, and cell toxicity in astrocytes. Moreover, GLP-1 also promoted the neuronal supportive ability of Aβ-treated astrocytes via the cAMP/PKA pathway. This study revealed a new mechanism behind the neuroprotective effect of GLP-1 in AD.
    Keywords:  Alzheimer’s disease; Astrocyte; Glucagon-like peptide-1; Mitochondrial dysfunction; cAMP/PKA pathway
    DOI:  https://doi.org/10.1016/j.bcp.2021.114578
  3. Cells. 2021 Apr 13. pii: 885. [Epub ahead of print]10(4):
    Changes in Drp1 Function and Mitochondrial Morphology Are Associated with the α-Synuclein Pathology in a Transgenic Mouse Model of Parkinson's Disease.
    Philipp Portz, Michael K Lee.
      Alterations in mitochondrial function and morphology are associated with many human diseases, including cancer and neurodegenerative diseases. Mitochondrial impairment is linked to Parkinson's disease (PD) pathogenesis, and alterations in mitochondrial dynamics are seen in PD models. In particular, α-synuclein (αS) abnormalities are often associated with pathological changes to mitochondria. However, the relationship between αS pathology and mitochondrial dynamics remains poorly defined. Herein, we examined a mouse model of α-synucleinopathy for αS pathology-linked alterations in mitochondrial dynamics in vivo. We show that α-synucleinopathy in a transgenic (Tg) mouse model expressing familial PD-linked mutant A53T human αS (TgA53T) is associated with a decrease in Drp1 localization and activity in the mitochondria. In addition, we show that the loss of Drp1 function in the mitochondria is associated with two distinct phenotypes of enlarged neuronal mitochondria. Mitochondrial enlargement was only present in diseased animals and, apart from Drp1, other proteins involved in mitochondrial dynamics are unlikely to cause these changes, as their levels remained mostly unchanged. Further, the levels of Mfn1, a protein that facilitates mitochondrial fusion, was decreased nonspecifically with transgene expression. These results support the view that altered mitochondrial dynamics are a significant neuropathological factor in α-synucleinopathies.
    Keywords:  Drp1; Parkinson; alpha-synuclein; fission; fusion; mitochondria; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.3390/cells10040885
  4. Neurobiol Dis. 2021 Apr 24. pii: S0969-9961(21)00119-4. [Epub ahead of print] 105370
    Abnormalities of mitochondrial dynamics and bioenergetics in neuronal cells from CDKL5 deficiency disorder.
    Nicole J Van Bergen, Sean Massey, Tegan Stait, Molly Ellery, Boris Reljić, Luke E Formosa, Anita Quigley, Mirella Dottori, David Thorburn, David A Stroud, John Christodoulou.
      CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by pathogenic variants in the Cyclin-dependent kinase-like 5 (CDKL5) gene, resulting in dysfunctional CDKL5 protein. It predominantly affects females and causes seizures in the first few months of life, ultimately resulting in severe intellectual disability. In the absence of targeted therapies, treatment is currently only symptomatic. CDKL5 is a serine/threonine kinase that is highly expressed in the brain, with a critical role in neuronal development. Evidence of mitochondrial dysfunction in CDD is gathering, but has not been studied extensively. We used human patient-derived induced pluripotent stem cells with a pathogenic truncating mutation (p.Arg59*) and CRISPR/Cas9 gene-corrected isogenic controls, differentiated into neurons, to investigate the impact of CDKL5 mutation on cellular function. Quantitative proteomics indicated mitochondrial defects in CDKL5 p.Arg59* neurons and mitochondrial bioenergetics analysis confirmed decreased activity of mitochondrial respiratory chain complexes. Additionally, mitochondrial trafficking velocity was significantly impaired, and there was a higher percentage of stationary mitochondria. We propose mitochondrial dysfunction is contributing to CDD pathology, and should be a focus for development of targeted treatments for CDD.
    Keywords:  CDKL5 deficiency disorder; DKL5; Induced pluripotent stem cell; Mitochondria; Oxidative phosphorylation; Proteomics
    DOI:  https://doi.org/10.1016/j.nbd.2021.105370
  5. Cell Prolif. 2021 May 01. e13034
    PINK1-mediated mitophagy maintains pluripotency through optineurin.
    Chaoqun Wang, Kun Liu, Jiani Cao, Liang Wang, Qian Zhao, Zheng Li, Honghai Zhang, Quan Chen, Tongbiao Zhao.
       OBJECTIVES: Dysfunction of autophagy results in accumulation of depolarized mitochondria and breakdown of self-renewal and pluripotency in ESCs. However, the regulators that control how mitochondria are degraded by autophagy for pluripotency regulation remains largely unknown. This study aims to dissect the molecular mechanisms that regulate mitochondrial homeostasis for pluripotency regulation in mouse ESCs.
    MATERIALS AND METHODS: Parkin+/+ and parkin-/- ESCs were established from E3.5 blastocysts of parkin+/- x parkin+/- mating mice. The pink1-/- , optn-/- and ndp52-/- ESCs were generated by CRISPR-Cas9. shRNAs were used for function loss assay of target genes. Mito-Keima, ROS and ATP detection were used to investigate the mitophagy and mitochondrial function. Western blot, Q-PCR, AP staining and teratoma formation assay were performed to evaluate the PSC stemness.
    RESULTS: PINK1 or OPTN depletion impairs the degradation of dysfunctional mitochondria during reprogramming, and reduces the reprogramming efficiency and quality. In ESCs, PINK1 or OPTN deficiency leads to accumulation of dysfunctional mitochondria and compromised pluripotency. The defective mitochondrial homeostasis and pluripotency in pink1-/- ESCs can be compensated by gain expression of phosphomimetic Ubiquitin (Ub-S65D) together with WT or a constitutively active phosphomimetic OPTN mutant (S187D, S476D, S517D), rather than constitutively inactive OPTN (S187A, S476A, S517A) or a Ub-binding dead OPTN mutant (D477N).
    CONCLUSIONS: The mitophagy receptor OPTN guards ESC mitochondrial homeostasis and pluripotency by scavenging damaged mitochondria through TBK1-activated OPTN binding of PINK1-phosphorylated Ubiquitin.
    Keywords:  OPTN; PINK1; embryonic stem cells; mitochondria; mitophagy; reprogramming
    DOI:  https://doi.org/10.1111/cpr.13034
  6. Mol Neurodegener. 2021 Apr 26. 16(1): 28
    Mitochondrial complex I abnormalities is associated with tau and clinical symptoms in mild Alzheimer's disease.
    Tatsuhiro Terada, Joseph Therriault, Min Su Peter Kang, Melissa Savard, Tharick Ali Pascoal, Firoza Lussier, Cecile Tissot, Yi-Ting Wang, Andrea Benedet, Takashi Matsudaira, Tomoyasu Bunai, Tomokazu Obi, Hideo Tsukada, Yasuomi Ouchi, Pedro Rosa-Neto.
       BACKGROUND: Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer's disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [18F]BCPP-EF.
    METHODS: Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [18F]BCPP-EF mitochondrial function, [11C]PBB3 for tau deposition, and [11C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed.
    RESULTS: The [18F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [11C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [18F]BCPP-EF SUVR and [11C]PBB3 BPND (R = 0.2679, p = 0.04), but not [11C] PiB SUVR.
    CONCLUSIONS: Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [11C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.
    Keywords:  Alzheimer’s disease (AD); Amyloid; Mitochondria; PET; Tau; [18F]BCPP-EF
    DOI:  https://doi.org/10.1186/s13024-021-00448-1
  7. FEBS Lett. 2021 Apr 30.
    Telencephalon-specific Alkbh1 conditional knockout mice display hippocampal atrophy and impaired learning.
    Layla Kawarada, Masahiro Fukaya, Ryo Saito, Hidetoshi Kassai, Hiroyuki Sakagami, Atsu Aiba.
      AlkB homolog 1 (ALKBH1) is responsible for the biogenesis of 5-formylcytidine (f5 C) on mitochondrial tRNAMet and essential for mitochondrial protein synthesis. The brain, especially the hippocampus, is highly susceptible to mitochondrial dysfunction; hence, the maintenance of mitochondrial activity is strongly required to prevent disorders associated with hippocampal malfunction. To study the role of ALKBH1 in the hippocampus, we generated dorsal telencephalon-specific Alkbh1 conditional KO (cKO) mice in inbred C57BL/6 background. These mice showed reduced activity of the respiratory chain complex, hippocampal atrophy and CA1 pyramidal neuron abnormalities. Furthermore, performances in the fear-conditioning and Morris water maze tests in cKO mice indicated that the hippocampal abnormalities led to impaired hippocampus-dependent learning. These findings indicate critical roles of ALKBH1 in the hippocampus.
    Keywords:  Alkbh1; hippocampus; knockout mice; learning and memory; mitochondria
    DOI:  https://doi.org/10.1002/1873-3468.14098
  8. Neuroscience. 2021 Apr 22. pii: S0306-4522(21)00199-8. [Epub ahead of print]
    PTEN regulates mitochondrial biogenesis via the AKT/GSK-3β/PGC-1α pathway in autism.
    Chenxi Feng, Yajing Chen, Yuyang Zhang, Yinghui Yan, Mengjie Yang, Huan Gui, Mei Wang.
      Autism spectrum disorder (ASD) is a widespread, complex and serious neurodevelopmental disorder. Complex genetic and environmental factors are thought to contribute to the development of ASD. Genome-wide association analysis has identified multiple autism-related genes. Mutation of the phosphatase and tensin homolog (Pten) is closely related to autism and accounts for 5-17% of cases of autism. However, the detailed mechanism is still unclear. Recently, mitochondrial dysfunction was tightly associated with ASD pathogenesis, such as developmental degeneration, learning and various behavioral disorders. The mitochondrial DNA (mtDNA) copy number in children with autism is also significantly increased. The correlation between Pten and mitochondrial dysfunction in autism is still unknown. In this study, we examined how Pten regulates mitochondrial biogenesis through the AKT/GSK-3β/PGC-1α signaling pathways. We found that PTEN could dephosphorylate AKT to inhibit its activity, leading to decreased GSK3β phosphorylation. This decrease in GSK3β phosphorylation, which could activate itself, increased PGC-1α phosphorylation to promote its degradation and then regulated mitochondrial biogenesis by NRF-1 and TFAM downstream of PGC-1α. In the Valproic acid (VPA) induced autism mouse model, the PTEN protein level was significantly decreased while PGC-1α and COX IV levels were increased in the hippocampus and cortex. Our data suggest that there is a correlation between PTEN and mitochondrial dysfunction and this correlation may be a potential mechanism of ASD.
    Keywords:  Autism; Mitochondrial dysfunction; PTEN
    DOI:  https://doi.org/10.1016/j.neuroscience.2021.04.010
  9. Antioxidants (Basel). 2021 Apr 12. pii: 592. [Epub ahead of print]10(4):
    The Mia40/CHCHD4 Oxidative Folding System: Redox Regulation and Signaling in the Mitochondrial Intermembrane Space.
    Eleanor Dickson-Murray, Kenza Nedara, Nazanine Modjtahedi, Kostas Tokatlidis.
      Mitochondria are critical for several cellular functions as they control metabolism, cell physiology, and cell death. The mitochondrial proteome consists of around 1500 proteins, the vast majority of which (about 99% of them) are encoded by nuclear genes, with only 13 polypeptides in human cells encoded by mitochondrial DNA. Therefore, it is critical for all the mitochondrial proteins that are nuclear-encoded to be targeted precisely and sorted specifically to their site of action inside mitochondria. These processes of targeting and sorting are catalysed by protein translocases that operate in each one of the mitochondrial sub-compartments. The main protein import pathway for the intermembrane space (IMS) recognises proteins that are cysteine-rich, and it is the only import pathway that chemically modifies the imported precursors by introducing disulphide bonds to them. In this manner, the precursors are trapped in the IMS in a folded state. The key component of this pathway is Mia40 (called CHCHD4 in human cells), which itself contains cysteine motifs and is subject to redox regulation. In this review, we detail the basic components of the MIA pathway and the disulphide relay mechanism that underpins the electron transfer reaction along the oxidative folding mechanism. Then, we discuss the key protein modulators of this pathway and how they are interlinked to the small redox-active molecules that critically affect the redox state in the IMS. We present also evidence that the mitochondrial redox processes that are linked to iron-sulfur clusters biogenesis and calcium homeostasis coalesce in the IMS at the MIA machinery. The fact that the MIA machinery and several of its interactors and substrates are linked to a variety of common human diseases connected to mitochondrial dysfunction highlight the potential of redox processes in the IMS as a promising new target for developing new treatments for some of the most complex and devastating human diseases.
    Keywords:  Mia40; intermembrane space; mitochondria; oxidative folding; redox signaling
    DOI:  https://doi.org/10.3390/antiox10040592
  10. Int J Mol Sci. 2021 Apr 28. pii: 4643. [Epub ahead of print]22(9):
    Genes Implicated in Familial Parkinson's Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage.
    Rafael Franco, Rafael Rivas-Santisteban, Gemma Navarro, Annalisa Pinna, Irene Reyes-Resina.
      The mechanism of nigral dopaminergic neuronal degeneration in Parkinson's disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a narrative review that takes advantage of information related to genes (SNCA, LRRK2, GBA, UCHL1, VPS35, PRKN, PINK1, ATP13A2, PLA2G6, DNAJC6, SYNJ1, DJ-1/PARK7 and FBXO7) involved in familial cases of Parkinson's disease (PD) to explore their usefulness in deciphering the origin of dopaminergic denervation in many types of PD. Direct or functional interactions between genes or gene products are evaluated using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The rationale is to propose a map of the interactions between SNCA, the gene encoding for α-syn that aggregates in PD, and other genes, the mutations of which lead to early-onset PD. The map contrasts with the findings obtained using animal models that are the knockout of one of those genes or that express the mutated human gene. From combining in silico data from STRING-based assays with in vitro and in vivo data in transgenic animals, two likely mechanisms appeared: (i) the processing of native α-syn is altered due to the mutation of genes involved in vesicular trafficking and protein processing, or (ii) α-syn mutants alter the mechanisms necessary for the correct vesicular trafficking and protein processing. Mitochondria are a common denominator since both mechanisms require extra energy production, and the energy for the survival of neurons is obtained mainly from the complete oxidation of glucose. Dopamine itself can result in an additional burden to the mitochondria of dopaminergic neurons because its handling produces free radicals. Drugs acting on G protein-coupled receptors (GPCRs) in the mitochondria of neurons may hopefully end up targeting those receptors to reduce oxidative burden and increase mitochondrial performance. In summary, the analysis of the data of genes related to familial PD provides relevant information on the etiology of sporadic cases and might suggest new therapeutic approaches.
    Keywords:  Lewy bodies; early-onset Parkinson’s disease; familial Parkinson’s disease; mitochondria; mitophagy; synuclein aggregation; vesicular transport
    DOI:  https://doi.org/10.3390/ijms22094643
  11. Biomedicines. 2021 Apr 02. pii: 376. [Epub ahead of print]9(4):
    Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies.
    Chantal B Lucini, Ralf J Braun.
      In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.
    Keywords:  TDP-43; apoptosis; cell death; mitochondria; mitochondrial permeabilization; mtDNA; proteinopathy
    DOI:  https://doi.org/10.3390/biomedicines9040376
  12. Antioxidants (Basel). 2021 Apr 08. pii: 573. [Epub ahead of print]10(4):
    Treating Neurodegenerative Disease with Antioxidants: Efficacy of the Bioactive Phenol Resveratrol and Mitochondrial-Targeted MitoQ and SkQ.
    Lindsey J Shinn, Sarita Lagalwar.
      Growing evidence from neurodegenerative disease research supports an early pathogenic role for mitochondrial dysfunction in affected neurons that precedes morphological and functional deficits. The resulting oxidative stress and respiratory malfunction contribute to neuronal toxicity and may enhance the vulnerability of neurons to continued assault by aggregation-prone proteins. Consequently, targeting mitochondria with antioxidant therapy may be a non-invasive, inexpensive, and viable means of strengthening neuronal health and slowing disease progression, thereby extending quality of life. We review the preclinical and clinical findings available to date of the natural bioactive phenol resveratrol and two synthetic mitochondrial-targeted antioxidants, MitoQ and SkQ.
    Keywords:  MitoQ; SkQ; antioxidants; neurodegenerative disease; resveratrol
    DOI:  https://doi.org/10.3390/antiox10040573
  13. Adv Protein Chem Struct Biol. 2021 ;pii: S1876-1623(20)30087-0. [Epub ahead of print]125 51-72
    TRPM2 channel in oxidative stress-induced mitochondrial dysfunction and apoptotic cell death.
    Philippa Malko, Ran Ding, Lin-Hua Jiang.
      Mitochondria, conserved intracellular organelles best known as the powerhouse of cells for generating ATP, play an important role in apoptosis. Oxidative stress can induce mitochondrial dysfunction and activate mitochondria-mediated apoptotic cell death. TRPM2 is a Ca2+-permeable cation channel that is activated by pathologically relevant concentrations of reactive oxygen species (ROS) and one of its well-recognized roles is to confer susceptibility to ROS-induced cell death. Increasing evidence from recent studies supports TRPM2 channel-mediated cell death as an important cellular mechanism linking miscellaneous oxidative stress-inducing pathological factors to associated diseased conditions. In this chapter, we will discuss the role of the TRPM2 channel in neurons in the brain and pancreatic β-cells in mediating mitochondrial dysfunction and cell death, focusing mainly on apoptotic cell death, that are induced by pathological stimuli implicated in the pathogenesis of neurodegenerative diseases, ischemic stroke and diabetes.
    Keywords:  Apoptotic cell death; Diabetes; Ischemic stroke; Mitochondrial dysfunction; Neurodegenerative diseases; Pancreatic β-cells; Reactive oxygen species; TRPM2 channel
    DOI:  https://doi.org/10.1016/bs.apcsb.2020.12.001
  14. Int J Mol Sci. 2021 Apr 07. pii: 3827. [Epub ahead of print]22(8):
    Human Mitoribosome Biogenesis and Its Emerging Links to Disease.
    Maria Isabel G Lopez Sanchez, Annika Krüger, Dmitrii I Shiriaev, Yong Liu, Joanna Rorbach.
      Mammalian mitochondrial ribosomes (mitoribosomes) synthesize a small subset of proteins, which are essential components of the oxidative phosphorylation machinery. Therefore, their function is of fundamental importance to cellular metabolism. The assembly of mitoribosomes is a complex process that progresses through numerous maturation and protein-binding events coordinated by the actions of several assembly factors. Dysregulation of mitoribosome production is increasingly recognized as a contributor to metabolic and neurodegenerative diseases. In recent years, mutations in multiple components of the mitoribosome assembly machinery have been associated with a range of human pathologies, highlighting their importance to cell function and health. Here, we provide a review of our current understanding of mitoribosome biogenesis, highlighting the key factors involved in this process and the growing number of mutations in genes encoding mitoribosomal RNAs, proteins, and assembly factors that lead to human disease.
    Keywords:  assembly factors; mitochondria; mitochondrial disease; mitoribosome; rRNA
    DOI:  https://doi.org/10.3390/ijms22083827
  15. Mitochondrion. 2021 Apr 21. pii: S1567-7249(21)00056-8. [Epub ahead of print]
    Homoplasmy of the m. 8993 T>G variant in a patient without MRI findings of Leigh syndrome, ataxia or retinal abnormalities.
    Russell P Saneto, Kristina E Patrick, Francisco A Perez.
      Leigh syndrome is a progressive neurodegenerative syndrome caused by multiple mitochondrial DNA and nuclear DNA pathological variants. Patients with Leigh syndrome consistently have distinct brain lesions found on MRI scanning involving abnormal signal in the basal ganglia, brainstem and/or cerebellum. Other clinical findings vary depending on the genetic etiology and epigenetic factors. Mitochondrial DNA-derived Leigh syndrome phenotype is thought to be modulated by heteroplasmy level. The classic example is the clinical expression of the pathological variant, m. 8993 T>G. At heteroplasmy levels above 90%, the resulting phenotype is Leigh syndrome, but at levels 70 - 90% patients present with a syndrome of neuropathy, ataxia and retinitis pigmentosa. We describe a 15-year old girl with homoplasmic variant in m.8993 T>G and clinical and biochemical findings consistent with Leigh syndrome but with normal brain MRI findings and without retinal abnormalities or ataxia.
    Keywords:  Leigh syndrome; MRI brain; basal ganglia; homoplasmy; m. 8993 T>G; mitochondrial disease
    DOI:  https://doi.org/10.1016/j.mito.2021.04.010
  16. Biochimie. 2021 Apr 27. pii: S0300-9084(21)00105-X. [Epub ahead of print]
    BAP31: Physiological functions and roles in disease.
    Esben M Quistgaard.
      B-cell receptor-associated protein 31 (BAP31 or BCAP31) is a ubiquitously expressed transmembrane protein found mainly in the endoplasmic reticulum (ER), including at mitochondria-associated membranes (MAMs). It acts as a broad-specificity membrane protein chaperone and quality control factor, which can promote different fates for its clients, including ER retention, ER export, ER-associated degradation (ERAD), or evasion of degradation, and it also acts as a MAM tetherer and regulatory protein. It is involved in several cellular processes - it supports ER and mitochondrial homeostasis, promotes proliferation and migration, plays several roles in metabolism and the immune system, and regulates autophagy and apoptosis. Full-length BAP31 can be anti-apoptotic, but can also mediate activation of caspase-8, and itself be cleaved by caspase-8 into p20-BAP31, which promotes apoptosis by mobilizing ER calcium stores at MAMs. BAP31 loss-of-function mutations is the cause of 'deafness, dystonia, and central hypomyelination' (DDCH) syndrome, characterized by severe neurological symptoms and early death. BAP31 is furthermore implicated in a growing number of cancers and other diseases, and several viruses have been found to target it to promote their survival or life cycle progression. The purpose of this review is to provide an overview and examination of the basic properties, functions, mechanisms, and roles in disease of BAP31.
    Keywords:  Apoptosis; Chaperone; ER stress; Mitochondria-associated membrane (MAM); Unfolded protein response (UPR); X-linked intellectual disability (XLID)
    DOI:  https://doi.org/10.1016/j.biochi.2021.04.008
  17. Antioxidants (Basel). 2021 Apr 02. pii: 552. [Epub ahead of print]10(4):
    The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS.
    Jasmine Harley, Benjamin E Clarke, Rickie Patani.
      RNA binding proteins fulfil a wide number of roles in gene expression. Multiple mechanisms of RNA binding protein dysregulation have been implicated in the pathomechanisms of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Oxidative stress and mitochondrial dysfunction also play important roles in these diseases. In this review, we highlight the mechanistic interplay between RNA binding protein dysregulation, oxidative stress and mitochondrial dysfunction in ALS. We also discuss different potential therapeutic strategies targeting these pathways.
    Keywords:  ALS; RNA binding protein; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3390/antiox10040552
  18. J Neurochem. 2021 Apr 27.
    The human brain acetylome reveals that decreased acetylation of mitochondrial proteins associates with Alzheimer's disease.
    Lidan Sun, Ruchika Bhawal, Hui Xu, Huanlian Chen, Elizabeth T Anderson, Vahrum Haroutunian, Abigail C Cross, Sheng Zhang, Gary E Gibson.
      Metabolic changes that correlate to cognitive changes are well known in AD. Metabolism is often linked to functional changes in proteins by post-translational modifications. The importance of the regulation of transcription by acetylation is well documented. Advanced mass spectrometry reveals hundreds of acetylated proteins in multiple tissues, but the acetylome of human brain, its functional significance and the changes with disease are unknown. Filling this gap is critical for understanding the pathophysiology and development of therapies. To fill this gap, we assessed the human brain acetylome in human brain and its changes with Alzheimer's Disease (AD). More than 5% of the 4,442 proteins from the human brain global proteome were acetylated. Acetylated proteins were primarily found in the cytosol (148), mitochondria (100), nucleus (91) and plasma membrane (58). The comparison of the brain acetylome in controls to that of patients with AD revealed striking and selective differences in terms of its abundances of acetylated peptides/sites. Acetylation of 18 mitochondrial proteins decreased, while acetylation of two cytosolic proteins, tau and GFAP, increased. Our experiments demonstrate that acetylation at some specific lysine sites alters enzyme function. The results indicate that general activation of de-acetylases (i.e., sirtuins) is not an appropriate therapeutic approach for AD.
    Keywords:  Alzheimer’s disease; acetylation; human brain; ketoglutarate dehydrogenase complex; pyruvate dehydrogenase complex
    DOI:  https://doi.org/10.1111/jnc.15377
  19. Nat Metab. 2021 Apr 26.
    Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity.
    Hans-Georg Sprenger, Thomas MacVicar, Amir Bahat, Kai Uwe Fiedler, Steffen Hermans, Denise Ehrentraut, Katharina Ried, Dusanka Milenkovic, Nina Bonekamp, Nils-Göran Larsson, Hendrik Nolte, Patrick Giavalisco, Thomas Langer.
      Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP-AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS-STING-TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS-STING-TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.
    DOI:  https://doi.org/10.1038/s42255-021-00385-9
  20. Int J Mol Sci. 2021 Apr 09. pii: 3903. [Epub ahead of print]22(8):
    Mitophagy in Human Diseases.
    Laura Doblado, Claudia Lueck, Claudia Rey, Alejandro K Samhan-Arias, Ignacio Prieto, Alessandra Stacchiotti, Maria Monsalve.
      Mitophagy is a selective autophagic process, essential for cellular homeostasis, that eliminates dysfunctional mitochondria. Activated by inner membrane depolarization, it plays an important role during development and is fundamental in highly differentiated post-mitotic cells that are highly dependent on aerobic metabolism, such as neurons, muscle cells, and hepatocytes. Both defective and excessive mitophagy have been proposed to contribute to age-related neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, metabolic diseases, vascular complications of diabetes, myocardial injury, muscle dystrophy, and liver disease, among others. Pharmacological or dietary interventions that restore mitophagy homeostasis and facilitate the elimination of irreversibly damaged mitochondria, thus, could serve as potential therapies in several chronic diseases. However, despite extraordinary advances in this field, mainly derived from in vitro and preclinical animal models, human applications based on the regulation of mitochondrial quality in patients have not yet been approved. In this review, we summarize the key selective mitochondrial autophagy pathways and their role in prevalent chronic human diseases and highlight the potential use of specific interventions.
    Keywords:  Alzheimer’s; Huntington’s; PINK1; Parkin; Parkinson’s; aging; atherosclerosis; dementia; diabetes; exercise; heart failure; mice; mitophagy; muscle wasting; rats
    DOI:  https://doi.org/10.3390/ijms22083903
  21. Metabolites. 2021 Apr 10. pii: 233. [Epub ahead of print]11(4):
    Clinical Insights into Mitochondrial Neurodevelopmental and Neurodegenerative Disorders: Their Biosignatures from Mass Spectrometry-Based Metabolomics.
    Haorong Li, Martine Uittenbogaard, Ling Hao, Anne Chiaramello.
      Mitochondria are dynamic multitask organelles that function as hubs for many metabolic pathways. They produce most ATP via the oxidative phosphorylation pathway, a critical pathway that the brain relies on its energy need associated with its numerous functions, such as synaptic homeostasis and plasticity. Therefore, mitochondrial dysfunction is a prevalent pathological hallmark of many neurodevelopmental and neurodegenerative disorders resulting in altered neurometabolic coupling. With the advent of mass spectrometry (MS) technology, MS-based metabolomics provides an emerging mechanistic understanding of their global and dynamic metabolic signatures. In this review, we discuss the pathogenetic causes of mitochondrial metabolic disorders and the recent MS-based metabolomic advances on their metabolomic remodeling. We conclude by exploring the MS-based metabolomic functional insights into their biosignatures to improve diagnostic platforms, stratify patients, and design novel targeted therapeutic strategies.
    Keywords:  mass spectrometry; metabolomics; mitochondrial genetics; mitochondrial neurodevelopmental disorders; neurometabolic coupling; secondary mitochondrial neurodegenerative diseases
    DOI:  https://doi.org/10.3390/metabo11040233
  22. Int J Mol Sci. 2021 Apr 03. pii: 3746. [Epub ahead of print]22(7):
    High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer's Disease Signatures.
    Ilaria Zuliani, Chiara Lanzillotta, Antonella Tramutola, Eugenio Barone, Marzia Perluigi, Serena Rinaldo, Alessio Paone, Francesca Cutruzzolà, Francesco Bellanti, Matteo Spinelli, Francesca Natale, Salvatore Fusco, Claudio Grassi, Fabio Di Domenico.
      The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer's disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.
    Keywords:  brain insulin resistance; high-fat diet; mitochondria; neurodegeneration; protein O-GlcNAcylation
    DOI:  https://doi.org/10.3390/ijms22073746
  23. EMBO J. 2021 Apr 29. e106868
    IFN-β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1.
    Emilie Tresse, Lluís Riera-Ponsati, Elham Jaberi, Wei Qi Guinevere Sew, Karsten Ruscher, Shohreh Issazadeh-Navikas.
      Mitochondrial homeostasis is essential for providing cellular energy, particularly in resource-demanding neurons, defects in which cause neurodegeneration, but the function of interferons (IFNs) in regulating neuronal mitochondrial homeostasis is unknown. We found that neuronal IFN-β is indispensable for mitochondrial homeostasis and metabolism, sustaining ATP levels and preventing excessive ROS by controlling mitochondrial fission. IFN-β induces events that are required for mitochondrial fission, phosphorylating STAT5 and upregulating PGAM5, which phosphorylates serine 622 of Drp1. IFN-β signaling then recruits Drp1 to mitochondria, oligomerizes it, and engages INF2 to stabilize mitochondria-endoplasmic reticulum (ER) platforms. This process tethers damaged mitochondria to the ER to separate them via fission. Lack of neuronal IFN-β in the Ifnb-/- model of Parkinson disease (PD) disrupts STAT5-PGAM5-Drp1 signaling, impairing fission and causing large multibranched, damaged mitochondria with insufficient ATP production and excessive oxidative stress to accumulate. In other PD models, IFN-β rescues dopaminergic neuronal cell death and pathology, associated with preserved mitochondrial homeostasis. Thus, IFN-β activates mitochondrial fission in neurons through the pSTAT5/PGAM5/S622 Drp1 pathway to stabilize mitochondria/ER platforms, constituting an essential neuroprotective mechanism.
    Keywords:  ATP; Parkinson disease; ROS; hydroxydopamine; mitochondrial metabolism
    DOI:  https://doi.org/10.15252/embj.2020106868
  24. Front Neurosci. 2021 ;15 654785
    Mitochondrial Dynamics: A Key Role in Neurodegeneration and a Potential Target for Neurodegenerative Disease.
    Danying Yang, Jun Ying, Xifeng Wang, Tiancheng Zhao, Sungtae Yoon, Yang Fang, Qingcui Zheng, Xing Liu, Wen Yu, Fuzhou Hua.
      In neurodegenerative diseases, neurodegeneration has been related to several mitochondrial dynamics imbalances such as excessive fragmentation of mitochondria, impaired mitophagy, and blocked mitochondria mitochondrial transport in axons. Mitochondria are dynamic organelles, and essential for energy conversion, neuron survival, and cell death. As mitochondrial dynamics have a significant influence on homeostasis, in this review, we mainly discuss the role of mitochondrial dynamics in several neurodegenerative diseases. There is evidence that several mitochondrial dynamics-associated proteins, as well as related pathways, have roles in the pathological process of neurodegenerative diseases with an impact on mitochondrial functions and metabolism. However, specific pathological mechanisms need to be better understood in order to propose new therapeutic strategies targeting mitochondrial dynamics that have shown promise in recent studies.
    Keywords:  mitochondrial dynamics; mitochondrial fusion and fission; mitochondrial transport; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.3389/fnins.2021.654785
  25. Neural Regen Res. 2021 Dec;16(12): 2438-2445
    Protein profiling identified mitochondrial dysfunction and synaptic abnormalities after dexamethasone intervention in rats with traumatic brain injury.
    Fei Niu, Bin Zhang, Jie Feng, Xiang Mao, Xiao-Jian Xu, Jin-Qian Dong, Bai-Yun Liu.
      Dexamethasone has been widely used after various neurosurgical procedures due to its anti-inflammatory property and the abilities to restore vascular permeability, inhibit free radicals, and reduce cerebrospinal fluid production. According to the latest guidelines for the treatment of traumatic brain injury in the United States, high-dose glucocorticoids cause neurological damage. To investigate the reason why high-dose glucocorticoids after traumatic brain injury exhibit harmful effect, rat controlled cortical impact models of traumatic brain injury were established. At 1 hour and 2 days after surgery, rat models were intraperitoneally administered dexamethasone 10 mg/kg. The results revealed that 31 proteins were significantly upregulated and 12 proteins were significantly downregulated in rat models of traumatic brain injury after dexamethasone treatment. The Ingenuity Pathway Analysis results showed that differentially expressed proteins were enriched in the mitochondrial dysfunction pathway and synaptogenesis signaling pathway. Western blot analysis and immunohistochemistry results showed that Ndufv2, Maob and Gria3 expression and positive cell count in the dexamethasone-treated group were significantly greater than those in the model group. These findings suggest that dexamethasone may promote a compensatory increase in complex I subunits (Ndufs2 and Ndufv2), increase the expression of mitochondrial enzyme Maob, and upregulate synaptic-transmission-related protein Gria3. These changes may be caused by nerve injury after traumatic brain injury treatment by dexamethasone. The study was approved by Institutional Ethics Committee of Beijing Neurosurgical Institute (approval No. 201802001) on June 6, 2018.
    Keywords:  Gria3; Maob; Ndufs2; Ndufv2; dexamethasone; mass spectrometry; mitochondrial dysfunction; proteomics; synaptic abnormalities; traumatic brain injury
    DOI:  https://doi.org/10.4103/1673-5374.313047
  26. ACS Chem Neurosci. 2021 Apr 27.
    A Mechanism for the Inhibition of Tau Neurotoxicity: Studies with Artificial Membranes, Isolated Mitochondria, and Intact Cells.
    Segev Naveh Tassa, Shani Ben Zichri, Shiran Lacham-Hartman, Ofek Oren, Zeev Slobodnik, Ekaterina Eremenko, Debra Toiber, Raz Jelinek, Niv Papo.
      It is currently believed that molecular agents that specifically bind to and neutralize the toxic proteins/peptides, amyloid β (Aβ42), tau, and the tau-derived peptide PHF6, hold the key to attenuating the progression of Alzheimer's disease (AD). We thus tested our previously developed nonaggregating Aβ42 double mutant (Aβ42DM) as a multispecific binder for three AD-associated molecules, wild-type Aβ42, the tauK174Q mutant, and a synthetic PHF6 peptide. Aβ42DM acted as a functional inhibitor of these molecules in in vitro assays and in neuronal cell-based models of AD. The double mutant bound both cytotoxic tauK174Q and synthetic PHF6 and protected neuronal cells from the accumulation of tau in cell lysates and mitochondria. Aβ42DM also reduced toxic intracellular levels of calcium and the overall cell toxicity induced by overexpressed tau, synthetic PHF6, Aβ42, or a combination of PHF6and Aβ42. Aβ42DM inhibited PHF6-induced overall mitochondrial dysfunction: In particular, Aβ42DM inhibited PHF6-induced damage to submitochondrial particles (SMPs) and suppressed PHF6-induced elevation of the ζ-potential of inverted SMPs (proxy for the inner mitochondrial membrane, IMM). PHF6 reduced the lipid fluidity of cardiolipin/DOPC vesicles (that mimic the IMM) but not DOPC (which mimics the outer mitochondrial membrane), and this effect was inhibited by Aβ42DM. This inhibition may be explained by the conformational changes in PHF6 induced by Aβ42DM in solution and in membrane mimetics. On this basis, the paper presents a mechanistic explanation for the inhibitory activity of Aβ42DM against Aβ42- and tau-induced membrane permeability and cell toxicity and provides confirmatory evidence for its protective function in neuronal cells.
    Keywords:  Alzheimer’s disease; Aβ42; PHF6; Tau; amyloids; neurodegeneration
    DOI:  https://doi.org/10.1021/acschemneuro.1c00045
  27. Life (Basel). 2021 Apr 25. pii: 388. [Epub ahead of print]11(5):
    The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer's Disease Pathology.
    Mariona Jové, Natàlia Mota-Martorell, Pascual Torres, Victoria Ayala, Manuel Portero-Otin, Isidro Ferrer, Reinald Pamplona.
      Current shreds of evidence point to the entorhinal cortex (EC) as the origin of the Alzheimer's disease (AD) pathology in the cerebrum. Compared with other cortical areas, the neurons from this brain region possess an inherent selective vulnerability derived from particular oxidative stress conditions that favor increased mitochondrial molecular damage with early bioenergetic involvement. This alteration of energy metabolism is the starting point for subsequent changes in a multitude of cell mechanisms, leading to neuronal dysfunction and, ultimately, cell death. These events are induced by changes that come with age, creating the substrate for the alteration of several neuronal pathways that will evolve toward neurodegeneration and, consequently, the development of AD pathology. In this context, the present review will focus on description of the biological mechanisms that confer vulnerability specifically to neurons of the entorhinal cortex, the changes induced by the aging process in this brain region, and the alterations at the mitochondrial level as the earliest mechanism for the development of AD pathology. Current findings allow us to propose the existence of an altered allostatic mechanism at the entorhinal cortex whose core is made up of mitochondrial oxidative stress, lipid metabolism, and energy production, and which, in a positive loop, evolves to neurodegeneration, laying the basis for the onset and progression of AD pathology.
    Keywords:  ATP synthase; aging; energy metabolism; entorhinal cortex; lipoxidation-derived damage; mitochondrial dysfunction; neurodegeneration; oxidative damage
    DOI:  https://doi.org/10.3390/life11050388
  28. Sci Rep. 2021 Apr 29. 11(1): 9319
    Inducible knockout of Clec16a in mice results in sensory neurodegeneration.
    Heather S Hain, Rahul Pandey, Marina Bakay, Bryan P Strenkowski, Danielle Harrington, Micah Romer, William W Motley, Jian Li, Eunjoo Lancaster, Lindsay Roth, Judith B Grinspan, Steven S Scherer, Hakon Hakonarson.
      CLEC16A has been shown to play a role in autophagy/mitophagy processes. Additionally, genetic variants in CLEC16A have been implicated in multiple autoimmune diseases. We generated an inducible whole-body knockout, Clec16aΔUBC mice, to investigate the loss of function of CLEC16A. The mice exhibited a neuronal phenotype including tremors and impaired gait that rapidly progressed to dystonic postures. Nerve conduction studies and pathological analysis revealed loss of sensory axons that are associated with this phenotype. Activated microglia and astrocytes were found in regions of the CNS. Several mitochondrial-related proteins were up- or down-regulated. Upregulation of interferon stimulated gene 15 (IGS15) were observed in neuronal tissues. CLEC16A expression inversely related to IGS15 expression. ISG15 may be the link between CLEC16A and downstream autoimmune, inflammatory processes. Our results demonstrate that a whole-body, inducible knockout of Clec16a in mice results in an inflammatory neurodegenerative phenotype resembling spinocerebellar ataxia.
    DOI:  https://doi.org/10.1038/s41598-021-88895-0
  29. Front Cell Dev Biol. 2021 ;9 653322
    Mitochondria Donation by Mesenchymal Stem Cells: Current Understanding and Mitochondria Transplantation Strategies.
    Marina O Gomzikova, Victoria James, Albert A Rizvanov.
      The phenomenon of mitochondria donation is found in various tissues of humans and animals and is attracting increasing attention. To date, numerous studies have described the transfer of mitochondria from stem cells to injured cells, leading to increased ATP production, restoration of mitochondria function, and rescue of recipient cells from apoptosis. Mitochondria transplantation is considered as a novel therapeutic approach for the treatment of mitochondrial diseases and mitochondrial function deficiency. Mitochondrial dysfunction affects cells with high energy needs such as neural, skeletal muscle, heart, and liver cells and plays a crucial role in type 2 diabetes, as well as Parkinson's, Alzheimer's diseases, ischemia, stroke, cancer, and age-related disorders. In this review, we summarize recent findings in the field of mitochondria donation and mechanism of mitochondria transfer between cells. We review the existing clinical trials and discuss advantages and disadvantages of mitochondrial transplantation strategies based on the injection of stem cells, isolated functional mitochondria, or EVs containing mitochondria.
    Keywords:  cell fusion; extracellular vesicles; isolated mitochondria; mitochondria donation; mitochondria transplantation; tunneling nanotubes
    DOI:  https://doi.org/10.3389/fcell.2021.653322
  30. J Cereb Blood Flow Metab. 2021 Apr 25. 271678X211010353
    Low neuronal metabolism during isoflurane-induced burst suppression is related to synaptic inhibition while neurovascular coupling and mitochondrial function remain intact.
    Nikolaus Berndt, Richard Kovács, Karl Schoknecht, Jörg Rösner, Clemens Reiffurth, Mathilde Maechler, Hermann-Georg Holzhütter, Jens P Dreier, Claudia Spies, Agustin Liotta.
      Deep anaesthesia may impair neuronal, vascular and mitochondrial function facilitating neurological complications, such as delirium and stroke. On the other hand, deep anaesthesia is performed for neuroprotection in critical brain diseases such as status epilepticus or traumatic brain injury. Since the commonly used anaesthetic propofol causes mitochondrial dysfunction, we investigated the impact of the alternative anaesthetic isoflurane on neuro-metabolism. In deeply anaesthetised Wistar rats (burst suppression pattern), we measured increased cortical tissue oxygen pressure (ptiO2), a ∼35% drop in regional cerebral blood flow (rCBF) and burst-associated neurovascular responses. In vitro, 3% isoflurane blocked synaptic transmission and impaired network oscillations, thereby decreasing the cerebral metabolic rate of oxygen (CMRO2). Concerning mitochondrial function, isoflurane induced a reductive shift in flavin adenine dinucleotide (FAD) and decreased stimulus-induced FAD transients as Ca2+ influx was reduced by ∼50%. Computer simulations based on experimental results predicted no direct effects of isoflurane on mitochondrial complexes or ATP-synthesis. We found that isoflurane-induced burst suppression is related to decreased ATP consumption due to inhibition of synaptic activity while neurovascular coupling and mitochondrial function remain intact. The neurometabolic profile of isoflurane thus appears to be superior to that of propofol which has been shown to impair the mitochondrial respiratory chain.
    Keywords:  Anaesthesia; burst suppression; cerebral blood flow; isoflurane; mitochondria
    DOI:  https://doi.org/10.1177/0271678X211010353
  31. Biomedicines. 2021 Apr 05. pii: 384. [Epub ahead of print]9(4):
    New Insights of the NEET Protein CISD2 Reveals Distinct Features Compared to Its Close Mitochondrial Homolog mitoNEET.
    Myriam Salameh, Sylvie Riquier, Olivier Guittet, Meng-Er Huang, Laurence Vernis, Michel Lepoivre, Marie-Pierre Golinelli-Cohen.
      Human CISD2 and mitoNEET are two NEET proteins anchored in the endoplasmic reticulum and mitochondria membranes respectively, with an Fe-S containing domain stretching out in the cytosol. Their cytosolic domains are close in sequence and structure. In the present study, combining cellular and biochemical approaches, we compared both proteins in order to possibly identify specific roles and mechanisms of action in the cell. We show that both proteins exhibit a high intrinsic stability and a sensitivity of their cluster to oxygen. In contrast, they differ in according to expression profiles in tissues and intracellular half-life. The stability of their Fe-S cluster and its ability to be transferred in vitro are affected differently by pH variations in a physiological and pathological range for cytosolic pH. Finally, we question a possible role for CISD2 in cellular Fe-S cluster trafficking. In conclusion, our work highlights unexpected major differences in the cellular and biochemical features between these two structurally close NEET proteins.
    Keywords:  CISD2; Fe–S cluster lability; Fe–S cluster transfer; UV-visible absorption spectroscopy; Wolfram syndrome; iron-sulfur protein
    DOI:  https://doi.org/10.3390/biomedicines9040384
  32. Sci Rep. 2021 Apr 26. 11(1): 8927
    Quantitative imaging of membrane contact sites for sterol transfer between endo-lysosomes and mitochondria in living cells.
    Alice Dupont Juhl, Christian W Heegaard, Stephan Werner, Gerd Schneider, Kathiresan Krishnan, Douglas F Covey, Daniel Wüstner.
      Mitochondria receive cholesterol from late endosomes and lysosomes (LE/LYSs) or from the plasma membrane for production of oxysterols and steroid hormones. This process depends on the endo-lysosomal sterol transfer protein Niemann Pick C2 (NPC2). Using the intrinsically fluorescent cholesterol analog, cholestatrienol, we directly observe sterol transport to mitochondria in fibroblasts upon treating NPC2 deficient human fibroblasts with NPC2 protein. Soft X-ray tomography reveals the ultrastructure of mitochondria and discloses close contact to endosome-like organelles. Using fluorescence microscopy, we localize endo-lysosomes containing NPC2 relative to mitochondria based on the Euclidian distance transform and use statistical inference to show that about 30% of such LE/LYSs are in contact to mitochondria in human fibroblasts. Using Markov Chain Monte Carlo image simulations, we show that interaction between both organelle types, a defining feature of membrane contact sites (MCSs) can give rise to the observed spatial organelle distribution. We devise a protocol to determine the surface fraction of endo-lysosomes in contact with mitochondria and show that this fraction does not depend on functional NPC1 or NPC2 proteins. Finally, we localize MCSs between LE/LYSs containing NPC2 and mitochondria in time-lapse image sequences and show that they either form transiently or remain stable for tens of seconds. Lasting MCSs between endo-lysosomes containing NPC2 and mitochondria move by slow anomalous sub-diffusion, providing location and time for sterol transport between both organelles. Our quantitative imaging strategy will be of high value for characterizing the dynamics and function of MCSs between various organelles in living cells.
    DOI:  https://doi.org/10.1038/s41598-021-87876-7
  33. Turk J Pediatr. 2021 ;pii: 2290. [Epub ahead of print]63(2): 314-318
    Brown Vialetto Van Laere syndrome: presenting with left ventricular non-compaction and mimicking mitochondrial disorders.
    Berna Şeker Yılmaz, Serdar Ceylaner, Neslihan Önenli Mungan.
       BACKGROUND: Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare, treatable neurodegenerative disorder with a variable clinical presentation, caused by mutations in three different riboflavin transporter genes.
    CASE: An 11-year-old-boy presented with respiratory insufficiency and a rapidly progressive muscle weakness. He was the fifth child of a consanguineous marriage with a medical history of hearing loss. He was peripherally week with a reduced muscle tone. Upper extremity muscles were effected more than lower limbs. He deteriorated rapidly and became quadriplegic. Brain magnetic resonance imaging and magnetic resonance spectroscopy were normal. Echocardiography revealed left ventricular non-compaction. A homozygous c.1088C > T (p.363L) missense mutation was identified in SLC52A2 gene. Significant clinical improvement was seen with high dose riboflavin.
    CONCLUSION: This is the first reported BVVLS case presented with left ventricle-non compaction which may be caused by a secondary respiratory chain deficiency. Riboflavin transporter deficiencies should be considered in the differential diagnosis of mitochondrial disorders and secondary respiratory chain deficiencies should be thought during the follow-up of BVVLS.
    Keywords:  Brown-Vialetto-Van Laere syndrome; left ventricle-non compaction; mitochondrial disorders; riboflavin
    DOI:  https://doi.org/10.24953/turkjped.2021.02.016
  34. Biology (Basel). 2021 Apr 28. pii: 382. [Epub ahead of print]10(5):
    Deletion of Mitochondrial Translocator Protein (TSPO) Gene Decreases Oxidative Retinal Pigment Epithelial Cell Death via Modulation of TRPM2 Channel.
    Dilek Özkaya, Xinhua Shu, Mustafa Nazıroğlu.
      The current results indicated the possible protective actions of 18 kDa mitochondrial translocator protein (TSPO) deletion on TRPM2 stimulation, mitochondrial free ROS (Mito-fROS) and apoptotic harmful actions in the cells of adult retinal pigment epithelial19 (ARPE19). There was a direct relationship between TSPO and the disease of age-related macular degeneration. The nature of TSPO implicates upregulation of Mito-fROS and apoptosis via the activation of Ca2+ channels in ARPE19, although deletion of TSPO gene downregulates the activation. The decrease of oxidative cytotoxicity and apoptosis might induce in TSPO gene deleted cells by the inhibition of Mito-fROS and PARP-1 activation-induced TRPM2 cation channel activation. The ARPE19 cells were divided into two main groups as TSPO expressing (ARPE19) and non-expressing cells (ARPE19-KO). The levels of caspase -3 (Casp -3), caspase -9 (Casp -9), apoptosis, Mito-fROS, TRPM2 current and intracellular free Ca2+ were upregulated in the ARPE19 by the stimulations of H2O2 and ADP-ribose, although their levels were downregulated in the cells by the modulators of PARP-1 (DPQ and PJ34), TRPM2 (ACA and 2APB) and glutathione. However, the H2O2 and ADP-ribose-mediated increases were not observed in the ARPE19-KO. The expression levels of Bax, Casp -3, Casp -9 and PARP-1 were higher in the ARPE19 group as compared to the ARPE19-KO group. In summary, current results confirmed that TRPM2-mediated cell death and oxidative cytotoxicity in the ARPE19 cells were occurred by the presence of TSPO. The deletion of TSPO may be considered as a therapeutic way to TRPM2 activation-mediated retinal oxidative injury.
    Keywords:  ARPE19 cells; TRPM2 channel; cell death; mitochondrial oxidative cytotoxicity; mitochondrial translocator protein
    DOI:  https://doi.org/10.3390/biology10050382
  35. Cell Death Dis. 2021 Apr 30. 12(5): 423
    The hypoxia sensitive metal transcription factor MTF-1 activates NCX1 brain promoter and participates in remote postconditioning neuroprotection in stroke.
    Valeria Valsecchi, Giusy Laudati, Ornella Cuomo, Rossana Sirabella, Lucio Annunziato, Giuseppe Pignataro.
      Remote limb ischemic postconditioning (RLIP) is an experimental strategy in which short femoral artery ischemia reduces brain damage induced by a previous harmful ischemic insult. Ionic homeostasis maintenance in the CNS seems to play a relevant role in mediating RLIP neuroprotection and among the effectors, the sodium-calcium exchanger 1 (NCX1) may give an important contribution, being expressed in all CNS cells involved in brain ischemic pathophysiology. The aim of this work was to investigate whether the metal responsive transcription factor 1 (MTF-1), an important hypoxia sensitive transcription factor, may (i) interact and regulate NCX1, and (ii) play a role in the neuroprotective effect mediated by RLIP through NCX1 activation. Here we demonstrated that in brain ischemia induced by transient middle cerebral occlusion (tMCAO), MTF-1 is triggered by a subsequent temporary femoral artery occlusion (FAO) and represents a mediator of endogenous neuroprotection. More importantly, we showed that MTF-1 translocates to the nucleus where it binds the metal responsive element (MRE) located at -23/-17 bp of Ncx1 brain promoter thus activating its transcription and inducing an upregulation of NCX1 that has been demonstrated to be neuroprotective. Furthermore, RLIP restored MTF-1 and NCX1 protein levels in the ischemic rat brain cortex and the silencing of MTF-1 prevented the increase of NCX1 observed in RLIP protected rats, thus demonstrating a direct regulation of NCX1 by MTF-1 in the ischemic cortex of rat exposed to tMCAO followed by FAO. Moreover, silencing of MTF-1 significantly reduced the neuroprotective effect elicited by RLIP as demonstrated by the enlargement of brain infarct volume observed in rats subjected to RLIP and treated with MTF-1 silencing. Overall, MTF-dependent activation of NCX1 and their upregulation elicited by RLIP, besides unraveling a new molecular pathway of neuroprotection during brain ischemia, might represent an additional mechanism to intervene in stroke pathophysiology.
    DOI:  https://doi.org/10.1038/s41419-021-03705-9
  36. Int J Mol Sci. 2021 Apr 27. pii: 4594. [Epub ahead of print]22(9):
    Mitochondrial DNA Methylation and Human Diseases.
    Andrea Stoccoro, Fabio Coppedè.
      Epigenetic modifications of the nuclear genome, including DNA methylation, histone modifications and non-coding RNA post-transcriptional regulation, are increasingly being involved in the pathogenesis of several human diseases. Recent evidence suggests that also epigenetic modifications of the mitochondrial genome could contribute to the etiology of human diseases. In particular, altered methylation and hydroxymethylation levels of mitochondrial DNA (mtDNA) have been found in animal models and in human tissues from patients affected by cancer, obesity, diabetes and cardiovascular and neurodegenerative diseases. Moreover, environmental factors, as well as nuclear DNA genetic variants, have been found to impair mtDNA methylation patterns. Some authors failed to find DNA methylation marks in the mitochondrial genome, suggesting that it is unlikely that this epigenetic modification plays any role in the control of the mitochondrial function. On the other hand, several other studies successfully identified the presence of mtDNA methylation, particularly in the mitochondrial displacement loop (D-loop) region, relating it to changes in both mtDNA gene transcription and mitochondrial replication. Overall, investigations performed until now suggest that methylation and hydroxymethylation marks are present in the mtDNA genome, albeit at lower levels compared to those detectable in nuclear DNA, potentially contributing to the mitochondria impairment underlying several human diseases.
    Keywords:  D-loop region; environmental factors; human diseases; mitochondria impairment; mitoepigenetics; mtDNA methylation
    DOI:  https://doi.org/10.3390/ijms22094594
  37. Int J Mol Sci. 2021 Apr 28. pii: 4661. [Epub ahead of print]22(9):
    Blood-Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration.
    Alla B Salmina, Ekaterina V Kharitonova, Yana V Gorina, Elena A Teplyashina, Natalia A Malinovskaya, Elena D Khilazheva, Angelina I Mosyagina, Andrey V Morgun, Anton N Shuvaev, Vladimir V Salmin, Olga L Lopatina, Yulia K Komleva.
      Pathophysiology of chronic neurodegeneration is mainly based on complex mechanisms related to aberrant signal transduction, excitation/inhibition imbalance, excitotoxicity, synaptic dysfunction, oxidative stress, proteotoxicity and protein misfolding, local insulin resistance and metabolic dysfunction, excessive cell death, development of glia-supported neuroinflammation, and failure of neurogenesis. These mechanisms tightly associate with dramatic alterations in the structure and activity of the neurovascular unit (NVU) and the blood-brain barrier (BBB). NVU is an ensemble of brain cells (brain microvessel endothelial cells (BMECs), astrocytes, pericytes, neurons, and microglia) serving for the adjustment of cell-to-cell interactions, metabolic coupling, local microcirculation, and neuronal excitability to the actual needs of the brain. The part of the NVU known as a BBB controls selective access of endogenous and exogenous molecules to the brain tissue and efflux of metabolites to the blood, thereby providing maintenance of brain chemical homeostasis critical for efficient signal transduction and brain plasticity. In Alzheimer's disease, mitochondria are the target organelles for amyloid-induced neurodegeneration and alterations in NVU metabolic coupling or BBB breakdown. In this review we discuss understandings on mitochondria-driven NVU and BBB dysfunction, and how it might be studied in current and prospective NVU/BBB in vitro models for finding new approaches for the efficient pharmacotherapy of Alzheimer's disease.
    Keywords:  Alzheimer’s disease; in vitro blood–brain barrier model; in vitro neurovascular unit model; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.3390/ijms22094661
  38. Pharmacol Ther. 2021 Apr 27. pii: S0163-7258(21)00076-0. [Epub ahead of print] 107874
    Mitochondrial K+ channels and their implications for disease mechanisms.
    Vanessa Checchetto, Luigi Leanza, Diego De Stefani, Rosario Rizzuto, Erich Gulbins, Ildiko Szabo.
      The field of mitochondrial ion channels underwent a rapid development during the last decade, thanks to the molecular identification of some of the nuclear-encoded organelle channels and to advances in strategies allowing specific pharmacological targeting of these proteins. Thereby, genetic tools and specific drugs aided definition of the relevance of several mitochondrial channels both in physiological as well as pathological conditions. Unfortunately, in the case of mitochondrial K+ channels, efforts of genetic manipulation provided only limited results, due to their dual localization to mitochondria and to plasma membrane in most cases. Although the impact of mitochondrial K+ channels on human diseases is still far from being genuinely understood, pre-clinical data strongly argue for their substantial role in the context of several pathologies, including cardiovascular and neurodegenerative diseases as well as cancer. Importantly, these channels are druggable targets, and their in-depth investigation could thus pave the way to the development of innovative small molecules with huge therapeutic potential. In the present review we summarize the available experimental evidences that mechanistically link mitochondrial potassium channels to the above pathologies and underline the possibility of exploiting them for therapy.
    Keywords:  Bioenergetics; Cancer; Cardiovascular diseases; Mitochondria; Potassium channels
    DOI:  https://doi.org/10.1016/j.pharmthera.2021.107874
  39. Int J Mol Sci. 2021 Apr 15. pii: 4082. [Epub ahead of print]22(8):
    Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases.
    Vladimir Zhemkov, Michal Geva, Michael R Hayden, Ilya Bezprozvanny.
      The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling functions are poorly understood. S1R is associated with cholesterol, and in our recent studies we demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited and retained in these microdomains. This hypothesis is consistent with the results of an unbiased screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxidase 2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleotropic signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various experimental systems.
    Keywords:  Alzheimer’s disease; Huntington’s disease; amyotrophic lateral sclerosis; cholesterol; contact sites; drug target; endoplasmic reticulum; mitochondria; neurodegeneration; sigma-1 receptor
    DOI:  https://doi.org/10.3390/ijms22084082
  40. Eur J Neurosci. 2021 Apr 27.
    Dexmedetomidine protects SH-SY5Y cells against MPP+ -induced declining of mitochondrial membrane potential and cell cycle deficits.
    Yaohua Chen, Dan Song, Cheng Chen, Tingting Liu, Oumei Cheng.
      Dexmedetomidine (Dex), an adrenergic α2 receptor agonist, is commonly used in deep-brain stimulation surgery for Parkinson's disease (PD). However, there is evidence that the use of anesthetics may accelerate the progression of neurodegenerative diseases. The effect of Dex on PD remains unclear. Here, we cultured the all-trans-retinoicacid (ATRA) differentiated SH-SY5Y cells in vitro and then treated with MPP+ (1.5mM) with or without Dex (10nM) or Dex combined with Atipamezole (Ati,100nM, adrenergic α2 receptor inhibitor). The ratio of apoptotic cells, mitochondrial membrane potential (Δψm), reactive oxygen species (ROS), cell cycle and apoptotic markers (Cleaved caspase-3, 9) were analyzed by flow cytometry and immunofluorescence. We found that the levels of apoptotic ratio and cleaved caspase-3, 9 increased, ROS accumulated, and mitochondrial membrane potential decreased after MPP+ treatment, while these changes were partially reversed by Dex. Dex also prevented MPP+ induced cell arrest by increasing G1 phase cells, decreasing S phase cells, and decreasing the expression of cyclinD1 and Cdk4. Moreover, the effects of Dex were partially reversed by Ati. These findings reveal that Dex attenuated MPP+ -induced apoptosis of SH-SY5Y cells by preventing the loss of Δψm, reducing ROS, and regulating the cell cycle. Our findings indicated that Dex is more likely to be a potential drug for the treatment of PD.
    Keywords:  1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Cell Cycle; Dexmedetomidine; Oxidative insult; Parkinson's disease
    DOI:  https://doi.org/10.1111/ejn.15252
  41. EMBO J. 2021 May 01. e103563
    TFG binds LC3C to regulate ULK1 localization and autophagosome formation.
    Marianna Carinci, Beatrice Testa, Matteo Bordi, Giacomo Milletti, Massimo Bonora, Laura Antonucci, Caterina Ferraina, Marta Carro, Mukesh Kumar, Donatella Ceglie, Franziska Eck, Roberta Nardacci, Francois le Guerroué, Stefania Petrini, Maria E Soriano, Ignazio Caruana, Valentina Doria, Maria Manifava, Camille Peron, Matteo Lambrughi, Valeria Tiranti, Christian Behrends, Elena Papaleo, Paolo Pinton, Carlotta Giorgi, Nicholas T Ktistakis, Franco Locatelli, Francesca Nazio, Francesco Cecconi.
      The early secretory pathway and autophagy are two essential and evolutionarily conserved endomembrane processes that are finely interlinked. Although growing evidence suggests that intracellular trafficking is important for autophagosome biogenesis, the molecular regulatory network involved is still not fully defined. In this study, we demonstrate a crucial effect of the COPII vesicle-related protein TFG (Trk-fused gene) on ULK1 puncta number and localization during autophagy induction. This, in turn, affects formation of the isolation membrane, as well as the correct dynamics of association between LC3B and early ATG proteins, leading to the proper formation of both omegasomes and autophagosomes. Consistently, fibroblasts derived from a hereditary spastic paraparesis (HSP) patient carrying mutated TFG (R106C) show defects in both autophagy and ULK1 puncta accumulation. In addition, we demonstrate that TFG activity in autophagy depends on its interaction with the ATG8 protein LC3C through a canonical LIR motif, thereby favouring LC3C-ULK1 binding. Altogether, our results uncover a link between TFG and autophagy and identify TFG as a molecular scaffold linking the early secretion pathway to autophagy.
    Keywords:  ERGIC; LC3C; TFG; autophagy
    DOI:  https://doi.org/10.15252/embj.2019103563
  42. J Biol Chem. 2021 Apr 22. pii: S0021-9258(21)00493-2. [Epub ahead of print] 100704
    Sp1 is a substrate of Keap1 and regulates the activity of CRL4AWDR23 ubiquitin ligase toward Nrf2.
    Ferbian Milas Siswanto, Ami Oguro, Susumu Imaoka.
      Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical transcription factor that orchestrates cellular responses to oxidative stress. Since the dysregulation of Nrf2 has been implicated in many diseases, precise regulation of its protein level is crucial for maintaining homeostasis. Kelch-like-ECH-associated protein 1 (Keap1) and WD40 Repeat Protein 23 (WDR23) directly regulate Nrf2 levels via similar but distinct proteasome-dependent pathways. WDR23 forms a part of the WDR23-Cullin 4A-RING ubiquitin ligase complex (CRL4AWDR23), while Keap1 serves as a substrate adaptor for the Cullin 3-containing ubiquitin ligase complex. However, the mechanisms underlying crosstalk between these Keap1 and WDR23 pathways for the regulation of Nrf2 levels have not been investigated. Here, we showed that knockdown (KD) of Keap1 upregulated the expression of CUL4A in a specificity protein 1 (Sp1)-dependent manner. We also revealed that Sp1 interacted with Keap1, leading to ubiquitination of Sp1. Increases in Sp1 by Keap1 KD triggered Sp1 binding to the fourth Sp1-binding site (Sp1_M4) within the -230/+50 region of the CUL4A gene. We also demonstrated that the overexpression and KD of Sp1 reduced and increased Nrf2 protein levels, respectively. These effects were abrogated by the WDR23 KD, suggesting that Sp1 also regulates Nrf2 levels via the ubiquitin ligase complex CRL4AWDR23. In conclusion, we discovered Sp1 as a novel substrate of Keap1, and provided evidence that Sp1 regulates the expression of CUL4A. We revealed a novel role for Sp1 in mediating crosstalk between two independent regulators of Nrf2 protein levels.
    Keywords:  Cullin 4A-RING ligase (CRL4A); Cullin4A (CUL4A); DNA damage-binding protein 1 (DDB1); Kelch-like ECH-associated protein 1 (Keap1); Nuclear factor 2 (erythroid‐derived 2‐like factor) (NFE2L2) (Nrf2); Ring-Box 1 (RBX1); WD40 Repeat protein 23 (WDR23); gene regulation; oxidative stress; posttranslational regulation; specificity protein 1 (Sp1)
    DOI:  https://doi.org/10.1016/j.jbc.2021.100704
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:22.