bims-midneu 2021-04-25 papers

bims-midneu

Biomed News

on Mitochondrial dysfunction in neurodegeneration

Issue of 2021–04–25
35 papers selected by
Radha Desai, Merck Sharp & Dohme Corp.

The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons.
Understanding the Multiple Role of Mitochondria in Parkinson's Disease and Related Disorders: Lesson From Genetics and Protein-Interaction Network.
Mitochondrial Dysfunction in Alzheimer's Disease - a Proteomics Perspective.
Pharmacological Inhibition of USP30 activates Tissue-specific Mitophagy.
Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia.
Cleaved PGAM5 dephosphorylates nuclear serine/arginine-rich proteinsduring mitophagy.
ALS/FTD mutations in UBQLN2 are linked to mitochondrial dysfunction through loss-of-function in mitochondrial protein import.
Mitochondrial quality control protects photoreceptors against oxidative stress in the H2O2-induced models of retinal degeneration diseases.
Mitophagy pathways and Alzheimer's disease: From pathogenesis to treatment.
The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS.
Mitochondrial protein import as a quality control sensor.
Administration of quercetin improves mitochondria quality control and protects the neurons in 6-OHDA-lesioned Parkinson's disease models.
MiR-22 Inhibition Alleviates Cardiac Dysfunction in Doxorubicin-Induced Cardiomyopathy by Targeting the sirt1/PGC-1α Pathway.
Optic atrophy-associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I.
NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate.
Inflammatory injury and mitophagy of the brain in chicken exposed to Cr(VI).
Synergistic Enhancing-Memory Effect of D-serine and RU360, a Mitochondrial Calcium Uniporter Blocker in Rat Model of Alzheimer's disease.
FOXO3a protects glioma cells against temozolomide-induced DNA double strand breaks via promotion of BNIP3-mediated mitophagy.
Pulmonary arterial hypertension induces the release of circulating extracellular vesicles with oxidative content and alters redox and mitochondrial homeostasis in the brains of rats.
Unique Sleep and Circadian Rhythm Dysfunction Neuroinflammatory and Immune Profiles in Alzheimer's Disease with Mild Cognitive Impairment.
Unique and abnormal subependymal pseudocysts in a newborn with mitochondrial disease.
Altered metabolic pathways in a transgenic mouse model suggest mechanistic role of amyloid precursor protein overexpression in Alzheimer's disease.
Structural basis of translation termination, rescue, and recycling in mammalian mitochondria.
High-fat diet-induced activation of SGK1 promotes Alzheimer's disease-associated tau pathology.
Lifestyle Changes Normalize Serum Lactate Levels in an m.3243A>G Carrier.
[11C]PK11195-PET Brain Imaging of the Mitochondrial Translocator Protein in Mitochondrial Disease.
Melatonin rescues cerebral ischemic events through upregulated tunneling nanotube-mediated mitochondrial transfer and downregulated mitochondrial oxidative stress in rat brain.
Ca2+-mediated coupling between neuromuscular junction and mitochondria in skeletal muscle.
Development of cerebral mitochondrial respiratory function is impaired by thyroid hormone deficiency before birth in a region-specific manner.
MitopatHs: a new logically-framed tool for visualizing multiple mitochondrial pathways.
Downregulation of glob1 suppresses pathogenesis of human neuronal tauopathies in Drosophila by regulating tau phosphorylation and ROS generation.
HIV-1 Vpr protein impairs lysosome clearance causing SNCA/alpha-synuclein accumulation in neurons.
Lipid-mediated motor-adaptor sequestration impairs axonal lysosome delivery leading to autophagic stress and dystrophy in Niemann-Pick type C.
VGLUT2 is a determinant of dopamine neuron resilience in a rotenone model of dopamine neurodegeneration.
Homozygous missense mutation in UQCRC2 associated with severe encephalomyopathy, mitochondrial complex III assembly defect and activation of mitochondrial protein quality control.

Stem Cell Reports. 2021 Apr 13. pii: S2213-6711(21)00161-2. [Epub ahead of print]

The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons.

Anna Poon, Harpreet Saini, Siddharth Sethi, Gregory A O'Sullivan, Hélène Plun-Favreau, Selina Wray, Lee A Dawson, James M McCarthy.

  Sequestosome-1 (SQSTM1/p62) is involved in cellular processes such as autophagy and metabolic reprogramming. Mutations resulting in the loss of function of SQSTM1 lead to neurodegenerative diseases including frontotemporal dementia. The pathogenic mechanism that contributes to SQSTM1-related neurodegeneration has been linked to its role as an autophagy adaptor, but this is poorly understood, and its precise role in mitochondrial function and clearance remains to be clarified. Here, we assessed the importance of SQSTM1 in human induced pluripotent stem cell (iPSC)-derived cortical neurons through the knockout of SQSTM1. We show that SQSTM1 depletion causes altered mitochondrial gene expression and functionality, as well as autophagy flux, in iPSC-derived neurons. However, SQSTM1 is not essential for mitophagy despite having a significant impact on early PINK1-dependent mitophagy processes including PINK1 recruitment and phosphorylation of ubiquitin on depolarized mitochondria. These findings suggest that SQSTM1 is important for mitochondrial function rather than clearance.

Keywords:  FTD; SQSTM1; iPSC disease modeling; mitochondria

DOI:  https://doi.org/10.1016/j.stemcr.2021.03.030
Front Cell Dev Biol. 2021 ;9 636506

Understanding the Multiple Role of Mitochondria in Parkinson's Disease and Related Disorders: Lesson From Genetics and Protein-Interaction Network.

Valentina Nicoletti, Giovanni Palermo, Eleonora Del Prete, Michelangelo Mancuso, Roberto Ceravolo.

  As neurons are highly energy-demanding cell, increasing evidence suggests that mitochondria play a large role in several age-related neurodegenerative diseases. Synaptic damage and mitochondrial dysfunction have been associated with early events in the pathogenesis of major neurodegenerative diseases, including Parkinson's disease, atypical parkinsonisms, and Huntington disease. Disruption of mitochondrial structure and dynamic is linked to increased levels of reactive oxygen species production, abnormal intracellular calcium levels, and reduced mitochondrial ATP production. However, recent research has uncovered a much more complex involvement of mitochondria in such disorders than has previously been appreciated, and a remarkable number of genes and proteins that contribute to the neurodegeneration cascade interact with mitochondria or affect mitochondrial function. In this review, we aim to summarize and discuss the deep interconnections between mitochondrial dysfunction and basal ganglia disorders, with an emphasis into the molecular triggers to the disease process. Understanding the regulation of mitochondrial pathways may be beneficial in finding pharmacological or non-pharmacological interventions to delay the onset of neurodegenerative diseases.

Keywords:  Huntington disease; Parkinson’s disease; Pink1/parkin pathway; alpha-synuclein; atypical parkinsonism; mitochondrial dysfunction; neurodegenerative diseases

DOI:  https://doi.org/10.3389/fcell.2021.636506
Expert Rev Proteomics. 2021 Apr 19.

Mitochondrial Dysfunction in Alzheimer's Disease - a Proteomics Perspective.

Morteza Abyadeh, Vivek Gupta, Nitin Chitranshi, Veer Gupta, Yunqi Wu, Danit Saks, Roshana Wander Wall, Matthew J Fitzhenry, Devaraj Basavarajappa, Yuyi You, Ghasem H Salekdeh, Paul A Haynes, Stuart L Graham, Mehdi Mirzaei.

  Mitochondrial dysfunction is involved in Alzheimer's disease (AD) pathogenesis. Mitochondria have their own genetic material; however, most of their proteins (∼99%) are synthesized as precursors on cytosolic ribosomes, and then imported into the mitochondria. Therefore, exploring proteome changes in these organelles can yield valuable information and shed light on the molecular mechanisms underlying mitochondrial dysfunction in AD. Here we review AD associated mitochondrial changes including the effects of amyloid beta and tau protein accumulation on the mitochondrial proteome. We also discuss the relationship of ApoE genetic polymorphism with mitochondrial changes, and present a meta-analysis of various differentially expressed proteins in the mitochondria in AD.
AREA COVERED: Proteomics studies and their contribution to our understanding of mitochondrial dysfunction in AD pathogenesis.
EXPERT OPINION: Proteomics has proved to be an efficient tool to uncover various aspects of this complex organelle, which will broaden our understanding of mitochondrial dysfunction in AD. Evidently, mitochondrial dysfunction is an early biochemical event that might play a central role in driving AD pathogenesis.

Keywords:  Alzheimer’s disease; Mitochondrial dysfunction; Proteomics

DOI:  https://doi.org/10.1080/14789450.2021.1918550
Acta Physiol (Oxf). 2021 Apr 23. e13666

Pharmacological Inhibition of USP30 activates Tissue-specific Mitophagy.

Hongke Luo, Judith Krigman, Ruohan Zhang, Mingchong Yang, Nuo Sun.

   AIM: Mitophagy is the regulated process that targets damaged or dysfunctional mitochondria for lysosomal-mediated removal. This process is an essential element of mitochondrial quality control, and dysregulation of mitophagy may contribute to a host of diseases, most notably neurodegenerative conditions such as Parkinson's disease. Mitochondria targeted for mitophagic destruction are molecularly marked by the ubiquitination of several outer mitochondrial membrane (OMM) proteins. This ubiquitination is positively regulated, in part, by the mitochondrial-targeted kinase PINK1 and the E3 ubiquitin ligase Parkin. In contrast, the reverse phenomenon, deubiquitination, removes ubiquitin from Parkin substrates embedded in the OMM proteins, antagonizing mitophagy. Recent evidence suggests that the mitochondrial deubiquitinase USP30 negatively regulates Parkin mediated mitophagy, providing opportunities to identify USP30 inhibitors and test for their effects in augmenting mitophagy. Here we will characterize a USP30 inhibitor and demonstrate how the pharmacological inhibition of USP30 can augment stress-induced mitophagic flux.
METHODS: We have conducted mitophagy and mitochondrial analyses in cultured cells. We have determined the plasma pharmacokinetics of the USP30 inhibitor in mice and conducted analyses using the mt-Keima mice to measure in vivo mitophagy directly.
RESULTS: The compound has minimal mitochondrial toxicity in cultured cells and is tolerated well in mice. Interestingly, we demonstrated tissue-specific induction of mitophagy following USP30 pharmacological inhibition. In particular, pharmacological inhibition of USP30 induces a significant increase in cardiac mitophagy without detriment to cardiac function.
CONCLUSION: Our data support the evidence that USP30 inhibition may serve as a specific strategy to selectively increase mitophagic flux, allowing for the development of novel therapeutic approaches.

Keywords:  Mitophagy; PINK1; Parkin; USP30; mitochondrial deubiquitination; mt-Keima

DOI:  https://doi.org/10.1111/apha.13666
Brain. 2021 Apr 23. pii: awab071. [Epub ahead of print]

Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia.

Adriana P Rebelo, Ilse Eidhof, Vivian P Cintra, Léna Guillot-Noel, Claudia V Pereira, Dagmar Timmann, Andreas Traschütz, Ludger Schöls, Giulia Coarelli, Alexandra Durr, Mathieu Anheim, Christine Tranchant, Bart van de Warrenburg, Claire Guissart, Michel Koenig, Jack Howell, Carlos T Moraes, Annette Schenck, Giovanni Stevanin, Stephan Züchner, Matthis Synofzik.

  Peroxiredoxin 3 (PRDX3) belongs to a superfamily of peroxidases that function as protective antioxidant enzymes. Among the six isoforms (PRDX1-PRDX6), PRDX3 is the only protein exclusively localized to the mitochondria, which are the main source of reactive oxygen species. Excessive levels of reactive oxygen species are harmful to cells, inducing mitochondrial dysfunction, DNA damage, lipid and protein oxidation and ultimately apoptosis. Neuronal cell damage induced by oxidative stress has been associated with numerous neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Leveraging the large aggregation of genomic ataxia datasets from the PREPARE (Preparing for Therapies in Autosomal Recessive Ataxias) network, we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration. The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration. Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity. Moreover, PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species. Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress. Our findings reveal a central role for mitochondria and the implication of oxidative stress in PRDX3 disease pathogenesis and cerebellar vulnerability and suggest targets for future therapeutic approaches.

Keywords:  PRDX3; ROS; ataxia

DOI:  https://doi.org/10.1093/brain/awab071
Biochim Biophys Acta Mol Cell Res. 2021 Apr 16. pii: S0167-4889(21)00099-9. [Epub ahead of print] 119045

Cleaved PGAM5 dephosphorylates nuclear serine/arginine-rich proteinsduring mitophagy.

Taiki Baba, Susumu Tanimura, Ayane Yamaguchi, Koichiro Horikawa, Masashi Yokozeki, Saki Hachiya, Shun-Ichiro Iemura, Tohru Natsume, Noriyuki Matsuda, Kohsuke Takeda.

  PGAM5 is a protein phosphatase located in the inner mitochondrial membrane through its transmembrane (TM) domain and is cleaved within the TM domain upon mitochondrial dysfunction. We found previously that cleaved PGAM5 is released from mitochondria, following proteasome-mediated rupture of the outer mitochondrial membrane during mitophagy, a selective form of autophagy specific to mitochondria. Here, we examined the role of cleaved PGAM5 outside mitochondria. Deletion mutants that mimic cleaved PGAM5 existed not only in the cytosol but also in the nucleus, and a fraction of cleaved PGAM5 translocated to the nucleus during mitophagy induced by the uncoupler CCCP. We identified serine/arginine-related nuclear matrix protein of 160 kDa (SRm160)/SRRM1, which contains a highly phosphorylated domain rich in arginine/serine dipeptides, called the RS domain, as a nuclear protein that interacts with PGAM5. PGAM5 dephosphorylated SRm160, and incubation of lysates from WT cells, but not of those from PGAM5-deficient cells, induced dephosphorylation of SRm160 and another RS domain-containing protein SRSF1, one of the most characterized serine/arginine-rich (SR) proteins. Moreover, phosphorylation of these proteins and other SR proteins, which are commonly reactive toward the 1H4 monoclonal antibody that detects phosphorylated SR proteins, decreased during mitophagy, largely because of PGAM5 activity. These results suggest that PGAM5 regulates phosphorylation of these nuclear proteins during mitophagy. Because SRm160 and SR proteins play critical roles in mRNA metabolism, PGAM5 may coordinate cellular responses to mitochondrial stress at least in part through post-transcriptional and pre-translational events.

Keywords:  Mitochondria; Mitophagy; PGAM5; Parkin; Protein phosphatase; SR proteins

DOI:  https://doi.org/10.1016/j.bbamcr.2021.119045
Hum Mol Genet. 2021 Apr 22. pii: ddab116. [Epub ahead of print]

ALS/FTD mutations in UBQLN2 are linked to mitochondrial dysfunction through loss-of-function in mitochondrial protein import.

Brian C Lin, Trong H Phung, Nicole R Higgins, Jessie E Greenslade, Miguel A Prado, Daniel Finley, Mariusz Karbowski, Brian M Polster, Mervyn J Monteiro.

UBQLN2 mutations cause amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD), but the pathogenic mechanisms by which they cause disease remain unclear. Proteomic profiling identified 'mitochondrial proteins' as comprising the largest category of protein changes in the spinal cord (SC) of the P497S UBQLN2 mouse model of ALS/FTD. Immunoblots confirmed P497S animals have global changes in proteins predictive of a severe decline in mitochondrial health, including oxidative phosphorylation (OXPHOS), mitochondrial protein import, and network dynamics. Functional studies confirmed mitochondria purified from the SC of P497S animals have age-dependent decline in nearly all steps of OXPHOS. Mitochondria cristae deformities were evident in spinal motor neurons of aged P497S animals. Knockout (KO) of UBQLN2 in HeLa cells resulted in changes in mitochondrial proteins and OXPHOS activity similar to those seen in the SC. KO of UBQLN2 also compromised targeting and processing of the mitochondrial import factor, TIMM44, resulting in accumulation in abnormal foci. The functional OXPHOS deficits and TIMM44 targeting defects were rescued by re-expression of WT UBQLN2 but not by ALS/FTD mutant UBQLN2 proteins. In-vitro binding assays revealed ALS/FTD mutant UBQLN2 proteins bind weaker with TIMM44 than WT UBQLN2 protein, suggesting that the loss of UBQLN2 binding may underlie the import and/or delivery defect of TIMM44 to mitochondria. Our studies indicate a potential key pathogenic disturbance in mitochondrial health caused by UBQLN2 mutations.

DOI: https://doi.org/10.1093/hmg/ddab116
Cell Death Dis. 2021 Apr 20. 12(5): 413

Mitochondrial quality control protects photoreceptors against oxidative stress in the H2O2-induced models of retinal degeneration diseases.

Biting Zhou, Lijun Fang, Yanli Dong, Juhua Yang, Xiaole Chen, Nanwen Zhang, Yihua Zhu, Tianwen Huang.

Retinal degeneration diseases (RDDs) are common and devastating eye diseases characterized by the degeneration of photoreceptors, which are highly associated with oxidative stress. Previous studies reported that mitochondrial dysfunction is associated with various neurodegenerative diseases. However, the role of mitochondrial proteostasis mainly regulated by mitophagy and mitochondrial unfolded protein response (mtUPR) in RDDs is unclear. We hypothesized that the mitochondrial proteostasis is neuroprotective against oxidative injury in RDDs. In this study, the data from our hydrogen peroxide (H2O2)-treated mouse retinal cone cell line (661w) model of RDDs showed that nicotinamide riboside (NR)-activated mitophagy increased the expression of LC3B II and PINK1, and promoted the co-localization of LC3 and mitochondria, as well as PINK1 and Parkin in the H2O2-treated 661w cells. However, the NR-induced mitophagy was remarkably reversed by chloroquine (CQ) and cyclosporine A (CsA), mitophagic inhibitors. In addition, doxycycline (DOX), an inducer of mtUPR, up-regulated the expression of HSP60 and CHOP, the key proteins of mtUPR. Activation of both mitophagy and mtUPR increased the cell viability and reduced the level of apoptosis and oxidative damage in the H2O2-treated 661w cells. Furthermore, both mitophagy and mtUPR played a protective effect on mitochondria by increasing mitochondrial membrane potential and maintaining mitochondrial mass. By contrast, the inhibition of mitophagy by CQ or CsA reversed the beneficial effect of mitophagy in the H2O2-treated 661w cells. Together, our study suggests that the mitophagy and mtUPR pathways may serve as new therapeutic targets to delay the progression of RDDs through enhancing mitochondrial proteostasis.

DOI: https://doi.org/10.1038/s41419-021-03660-5
Mitochondrion. 2021 Apr 16. pii: S1567-7249(21)00053-2. [Epub ahead of print]

Mitophagy pathways and Alzheimer's disease: From pathogenesis to treatment.

Xian-Ji Pan, Afzal Misrani, Sidra Tabassum, Li Yang.

  Alzheimer's disease (AD) is an age-dependent, incurable mental illness that is associated with the accumulation of aggregates of amyloid-beta (Aβ) and hyperphosphorylated tau fragments (p-tau). Detailed studies on postmortem AD brains, cell lines, and mouse models of AD have shown that numerous cellular alterations, including mitochondrial deficits, synaptic disruption and glial/astrocytic activation, are involved in the disease process. Mitophagy is a cellular process by which damaged/weakened mitochondria are selectively eliminated from the cell. In AD, impairments in mitophagy trigger the gradual accumulation of defective mitochondria. This review will focus on the recent progress in understanding the molecular mechanisms and pathological role of mitophagy and its implications for AD pathogenesis. We will also discuss the novel concept of the regulation of mitophagy as a therapeutic avenue for the prevention and treatment of AD.

Keywords:  Alzheimer's disease; Mitophagy; lysosome; mitochondrial dysfunction; therapeutics

DOI:  https://doi.org/10.1016/j.mito.2021.04.007
Front Cell Neurosci. 2021 ;15 653688

The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS.

Ruxandra Dafinca, Paola Barbagallo, Kevin Talbot.

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. Despite this heterogeneity, a key pathological signature is the mislocalization and aggregation of specific proteins in the cytoplasm, suggesting that convergent pathogenic mechanisms focusing on disturbances in proteostasis are important in ALS. In addition, many cellular processes have been identified as potentially contributing to disease initiation and progression, such as defects in axonal transport, autophagy, nucleocytoplasmic transport, ER stress, calcium metabolism, the unfolded protein response and mitochondrial function. Here we review the evidence from in vitro and in vivo models of C9ORF72 and TDP-43-related ALS supporting a central role in pathogenesis for endoplasmic reticulum stress, which activates an unfolded protein response (UPR), and mitochondrial dysfunction. Disruption in the finely tuned signaling between the ER and mitochondria through calcium ions may be a crucial trigger of mitochondrial deficits and initiate an apoptotic signaling cascade, thus acting as a point of convergence for multiple upstream disturbances of cellular homeostasis and constituting a potentially important therapeutic target.

Keywords:  ALS; C9orf72; TDP-43; UPR; calcium homeostasis; endoplasmic reticulum; mitochondria

DOI:  https://doi.org/10.3389/fncel.2021.653688
Biol Cell. 2021 Apr 18.

Mitochondrial protein import as a quality control sensor.

Sebabrata Maity, Oishee Chakrabarti.

  Mitochondria are organelles involved in various functions related to cellular metabolism and homeostasis. Though mitochondria contain own genome, their nuclear counterparts encode most of the different mitochondrial proteins. These are synthesized as precursors in the cytosol and have to be delivered into the mitochondria. These organelles hence have elaborate machineries for the import of precursor proteins from cytosol. The protein import machineries present in both mitochondrial membrane and aqueous compartments show great variability in pre-protein recognition, translocation and sorting across or into it. Mitochondrial protein import machineries also interact transiently with other protein complexes of the respiratory chain or those involved in the maintenance of membrane architecture. Hence mitochondrial protein translocation is an indispensable part of the regulatory network that maintains protein biogenesis, bioenergetics, membrane dynamics and quality control of the organelle. Various stress conditions and diseases that are associated with mitochondrial import defects lead to changes in cellular transcriptomic and proteomic profiles. Dysfunction in mitochondrial protein import also causes over-accumulation of precursor proteins and their aggregation in the cytosol. Multiple pathways may be activated for buffering these harmful consequences. Here we present a comprehensive picture of import machinery and its role in cellular quality control in response to defective mitochondrial import. We also discuss the pathological consequences of dysfunctional mitochondrial protein import in neurodegeneration and cancer. This article is protected by copyright. All rights reserved.

Keywords:  Intracellular compartmentalization; Mitochondria; Protein degradation/proteases

DOI:  https://doi.org/10.1111/boc.202100002
Aging (Albany NY). 2021 Apr 20. 13

Administration of quercetin improves mitochondria quality control and protects the neurons in 6-OHDA-lesioned Parkinson's disease models.

Wen-Wen Wang, Ruiyu Han, Hai-Jun He, Jia Li, Si-Yan Chen, Yingying Gu, Chenglong Xie.

  Mounting evidence suggests that mitochondrial dysfunction and impaired mitophagy lead to Parkinson's disease (PD). Quercetin, one of the most abundant polyphenolic flavonoids, displays many health-promoting biological effects in many diseases. We explored the neuroprotective effect of quercetin in vivo in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD and in vitro in 6-OHDA-treated PC12 cells. In vitro, we found that quercetin (20 μM) treatment improved mitochondrial quality control, reduced oxidative stress, increased the levels of the mitophagy markers PINK1 and Parkin and decreased α-synuclein protein expression in 6-OHDA-treated PC12 cells. Moreover, our in vivo findings demonstrated that administration of quercetin also relieved 6-OHDA-induced progressive PD-like motor behaviors, mitigated neuronal death and reduced mitochondrial damage and α-synuclein accumulation in PD rats. Furthermore, the neuroprotective effect of quercetin was suppressed by knockdown of either Pink1 or Parkin.

Keywords:  Parkinson's disease; mitochondria quality control; mitophagy; quercetin

DOI:  https://doi.org/10.18632/aging.202868
Front Physiol. 2021 ;12 646903

MiR-22 Inhibition Alleviates Cardiac Dysfunction in Doxorubicin-Induced Cardiomyopathy by Targeting the sirt1/PGC-1α Pathway.

Runze Wang, Yuerong Xu, Xiaolin Niu, Yexian Fang, Dong Guo, Jiangwei Chen, Hanzhao Zhu, Jiaying Dong, Ran Zhao, Ying Wang, Bingchao Qi, Gaotong Ren, Xue Li, Li Liu, Mingming Zhang.

  Doxorubicin (DOX) cardiotoxicity is a life-threatening side effect that leads to a poor prognosis in patients receiving chemotherapy. We investigated the role of miR-22 in doxorubicin-induced cardiomyopathy and the underlying mechanism in vivo and in vitro. Specifically, we designed loss-of-function and gain-of-function experiments to identify the role of miR-22 in doxorubicin-induced cardiomyopathy. Our data suggested that inhibiting miR-22 alleviated cardiac fibrosis and cardiac dysfunction induced by doxorubicin. In addition, inhibiting miR-22 mitigated mitochondrial dysfunction through the sirt1/PGC-1α pathway. Knocking out miR-22 enhanced mitochondrial biogenesis, as evidenced by increased PGC-1α, TFAM, and NRF-1 expression in vivo. Furthermore, knocking out miR-22 rescued mitophagy, which was confirmed by increased expression of PINK1 and parkin and by the colocalization of LC3 and mitochondria. These protective effects were abolished by overexpressing miR-22. In conclusion, miR-22 may represent a new target to alleviate cardiac dysfunction in doxorubicin-induced cardiomyopathy and improve prognosis in patients receiving chemotherapy.

Keywords:  doxorubicin; miR-22; mitochondrial dysfunction; mitophagy; oxidative stress

DOI:  https://doi.org/10.3389/fphys.2021.646903
Proc Natl Acad Sci U S A. 2021 Apr 27. pii: e2019665118. [Epub ahead of print]118(17):

Optic atrophy-associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I.

Luke E Formosa, Boris Reljic, Alice J Sharpe, Daniella H Hock, Linden Muellner-Wong, David A Stroud, Michael T Ryan.

  Mitochondrial disease is a debilitating condition with a diverse genetic etiology. Here, we report that TMEM126A, a protein that is mutated in patients with autosomal-recessive optic atrophy, participates directly in the assembly of mitochondrial complex I. Using a combination of genome editing, interaction studies, and quantitative proteomics, we find that loss of TMEM126A results in an isolated complex I deficiency and that TMEM126A interacts with a number of complex I subunits and assembly factors. Pulse-labeling interaction studies reveal that TMEM126A associates with the newly synthesized mitochondrial DNA (mtDNA)-encoded ND4 subunit of complex I. Our findings indicate that TMEM126A is involved in the assembly of the ND4 distal membrane module of complex I. In addition, we find that the function of TMEM126A is distinct from its paralogue TMEM126B, which acts in assembly of the ND2-module of complex I.

Keywords:  complex I; membrane protein; mitochondria; optic atrophy; oxidative phosphorylation

DOI:  https://doi.org/10.1073/pnas.2019665118
Cell Rep. 2021 Apr 20. pii: S2211-1247(21)00316-8. [Epub ahead of print]35(3): 109002

NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate.

Luigi D'Angelo, Elisa Astro, Monica De Luise, Ivana Kurelac, Nikkitha Umesh-Ganesh, Shujing Ding, Ian M Fearnley, Giuseppe Gasparre, Massimo Zeviani, Anna Maria Porcelli, Erika Fernandez-Vizarra, Luisa Iommarini.

  Complex I (CI) is the largest enzyme of the mitochondrial respiratory chain, and its defects are the main cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we analyze the structural and functional consequences of the ablation of NDUFS3, a non-catalytic core subunit. We show that, in diverse mammalian cell types, a small amount of functional CI can still be detected in the complete absence of NDUFS3. In addition, we determine the dynamics of CI disassembly when the amount of NDUFS3 is gradually decreased. The process of degradation of the complex occurs in a hierarchical and modular fashion in which the ND4 module remains stable and bound to TMEM126A. We, thus, uncover the function of TMEM126A, the product of a disease gene causing recessive optic atrophy as a factor necessary for the correct assembly and function of CI.

Keywords:  CI; CI modules; NDUFS3; SILAC; TMEM126A; assembly factor; optic atrophy type 7; respiratory complex I

DOI:  https://doi.org/10.1016/j.celrep.2021.109002
Environ Sci Pollut Res Int. 2021 Apr 04.

Inflammatory injury and mitophagy of the brain in chicken exposed to Cr(VI).

Shuhua Guo, Xiaozhou Wang, Lumei Wang, Guodong Cheng, Meihua Zhang, Yuxiao Xing, Xiaona Zhao, Yongxia Liu, Jianzhu Liu.

  The aim of this study is to determine whether Cr(VI) can induce inflammatory injury in chicken brain and influence mitophagy and related mechanisms. A total of 120 hyline brown chickens (1 day old, 20±3g) were selected and randomly divided into four groups and given different doses of Cr(VI) (0, 10, 30, and 50 mg/kg) every day at 45 days. Results showed that excessive intake of Cr(VI) led to increased tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) levels and decreased interferon-gamma (IF-γ) level. Cr(VI) increased the production of mitochondrial reactive oxygen species (ROS) in chicken brain cells, causing the decline of mitochondrial membrane potential (MMP) and formation of autophagosomes for mitophagy. In addition, Cr(VI) promoted the translocation of Parkin to the mitochondrial outer membrane, increased LC3-II protein level, and inhibited p62 and TOM20 protein expression. In conclusion, excessive Cr(VI) intake can induce inflammatory injury and mitophagy in chicken brain.

Keywords:  Brain; Chickens; Cr(VI); Inflammatory; Mitophagy; Parkin

DOI:  https://doi.org/10.1007/s11356-021-13675-2
Behav Brain Res. 2021 Apr 16. pii: S0166-4328(21)00195-9. [Epub ahead of print] 113307

Synergistic Enhancing-Memory Effect of D-serine and RU360, a Mitochondrial Calcium Uniporter Blocker in Rat Model of Alzheimer's disease.

Zeynab Nikseresht, Nematollah Ahangar, Mahshid Badrikoohi, Parvin Babaei.

   BACKGROUND: Although Amyloid beta (Aβ) and N - methyl D- aspartate receptors (NMDARs are involved in Ca2+ neurotoxicity, the function of mitochondrial calcium uniporter in cognition deficit remain uncertain. Here, we examined the effect of mitochondrial calcium uniporter (MCU) blocker, together with NMDA receptor agonist D-cycloserine (DCS) on memory impairment in a rat model of AD.
METHODS: Forty adult male Wistar rats underwent stereotaxic cannulation for inducing AD by intracerebroventricular (ICV) injection of Aβ1-42 (5 μg /8 μl/rat). Then animals were divided into 5 groups of: Saline + Saline, Aβ + Saline, Aβ + RU360, Aβ + DCS, Aβ + RU360 + DCS. Two weeks after the treatments, Morris Water Maze (MWM) and step through passive avoidance learning (SPL) were undertaken for evaluating of spatial and associative memories, respectively. Hippocampal level of cyclic-AMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were measured by western blot and ELISA.
RESULTS: Co - administration of RU360 and DCS significantly improved both acquisition and retrieval of spatial memory as evident by decreased escape latency and increased time spent in the target quadrant (TTS) in MWM, together with increase in step-through latency, but reduced time spent in the dark compartment in SPL. Furthermore, there was a significant rise in the hippocampal level of CREB and BDNF in comparison with Aβ + Saline.
CONCLUSION: The present study supports the idea that co- administration of RU360 and DCS ameliorate memory impairment induced by Aβ 1-42 probably via CREB / BDNF signaling.

Keywords:  BDNF; CREB; NMDA; Neurodegenerative disease; amyloid beta (1-42); cognition deficit; mitochondrial calcium uniporter

DOI:  https://doi.org/10.1016/j.bbr.2021.113307
Acta Pharmacol Sin. 2021 Apr 20.

FOXO3a protects glioma cells against temozolomide-induced DNA double strand breaks via promotion of BNIP3-mediated mitophagy.

Chuan He, Shan Lu, Xuan-Zhong Wang, Chong-Cheng Wang, Lei Wang, Shi-Peng Liang, Tian-Fei Luo, Zhen-Chuan Wang, Mei-Hua Piao, Guang-Fan Chi, Peng-Fei Ge.

  FOXO3a (forkhead box transcription factor 3a) is involved in regulating multiple biological processes in cancer cells. BNIP3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein 3) is a receptor accounting for priming damaged mitochondria for autophagic removal. In this study we investigated the role of FOXO3a in regulating the sensitivity of glioma cells to temozolomide (TMZ) and its relationship with BNIP3-mediated mitophagy. We showed that TMZ dosage-dependently inhibited the viability of human U87, U251, T98G, LN18 and rat C6 glioma cells with IC50 values of 135.75, 128.26, 142.65, 155.73 and 111.60 μM, respectively. In U87 and U251 cells, TMZ (200 μM) induced DNA double strand breaks (DSBs) and nuclear translocation of apoptosis inducing factor (AIF), which was accompanied by BNIP3-mediated mitophagy and FOXO3a accumulation in nucleus. TMZ treatment induced intracellular ROS accumulation in U87 and U251 cells via enhancing mitochondrial superoxide, which not only contributed to DNA DSBs and exacerbated mitochondrial dysfunction, but also upregulated FOXO3a expression. Knockdown of FOXO3a aggravated TMZ-induced DNA DSBs and mitochondrial damage, as well as glioma cell death. TMZ treatment not only upregulated BNIP3 and activated autophagy, but also triggered mitophagy by prompting BNIP3 translocation to mitochondria and reinforcing BNIP3 interaction with LC3BII. Inhibition of mitophagy by knocking down BNIP3 with SiRNA or blocking autophagy with 3MA or bafilomycin A1 exacerbated mitochondrial superoxide and intracellular ROS accumulation. Moreover, FOXO3a knockdown inhibited TMZ-induced BNIP3 upregulation and autophagy activation. In addition, we showed that treatment with TMZ (100 mg·kg-1·d-1, ip) for 12 days in C6 cell xenograft mice markedly inhibited tumor growth accompanied by inducing FOXO3a upregulation, oxidative stress and BNIP3-mediated mitophagy in tumor tissues. These results demonstrate that FOXO3a attenuates temozolomide-induced DNA double strand breaks in human glioma cells via promoting BNIP3-mediated mitophagy.

Keywords:  3MA; BNIP3; DNA double strand break; FOXO3a; bafilomycin A; glioma; mitochondrial superoxide; mitophagy; oxidative stress; temozolomide

DOI:  https://doi.org/10.1038/s41401-021-00663-y
Hypertens Res. 2021 Apr 19.

Pulmonary arterial hypertension induces the release of circulating extracellular vesicles with oxidative content and alters redox and mitochondrial homeostasis in the brains of rats.

Giana Blume Corssac, Jéssica Poletto Bonetto, Cristina Campos-Carraro, Laura Reck Cechinel, Alexsandra Zimmer, Belisa Parmeggiani, Mateus Grings, Virgínia Mendes Carregal, André Ricardo Massensini, Ionara Siqueira, Guilhian Leipnitz, Adriane Belló-Klein.

  Pulmonary arterial hypertension (PAH) is characterized by increased resistance of the pulmonary vasculature and afterload imposed on the right ventricle (RV). Two major contributors to the worsening of this disease are oxidative stress and mitochondrial impairment. This study aimed to explore the effects of monocrotaline (MCT)-induced PAH on redox and mitochondrial homeostasis in the RV and brain and how circulating extracellular vesicle (EV) signaling is related to these phenomena. Wistar rats were divided into control and MCT groups (60 mg/kg, intraperitoneal), and EVs were isolated from blood on the day of euthanasia (21 days after MCT injections). There was an oxidative imbalance in the RV, brain, and EVs of MCT rats. PAH impaired mitochondrial function in the RV, as seen by a decrease in the activities of mitochondrial complex II and citrate synthase and manganese superoxide dismutase (MnSOD) protein expression, but this function was preserved in the brain. The key regulators of mitochondrial biogenesis, namely, proliferator-activated receptor gamma coactivator 1-alpha and sirtuin 1, were poorly expressed in the EVs of MCT rats, and this result was positively correlated with MnSOD expression in the RV and negatively correlated with MnSOD expression in the brain. Based on these findings, we can conclude that the RV is severely impacted by the development of PAH, but this pathological injury may signal the release of circulating EVs that communicate with different organs, such as the brain, helping to prevent further damage through the upregulation of proteins involved in redox and mitochondrial function.

Keywords:  Extracellular vesicles; Mitochondrial function; Monocrotaline; Oxidative stress; Pulmonary hypertension

DOI:  https://doi.org/10.1038/s41440-021-00660-y
J Alzheimers Dis. 2021 Mar 30.

Unique Sleep and Circadian Rhythm Dysfunction Neuroinflammatory and Immune Profiles in Alzheimer's Disease with Mild Cognitive Impairment.

Jagan A Pillai, James Bena, Lynn M Bekris, Nancy Foldvary-Schaefer, Catherine Heinzinger, Sujata Rao, Stephen M Rao, James B Leverenz, Reena Mehra.

  Sleep dysfunction has been identified in the pathophysiology of Alzheimer's disease (AD); however, the role and mechanism of circadian rhythm dysfunction is less well understood. In a well-characterized cohort of patients with AD at the mild cognitive impairment stage (MCI-AD), we identify that circadian rhythm irregularities were accompanied by altered humoral immune responses detected in both the cerebrospinal fluid and plasma as well as alterations of cerebrospinal fluid biomarkers of neurodegeneration. On the other hand, sleep disruption was more so associated with abnormalities in circulating markers of immunity and inflammation and decrements in cognition.

Keywords:  Alzheimer’s disease; circadian; immunity; inflammation; neurodegeneration; sleep

DOI:  https://doi.org/10.3233/JAD-201573
Sci Prog. 2021 Apr-Jun;104(2):104(2): 368504211011873

Unique and abnormal subependymal pseudocysts in a newborn with mitochondrial disease.

Yuki Sato, Ryoji Aoki, Nobuhiko Nagano, Chika Takano, Ayako Seimiya, Ryota Kato, Erika Ogawa, Mika Ishige, Yasushi Okazaki, Kei Murayama, Ichiro Morioka.

  Neonatal mitochondrial disease is occasionally observed in patients with intraventricular cysts in the brain. Atypical morphology is rarely seen in these cysts. Here, we report a case of neonatal lethal mitochondrial disease with IBA57 gene mutation. We have, for the first time, described a subependymal pseudocyst (SEPC) with a fluctuating membrane. Our findings suggest that SEPCs with fluctuating membranes can be a potential diagnostic indicator of neonatal mitochondrial disease.

Keywords:  Brain sonography; IBA57 gene; mitochondrial disease; newborn; subependymal pseudocyst

DOI:  https://doi.org/10.1177/00368504211011873
Metabolomics. 2021 Apr 19. 17(5): 42

Altered metabolic pathways in a transgenic mouse model suggest mechanistic role of amyloid precursor protein overexpression in Alzheimer's disease.

Hattapark Dejakaisaya, Anna Harutyunyan, Patrick Kwan, Nigel C Jones.

   INTRODUCTION: The mechanistic role of amyloid precursor protein (APP) in Alzheimer's disease (AD) remains unclear.
OBJECTIVES: Here, we aimed to identify alterations in cerebral metabolites and metabolic pathways in cortex, hippocampus and serum samples from Tg2576 mice, a widely used mouse model of AD.
METHODS: Metabolomic profilings using liquid chromatography-mass spectrometry were performed and analysed with MetaboAnalyst and weighted correlation network analysis (WGCNA).
RESULTS: Expressions of 11 metabolites in cortex, including hydroxyphenyllactate-linked to oxidative stress-and phosphatidylserine-lipid metabolism-were significantly different between Tg2576 and WT mice (false discovery rate < 0.05). Four metabolic pathways from cortex, including glycerophospholipid metabolism and pyrimidine metabolism, and one pathway (sulphur metabolism) from hippocampus, were significantly enriched in Tg2576 mice. Network analysis identified five pathways, including alanine, aspartate and glutamate metabolism, and mitochondria electron transport chain, that were significantly correlated with AD genotype.
CONCLUSIONS: Changes in metabolite concentrations and metabolic pathways are present in the early stage of APP pathology, and may be important for AD development and progression.

Keywords:  Amyloid-beta; Dementia; Glutamate; Lipids metabolism; Network analysis; Oxidative stress

DOI:  https://doi.org/10.1007/s11306-021-01793-4
Mol Cell. 2021 Apr 09. pii: S1097-2765(21)00263-X. [Epub ahead of print]

Structural basis of translation termination, rescue, and recycling in mammalian mitochondria.

Eva Kummer, Katharina Noel Schubert, Tanja Schoenhut, Alain Scaiola, Nenad Ban.

  The mitochondrial translation system originates from a bacterial ancestor but has substantially diverged in the course of evolution. Here, we use single-particle cryo-electron microscopy (cryo-EM) as a screening tool to identify mitochondrial translation termination mechanisms and to describe them in molecular detail. We show how mitochondrial release factor 1a releases the nascent chain from the ribosome when it encounters the canonical stop codons UAA and UAG. Furthermore, we define how the peptidyl-tRNA hydrolase ICT1 acts as a rescue factor on mitoribosomes that have stalled on truncated messages to recover them for protein synthesis. Finally, we present structural models detailing the process of mitochondrial ribosome recycling to explain how a dedicated elongation factor, mitochondrial EFG2 (mtEFG2), has specialized for cooperation with the mitochondrial ribosome recycling factor to dissociate the mitoribosomal subunits at the end of the translation process.

Keywords:  ICT1; cryo-EM; mitochondria; mtEFG2; mtRF1a; mtRRF; recycling; ribosome; termination; translation

DOI:  https://doi.org/10.1016/j.molcel.2021.03.042
Hum Mol Genet. 2021 Apr 22. pii: ddab115. [Epub ahead of print]

High-fat diet-induced activation of SGK1 promotes Alzheimer's disease-associated tau pathology.

Montasir Elahi, Yumiko Motoi, Shotaro Shimonaka, Yoko Ishida, Hiroyuki Hioki, Masashi Takanashi, Koichi Ishiguro, Yuzuru Imai, Nobutaka Hattori.

Type2 diabetes mellitus (T2DM) has long been considered a risk factor for Alzheimer's disease (ad). However, the molecular links between T2DM and ad remain obscure. Here, we reported that serum/glucocorticoid-regulated kinase1 (SGK1) is activated by administering a chronic high-fat diet (HFD), which increases the risk of T2DM, and thus promotes Tau pathology via the phosphorylation of tau at Ser214 and the activation of a key tau kinase, namely, GSK-3ß, forming SGK1-GSK-3ß-tau complex. SGK1 was activated under conditions of elevated glucocorticoid and hyperglycemia associated with HFD, but not of fatty acid-mediated insulin resistance. Elevated expression of SGK1 in the mouse hippocampus led to neurodegeneration and impairments in learning and memory. Upregulation and activation of SGK1, SGK1-GSK-3ß-tau complex were also observed in the hippocampi of ad cases. Our results suggest that SGK1 is a key modifier of tau pathology in ad, linking ad to corticosteroid effects and T2DM.

DOI: https://doi.org/10.1093/hmg/ddab115
Am J Case Rep. 2021 Apr 19. 22 e930175

Lifestyle Changes Normalize Serum Lactate Levels in an m.3243A>G Carrier.

Josef Finsterer.

BACKGROUND The normalization of serum lactate levels in a patient with non-syndromic mitochondrial disorder due to the m.3243A>G mitochondrial DNA (mtDNA) variant has not been previously reported. CASE REPORT A 57-year-old woman was diagnosed with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) due to the m.3243A>G variant, with low heteroplasmy rates (31%), at age 50. The initial manifestations were short stature, migraine, and diabetes. With progression of the disease, multisystem involvement developed, affecting the brain (stroke-like episode, mild cognitive impairment), eyes (pigmentary retinopathy), ears and the vestibular system (impaired hearing, tinnitus, imbalance, drop attacks, vertigo), intestines (constipation, distended abdomen, gastro-esophageal reflux, gastroparesis), and the muscles (muscle weakness). The gastrointestinal involvement was most prominent and most significantly lowered the patient's quality of life. The diabetes was well controlled with an insulin pump. Recurrent, acute deteriorations responded favorably to L-arginine. Owing to lifestyle and diet changes 2 years after diagnosis (start of art classes, increase in spin biking to 22.5 km 3 times per week, travel to Hawaii, adherence to low-carbohydrate high-protein diet), the patient managed to lower elevated serum lactate levels to largely normal values. CONCLUSIONS Gastrointestinal compromise may be the prominent manifestation of the m.3243A>G variant, lifestyle and diet changes may lower serum lactate in m.3243A>G carriers, and low heteroplasmy rates of the m.3243A>G variant in scarcely affected tissues do not exclude pathogenicity.

DOI: https://doi.org/10.12659/AJCR.930175
Neurology. 2021 Apr 21. pii: 10.1212/WNL.0000000000012033. [Epub ahead of print]

[11C]PK11195-PET Brain Imaging of the Mitochondrial Translocator Protein in Mitochondrial Disease.

Jelle van den Ameele, Young Hong, Roido Manavaki, Antonina Kouli, Heather Biggs, Zoe MacIntyre, Rita Horvath, Patrick Yu-Wai-Man, Evan Reid, Caroline H Williams-Gray, Ed Bullmore, Franklin Aigbirhio, Tim Fryer, Patrick Chinnery.

OBJECTIVE: To explore the possibilities of radioligands against the mitochondrial outer membrane protein TSPO as biomarkers for mitochondrial disease, we performed PET (PET)-MR brain imaging with [11C]PK11195 in 14 patients with genetically confirmed mitochondrial disease and 33 matched controls.
METHODS: A case-control study of PET-MR imaging with the TSPO radioligand [11C]PK11195.
RESULTS: Forty-six percent of symptomatic patients had volumes of abnormal radiotracer binding greater than the 95th percentile in controls. [11C]PK11195 binding was generally greater in grey matter and significantly decreased in white matter. This was most striking in patients with nuclear TYMP or mitochondrial m.3243A>G MT-TL1 mutations, in keeping with differences in mitochondrial density seen post mortem. Some regional binding patterns corresponded to clinical presentation and underlying mutation, even in the absence of structural changes on MRI. This was most obvious for the cerebellum, where patients with ataxia had decreased binding in the cerebellar cortex, but not necessarily volume loss. Overall, there was a positive correlation between aberrant [11C]PK11195 binding and clinical severity.
CONCLUSION: These findings endorse the use of PET imaging with TSPO radioligands as a non-invasive in vivo biomarker of mitochondrial pathology.
CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that PET-MR brain imaging with TSPO radioligands identifies mitochondrial pathology.

DOI: https://doi.org/10.1212/WNL.0000000000012033
Biomed Pharmacother. 2021 Apr 14. pii: S0753-3322(21)00378-4. [Epub ahead of print]139 111593

Melatonin rescues cerebral ischemic events through upregulated tunneling nanotube-mediated mitochondrial transfer and downregulated mitochondrial oxidative stress in rat brain.

Hon-Kan Yip, Navneet Kumar Dubey, Kun-Chen Lin, Pei-Hsun Sung, John Y Chiang, Yi-Ching Chu, Chi-Ruei Huang, Yi-Ling Chen, Yue-Hua Deng, Hsin-Chung Cheng, Win-Ping Deng.

   BACKGROUND: Cerebral ischemic events, comprising of excitotoxicity, reactive oxygen production, and inflammation, adversely impact the metabolic-redox circuit in highly active neuronal metabolic profile which maintains energy-dependent brain activities. Therefore, we investigated neuro-regenerative potential of melatonin (Mel), a natural biomaterial secreted by pineal gland.
METHODS: We specifically determined whether Mel could influence tunneling nanotubes (TNTs)-mediated transfer of functional mitochondria (Mito) which in turn may alter membrane potential, oxidative stress and apoptotic factors. In vitro studies assessed the effects of Mito on levels of cytochrome C, mitochondrial transfer, reactive oxygen species, membrane potential and mass, which were all further enhanced by Mel pre-treatment, whereas in vivo studies examined brain infarct area (BIA), neurological function, inflammation, brain edema and integrity of neurons and myelin sheath in control, ischemia stroke (IS), IS + Mito and IS + Mel-Mito group rats.
RESULTS: Results showed that Mel pre-treatment significantly increased mitochondrial transfer and antioxidants, and inhibited apoptosis. Mel-pretreated Mito also significantly reduced BIA with improved neurological function. Apoptotic, oxidative-stress, autophagic, mitochondrial/DNA-damaged biomarkers indices were also improved.
CONCLUSION: Conclusively, Mel is a potent biomaterial which could potentially impart neurogenesis through repairing impaired metabolic-redox circuit via enhanced TNT-mediated mitochondrial transfer, anti-oxidation, and anti-apoptotic activities in ischemia.

Keywords:  Acute ischemic stroke; Apoptosis; Melatonin; Mitochondria; Oxidative stress

DOI:  https://doi.org/10.1016/j.biopha.2021.111593
Neurosci Lett. 2021 Apr 15. pii: S0304-3940(21)00277-9. [Epub ahead of print]754 135899

Ca2+-mediated coupling between neuromuscular junction and mitochondria in skeletal muscle.

Jingsong Zhou.

  The volitional movement of skeletal is controlled by the motor neuron at the site of neuromuscular junction (NMJ) where the retrograde signals are also passed back from muscle to the motor neuron. As the normal function of muscle largely depends on mitochondria that determine the fate of a skeletal muscle myofiber, there must exist a fine-controlled functional coupling between NMJ and mitochondria in myofibers. This mini-review discusses recent publications that reveal how spatiotemporal profiles of intracellular free Ca2+ could couple mitochondrial function with the activity of NMJ in skeletal muscle myofibers.

Keywords:  Ca(2+) signaling; Mitochondria; Neuromuscular junction; Skeletal muscle

DOI:  https://doi.org/10.1016/j.neulet.2021.135899
FASEB J. 2021 May;35(5): e21591

Development of cerebral mitochondrial respiratory function is impaired by thyroid hormone deficiency before birth in a region-specific manner.

Katie L Davies, Danielle J Smith, Tatiana El-Bacha, Max E Stewart, Akshay Easwaran, Peter F P Wooding, Alison J Forhead, Andrew J Murray, Abigail L Fowden, Emily J Camm.

  Thyroid hormones regulate adult metabolism partly through actions on mitochondrial oxidative phosphorylation (OXPHOS). They also affect neurological development of the brain, but their role in cerebral OXPHOS before birth remains largely unknown, despite the increase in cerebral energy demand during the neonatal period. Thus, this study examined prepartum development of cerebral OXPHOS in hypothyroid fetal sheep. Using respirometry, Complex I (CI), Complex II (CII), and combined CI&CII OXPHOS capacity were measured in the fetal cerebellum and cortex at 128 and 142 days of gestational age (dGA) after surgical thyroidectomy or sham operation at 105 dGA (term ~145 dGA). Mitochondrial electron transfer system (ETS) complexes, mRNA transcripts related to mitochondrial biogenesis and ATP production, and mitochondrial density were quantified using molecular techniques. Cerebral morphology was assessed by immunohistochemistry and stereology. In the cortex, hypothyroidism reduced CI-linked respiration and CI abundance at 128 dGA and 142 dGA, respectively, and caused upregulation of PGC1α (regulator of mitochondrial biogenesis) and thyroid hormone receptor β at 128 dGA and 142 dGA, respectively. In contrast, in the cerebellum, hypothyroidism reduced CI&II- and CII-linked respiration at 128 dGA, with no significant effect on the ETS complexes. In addition, cerebellar glucocorticoid hormone receptor and adenine nucleotide translocase (ANT1) were downregulated at 128 dGA and 142 dGA, respectively. These alterations in mitochondrial function were accompanied by reduced myelination. The findings demonstrate the importance of thyroid hormones in the prepartum maturation of cerebral mitochondria and have implications for the etiology and treatment of the neurodevelopmental abnormalities associated with human prematurity and congenital hypothyroidism.

Keywords:  brain; fetus; mitochondria; thyroid hormones

DOI:  https://doi.org/10.1096/fj.202100075R
iScience. 2021 Apr 23. 24(4): 102324

MitopatHs: a new logically-framed tool for visualizing multiple mitochondrial pathways.

Saverio Marchi, Marco Zanella, Paolo Pinton, Silvia Crafa, Giovanni Boniolo.

  Mitochondria are key organelles inside the cell that house a wide range of molecular pathways involved in energy metabolism, ions homeostasis, and cell death. Several databases characterize the different mitochondrial aspects and thus support basic and clinical research. Here we present MitopatHs, a web-based data set that allows navigating among the biochemical signaling pathways (PatHs) of human (H) mitochondria (Mito). MitopatHs is designed to visualize and comprehend virtually all types of pathways in two complementary ways: a logical view, where the sequence of biochemical reactions is presented as logical deductions, and an intuitive graphical visualization, which enables the examination and the analysis of each step of the pathway. MitopatHs is a manually curated, open access and collaborative tool, whose goal is to enable the visualization and comprehension of complicated molecular routes in an easy and fast way.

Keywords:  Cell Biology; Molecular Network; Software

DOI:  https://doi.org/10.1016/j.isci.2021.102324
Neurochem Int. 2021 Apr 15. pii: S0197-0186(21)00086-3. [Epub ahead of print] 105040

Downregulation of glob1 suppresses pathogenesis of human neuronal tauopathies in Drosophila by regulating tau phosphorylation and ROS generation.

Nisha, Surajit Sarkar.

  Human tauopathies represent a group of neurodegenerative disorders, characterized by abnormal hyperphosphorylation and aggregation of tau protein, which ultimately cause neurodegeneration. The aberrant tau hyperphosphorylation is mostly attributed to the kinases/phosphatases imbalance, which is majorly contributed by the generation of reactive oxygen species (ROS). Globin(s) represent a well-conserved group of proteins which are involved in O2 management, regulation of cellular ROS in different cell types. Similarly, Drosophila globin1 (a homologue of human globin) with its known roles in oxygen management and development of nervous system exhibits striking similarities with the mammalian neuroglobin. Several recent evidences support the hypothesis that neuroglobins are associated with Alzheimer's disease pathogenesis. We herein noted that targeted expression of human-tau induces the cellular level of Glob1 protein in Drosophila tauopathy models. Subsequently, RNAi mediated restored level of Glob1 restricts the pathogenic effect of human-tau by minimizing its hyperphosphorylation via GSK-3β/p-Akt and p-JNK pathways. In addition, it also activates the Nrf2-keap1-ARE cascade to stabilize the tau-mediated increased level of ROS. These two parallel cellular events provide a significant rescue against human tau-mediated neurotoxicity in the fly models. For the first time we report a direct involvement of an oxygen sensing globin gene in tau etiology. In view of the fact that human genome encodes for the multiple Globin proteins including a nervous system specific neuroglobin; and therefore, our findings may pave the way to investigate if the conserved oxygen sensing globin gene(s) can be exploited in devising novel therapeutic strategies against tauopathies.

Keywords:  Drosophila; ROS; Tauopathies; glob1; neurodegeneration

DOI:  https://doi.org/10.1016/j.neuint.2021.105040
Autophagy. 2021 Apr 23. 1-15

HIV-1 Vpr protein impairs lysosome clearance causing SNCA/alpha-synuclein accumulation in neurons.

Maryline Santerre, Sterling P Arjona, Charles Ns Allen, Shannon Callen, Shilpa Buch, Bassel E Sawaya.

  Despite the promising therapeutic effects of combinatory antiretroviral therapy (cART), 20% to 30% of HIV/AIDS patients living with long term infection still exhibit related cognitive and motor disorders. Clinical studies in HIV-infected patients revealed evidence of basal ganglia dysfunction, tremors, fine motor movement deficits, gait, balance, and increased risk of falls. Among older HIV+ adults, the frequency of cases with SNCA/α-synuclein staining is higher than in older healthy persons and may predict an increased risk of developing a neurodegenerative disease. The accumulation of SNCA aggregates known as Lewy Bodies is widely described to be directly linked to motor dysfunction. These aggregates are naturally removed by Macroautophagy/autophagy, a cellular housekeeping mechanism, that can be disturbed by HIV-1. The molecular mechanisms involved in linking HIV-1 proteins and autophagy remain mostly unclear and necessitates further exploration. We showed that HIV-1 Vpr protein triggers the accumulation of SNCA in neurons after decreasing lysosomal acidification, deregulating lysosome positioning, and the expression levels of several proteins involved in lysosomal maturation. Viruses and retroviruses such as HIV-1 are known to manipulate autophagy in order to use it for their replication while blocking the degradative final step, which could destroy the virus itself. Our study highlights how the suppression of neuronal autophagy by HIV-1 Vpr is a mechanism leading to toxic protein aggregation and neurodegeneration.

Keywords:  Alpha-synuclein; HIV-1; Snapin; autophagy; lysosomes; motor dysfunction; neurons

DOI:  https://doi.org/10.1080/15548627.2021.1915641
Dev Cell. 2021 Apr 13. pii: S1534-5807(21)00307-5. [Epub ahead of print]

Lipid-mediated motor-adaptor sequestration impairs axonal lysosome delivery leading to autophagic stress and dystrophy in Niemann-Pick type C.

Joseph C Roney, Sunan Li, Tamar Farfel-Becker, Ning Huang, Tao Sun, Yuxiang Xie, Xiu-Tang Cheng, Mei-Yao Lin, Frances M Platt, Zu-Hang Sheng.

  Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterized by lipid accumulation in endolysosomes. An early pathologic hallmark is axonal dystrophy occurring at presymptomatic stages in NPC mice. However, the mechanisms underlying this pathologic change remain obscure. Here, we demonstrate that endocytic-autophagic organelles accumulate in NPC dystrophic axons. Using super-resolution and live-neuron imaging, we reveal that elevated cholesterol on NPC lysosome membranes sequesters kinesin-1 and Arl8 independent of SKIP and Arl8-GTPase activity, resulting in impaired lysosome transport into axons, contributing to axonal autophagosome accumulation. Pharmacologic reduction of lysosomal membrane cholesterol with 2-hydroxypropyl-β-cyclodextrin (HPCD) or elevated Arl8b expression rescues lysosome transport, thereby reducing axonal autophagic stress and neuron death in NPC. These findings demonstrate a pathological mechanism by which altered membrane lipid composition impairs lysosome delivery into axons and provide biological insights into the translational application of HPCD in restoring axonal homeostasis at early stages of NPC disease.

Keywords:  Niemann-Pick disease type C; autophagosome; axonal dystrophy; axonal transport; cholesterol; kinesin; lipid; lysosomal storage disorder; lysosome; neurodegeneration

DOI:  https://doi.org/10.1016/j.devcel.2021.03.032
J Neurosci. 2021 Apr 23. pii: JN-RM-2770-20. [Epub ahead of print]

VGLUT2 is a determinant of dopamine neuron resilience in a rotenone model of dopamine neurodegeneration.

Silas A Buck, Briana R De Miranda, Ryan W Logan, Kenneth N Fish, J Timothy Greenamyre, Zachary Freyberg.

Parkinson's disease (PD) is characterized by progressive dopamine (DA) neuron loss in the substantia nigra pars compacta (SNc). In contrast, DA neurons in the ventral tegmental area (VTA) are relatively protected from neurodegeneration, but the underlying mechanisms for this resilience remain poorly understood. Recent work suggests that expression of the vesicular glutamate transporter 2 (VGLUT2) selectively impacts midbrain DA neuron vulnerability. We investigated whether altered DA neuron VGLUT2 expression determines neuronal resilience in rats exposed to rotenone, a mitochondrial complex I inhibitor and toxicant model of PD. We discovered that VTA/SNc DA neurons that expressed VGLUT2 are more resilient to rotenone-induced DA neurodegeneration. Surprisingly, the density of neurons with detectable VGLUT2 expression in the VTA and SNc increases in response to rotenone. Furthermore, dopaminergic terminals within the nucleus accumbens, where the majority of VGLUT2-expressing DA neurons project, exhibit greater resilience compared to DA terminals in the caudate/putamen. More broadly, VGLUT2-expressing terminals are protected throughout the striatum from rotenone-induced degeneration. Together, our data demonstrate that a distinct subpopulation of VGLUT2-expressing DA neurons are relatively protected from rotenone neurotoxicity. Rotenone-induced upregulation of the glutamatergic machinery in VTA and SNc neurons and their projections may be part of a broader neuroprotective mechanism. These findings offer a putative new target for neuronal resilience that can be manipulated to prevent toxicant-induced DA neurodegeneration in PD.SIGNIFICANCE STATEMENT:Environmental exposures to pesticides contribute significantly to pathological processes that culminate in Parkinson's disease (PD). The pesticide rotenone has been used to generate a PD model that replicates key features of the illness including dopamine neurodegeneration. To date, longstanding questions remain: are there dopamine neuron subpopulations resilient to rotenone, and if so, what are the molecular determinants of this resilience? Here we show that the subpopulation of midbrain dopaminergic neurons that express the vesicular glutamate transporter 2 (VGLUT2) are more resilient to rotenone-induced neurodegeneration. Rotenone also upregulates VGLUT2 more broadly in the midbrain, suggesting VGLUT2 expression generally confers increased resilience to rotenone. VGLUT2 may therefore be a new target for boosting neuronal resilience to prevent toxicant-induced DA neurodegeneration in PD.

DOI: https://doi.org/10.1523/JNEUROSCI.2770-20.2021
Biochim Biophys Acta Mol Basis Dis. 2021 Apr 15. pii: S0925-4439(21)00080-6. [Epub ahead of print] 166147

Homozygous missense mutation in UQCRC2 associated with severe encephalomyopathy, mitochondrial complex III assembly defect and activation of mitochondrial protein quality control.

Daniela Burska, Lukas Stiburek, Jana Krizova, Marie Vanisova, Vaclav Martinek, Jana Sladkova, Josef Zamecnik, Tomas Honzik, Jiri Zeman, Hana Hansikova, Marketa Tesarova.

  The mitochondrial respiratory chain (MRC) complex III (CIII) associates with complexes I and IV (CI and CIV) into supercomplexes. We identified a novel homozygous missense mutation (c.665G>C; p.Gly222Ala) in UQCRC2 coding for structural subunit Core 2 in a patient with severe encephalomyopathy. The structural data suggest that the Gly222Ala exchange might result in an altered spatial arrangement in part of the UQCRC2 subunit, which could impact specific protein-protein interactions. Accordingly, we have found decreased levels of CIII and accumulation of CIII-specific subassemblies comprising MT-CYB, UQCRB, UQCRQ, UQCR10 and CYC1 subunits, but devoid of UQCRC1, UQCRC2, and UQCRFS1 in the patient's fibroblasts. The lack of UQCRC1 subunit-containing subassemblies could result from an impaired interaction with mutant UQCRC2Gly222Ala and subsequent degradation of both subunits by mitochondrial proteases. Indeed, we show an elevated amount of matrix CLPP protease, suggesting the activation of the mitochondrial protein quality control machinery in UQCRC2Gly222Ala fibroblasts. In line with growing evidence, we observed a rate-limiting character of CIII availability for the supercomplex formation, accompanied by a diminished amount of CI. Furthermore, we found impaired electron flux between CI and CIII in skeletal muscle and fibroblasts of the UQCRC2Gly222Ala patient. The ectopic expression of wild-type UQCRC2 in patient cells rescued maximal respiration rate, demonstrating the deleterious effect of the mutation on MRC. Our study expands the phenotypic spectrum of human disease caused by CIII Core protein deficiency, provides insight into the assembly pathway of human CIII, and supports the requirement of assembled CIII for a proper accumulation of CI.

Keywords:  Core 2); Mitochondrial dysfunction; UQCRC2 (Core2; caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP); mitochondrial complex III; mitochondrial protein quality control; respiratory supercomplexes

DOI:  https://doi.org/10.1016/j.bbadis.2021.166147