bims-midbra 2021-12-26 papers

bims-midbra

Biomed News

on Mitochondrial dynamics in brain cells

Issue of 2021–12–26
twelve papers selected by
Ana Paula Mendonça, University of Padova

The balance of mitochondrial fission and fusion in cortical axons depends on the kinases SadA and SadB.
Mitochondrial Phenotypes in Parkinson's Diseases-A Focus on Human iPSC-Derived Dopaminergic Neurons.
Disrupted expression of mitochondrial NCLX sensitizes neuroglial networks to excitotoxic stimuli and renders synaptic activity toxic.
Fuel for emotion: how mitophagy in the BLA can mediate increased anxiety in stressful social situations.
Administration of miR-195 Inhibitor Enhances Memory Function Through Improving Synaptic Degradation and Mitochondrial Dysfunction of the Hippocampal Neurons in SAMP8 Mice.
Mitophagy in neurological disorders.
Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons.
A Link between Mitochondrial Dysregulation and Idiopathic Autism Spectrum Disorder (ASD): Alterations in Mitochondrial Respiratory Capacity and Membrane Potential.
Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons.
Distinct subcellular autophagy impairments in induced neurons from Huntington's disease patients.
BNIP3L/NIX-mediated mitophagy: molecular mechanisms and implications for human disease.
AMPK-PINK1/Parkin Mediated Mitophagy Is Necessary for Alleviating Oxidative Stress-Induced Intestinal Epithelial Barrier Damage and Mitochondrial Energy Metabolism Dysfunction in IPEC-J2.

Cell Rep. 2021 Dec 21. pii: S2211-1247(21)01637-5. [Epub ahead of print]37(12): 110141

The balance of mitochondrial fission and fusion in cortical axons depends on the kinases SadA and SadB.

Danila Di Meo, Priyadarshini Ravindran, Tanmay Sadhanasatish, Pratibha Dhumale, Andreas W Püschel.

  Neurons are highly polarized cells that display characteristic differences in the organization of their organelles in axons and dendrites. The kinases SadA and SadB (SadA/B) promote the formation of distinct axonal and dendritic extensions during the development of cortical and hippocampal neurons. Here, we show that SadA/B are required for the specific dynamics of axonal mitochondria. Ankyrin B (AnkB) stimulates the activity of SadA/B that function as regulators of mitochondrial dynamics through the phosphorylation of tau. Suppression of SadA/B or AnkB in cortical neurons induces the elongation of mitochondria by disrupting the balance of fission and fusion. SadA/B-deficient neurons show an accumulation of hyper-fused mitochondria and activation of the integrated stress response (ISR). The normal dynamics of axonal mitochondria could be restored by mild actin destabilization. Thus, the elongation after loss of SadA/B results from an excessive stabilization of actin filaments and reduction of Drp1 recruitment to mitochondria.

Keywords:  Ankyrin; Brsk1; Brsk2; Drp1; F-actin; Mapt; hyperfusion; mitochondrial dynamics; mitochondrial fission; neuronal polarity

DOI:  https://doi.org/10.1016/j.celrep.2021.110141
Cells. 2021 Dec 07. pii: 3436. [Epub ahead of print]10(12):

Mitochondrial Phenotypes in Parkinson's Diseases-A Focus on Human iPSC-Derived Dopaminergic Neurons.

Leonie M Heger, Rachel M Wise, J Tabitha Hees, Angelika B Harbauer, Lena F Burbulla.

  Established disease models have helped unravel the mechanistic underpinnings of pathological phenotypes in Parkinson's disease (PD), the second most common neurodegenerative disorder. However, these discoveries have been limited to relatively simple cellular systems and animal models, which typically manifest with incomplete or imperfect recapitulation of disease phenotypes. The advent of induced pluripotent stem cells (iPSCs) has provided a powerful scientific tool for investigating the underlying molecular mechanisms of both familial and sporadic PD within disease-relevant cell types and patient-specific genetic backgrounds. Overwhelming evidence supports mitochondrial dysfunction as a central feature in PD pathophysiology, and iPSC-based neuronal models have expanded our understanding of mitochondrial dynamics in the development and progression of this devastating disorder. The present review provides a comprehensive assessment of mitochondrial phenotypes reported in iPSC-derived neurons generated from PD patients' somatic cells, with an emphasis on the role of mitochondrial respiration, morphology, and trafficking, as well as mitophagy and calcium handling in health and disease. Furthermore, we summarize the distinguishing characteristics of vulnerable midbrain dopaminergic neurons in PD and report the unique advantages and challenges of iPSC disease modeling at present, and for future mechanistic and therapeutic applications.

Keywords:  Parkinson’s disease; dopaminergic neurons; iPSC; mitochondria

DOI:  https://doi.org/10.3390/cells10123436
J Biol Chem. 2021 Dec 20. pii: S0021-9258(21)01318-1. [Epub ahead of print] 101508

Disrupted expression of mitochondrial NCLX sensitizes neuroglial networks to excitotoxic stimuli and renders synaptic activity toxic.

Anna M Hagenston, Jing Yan, Carlos Bas-Orth, Yanwei Tan, Israel Sekler, Hilmar Bading.

  The mitochondrial sodium/calcium/lithium exchanger (NCLX) is an important mediator of calcium extrusion from mitochondria. In this study, we tested the hypothesis that physiological expression levels of NCLX are essential for maintaining neuronal resilience in the face of excitotoxic challenge. Using a short hairpin RNA (shRNA)-mediated approach, we showed that reduced NCLX expression exacerbates neuronal mitochondrial calcium dysregulation, mitochondrial membrane potential (ΔΨm) breakdown, and reactive oxygen species (ROS) generation during excitotoxic stimulation of primary hippocampal cultures. Moreover, NCLX knockdown-which affected both neurons and glia-resulted not only in enhanced neurodegeneration following an excitotoxic insult, but also in neuronal and astrocytic cell death under basal conditions. Our data also revealed that synaptic activity, which promotes neuroprotective signaling, can become lethal upon NCLX depletion; expression of NCLX-targeted shRNA impaired the clearance of mitochondrial calcium following action potential bursts and was associated both with ΔΨmbreakdown and substantial neurodegeneration in hippocampal cultures undergoing synaptic activity. Finally, we showed that NCLX knockdown within the hippocampal cornu ammonis 1 (CA1) region in vivo causes substantial neuro- and astrodegeneration. In summary, we demonstrated that dysregulated NCLX expression not only sensitizes neuroglial networks to excitotoxic stimuli but notably also renders otherwise neuroprotective synaptic activity toxic. These findings may explain the emergence of neuro- and astrodegeneration in patients with disorders characterized by disrupted NCLX expression or function, and suggest that treatments aimed at enhancing or restoring NCLX function may prevent central nervous system damage in these disease states.

Keywords:  Calcium signaling; NCLX; gene expression; mitochondria; neurotoxicity; synaptic activity

DOI:  https://doi.org/10.1016/j.jbc.2021.101508
Autophagy. 2021 Dec 19. 1-2

Fuel for emotion: how mitophagy in the BLA can mediate increased anxiety in stressful social situations.

James Johnson, Zheng Li.

  Psychosocial stress is a common risk factor for anxiety disorders. The cellular mechanism for the anxiogenic effect of psychosocial stress is largely unclear. We recently showed that chronic social defeat (CSD) stress in mice causes mitochondrial impairment, which triggers the PINK1-PRKN/parkin mitophagy pathway selectively in the amygdala. This mitophagy elevation causes excessive mitochondrial elimination and consequent mitochondrial deficiency. Mitochondrial deficiency in the basolateral amygdalae (BLA) causes weakening of synaptic transmission in the BLA-BNST (bed nucleus of the stria terminalis) anxiolytic pathway and increased anxiety. The CSD-induced increase in anxiety-like behaviors is abolished in pink1-/- and prkn-/- mice and alleviated by optogenetic activation of the BLA-BNST synapse. This study identifies an unsuspected role of mitophagy in psychogenetic-stress-induced anxiety elevation and reveals that mitochondrial deficiency is sufficient to increase anxiety and underlies the psychosocial-stress-induced anxiety increase. Mitochondria and mitophagy, therefore, can be potentially targeted to ameliorate anxiety.

Keywords:  BNST; Mitophagy; amygdala; anxiety; mitochondria; psychological stress; social defeat stress

DOI:  https://doi.org/10.1080/15548627.2021.2014769
J Alzheimers Dis. 2021 Dec 17.

Administration of miR-195 Inhibitor Enhances Memory Function Through Improving Synaptic Degradation and Mitochondrial Dysfunction of the Hippocampal Neurons in SAMP8 Mice.

Zhaoyu Gao, Rui Zhang, Lei Jiang, Huimin Zhou, Qian Wang, Yingxin Ma, Di Zhang, Yushi Qin, Pei Tian, Nan Zhang, Zhongli Shi, Shunjiang Xu.

   BACKGROUND: Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD) and miR-195 is involved in mitochondrial disorder through targeting MFN-2 protein in hippocampal neurons of AD.
OBJECTIVE: To clarify if administration of miR-195 inhibitor could enhance the memory deficits through improving hippocampal neuron mitochondrial dysfunction in SAMP8 mice.
METHODS: The expression of miR-195 was detected by RT-qPCR in primary hippocampal neurons and HT-22 cells treated with Aβ 1-42. Morris water maze (MWM) was used to assess the learning and memory function in SAMP8 mice administrated with antagomir-195. Transmission electron microscopy was employed to determine the morphological changes of synapses and mitochondria of hippocampus in SAMP8 mice. Mitochondrial respiration was measured using a high-resolution oxygraph.
RESULTS: The expression of miR-195 were upregulated in the primary hippocampal neurons and HT-22 cells induced by Aβ 1-42. Inhibition of miR-195 ameliorated the mitochondrial dysfunction in HT-22 cells induced by Aβ 1-42, including mitochondrial morphologic damages, mitochondrial membrane potential, respiration function, and ATP production. Administration of antagomir-195 by the third ventricle injection markedly ameliorated the cognitive function, postsynaptic density thickness, length of synaptic active area, mitochondrial aspect ratio, and area in hippocampus of SAMP8 mice. Finally, antagomir-195 was able to promote an increase in the activity of respiratory chain complex CI and II in SAMP8 mice.
CONCLUSION: This study demonstrated that miR-195 inhibitor ameliorated the cognitive impairment of AD mice by improving mitochondrial structure damages and dysfunction in the hippocampal neurons, which provide an experimental basis for further exploring the treatment strategy of AD.

Keywords:  Alzheimer’s disease; cognitive dysfunction; microRNA-195; mitochondria; synaptic membranes

DOI:  https://doi.org/10.3233/JAD-215301
J Neuroinflammation. 2021 Dec 22. 18(1): 297

Mitophagy in neurological disorders.

Lijun Zhang, Lei Dai, Deyuan Li.

  Selective autophagy is an evolutionarily conserved mechanism that removes excess protein aggregates and damaged intracellular components. Most eukaryotic cells, including neurons, rely on proficient mitophagy responses to fine-tune the mitochondrial number and preserve energy metabolism. In some circumstances (such as the presence of pathogenic protein oligopolymers and protein mutations), dysfunctional mitophagy leads to nerve degeneration, with age-dependent intracellular accumulation of protein aggregates and dysfunctional organelles, leading to neurodegenerative disease. However, when pathogenic protein oligopolymers, protein mutations, stress, or injury are present, mitophagy prevents the accumulation of damaged mitochondria. Accordingly, mitophagy mediates neuroprotective effects in some forms of neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis) and acute brain damage (e.g., stroke, hypoxic-ischemic brain injury, epilepsy, and traumatic brain injury). The complex interplay between mitophagy and neurological disorders suggests that targeting mitophagy might be applicable for the treatment of neurodegenerative diseases and acute brain injury. However, due to the complexity of the mitophagy mechanism, mitophagy can be both harmful and beneficial, and future efforts should focus on maximizing its benefits. Here, we discuss the impact of mitophagy on neurological disorders, emphasizing the contrast between the positive and negative effects of mitophagy.

Keywords:  Alzheimer's disease; Autophagy; Huntington's disease; Mitophagy; Neurological diseases; Stroke

DOI:  https://doi.org/10.1186/s12974-021-02334-5
Front Aging Neurosci. 2021 ;13 766306

Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons.

Sandra Lizbeth Morales-Rosales, Roberto Santín-Márquez, Pedro Posadas-Rodriguez, Ruth Rincon-Heredia, Teresa Montiel, Raúl Librado-Osorio, Armando Luna-López, Nadia Alejandra Rivero-Segura, Claudio Torres, Agustina Cano-Martínez, Alejandro Silva-Palacios, Paulina Cortés-Hernández, Julio Morán, Lourdes Massieu, Mina Konigsberg.

  The decline in brain function during aging is one of the most critical health problems nowadays. Although senescent astrocytes have been found in old-age brains and neurodegenerative diseases, their impact on the function of other cerebral cell types is unknown. The aim of this study was to evaluate the effect of senescent astrocytes on the mitochondrial function of a neuron. In order to evaluate neuronal susceptibility to a long and constant senescence-associated secretory phenotype (SASP) exposure, we developed a model by using cellular cocultures in transwell plates. Rat primary cortical astrocytes were seeded in transwell inserts and induced to premature senescence with hydrogen peroxide [stress-induced premature senescence (SIPS)]. Independently, primary rat cortical neurons were seeded at the bottom of transwells. After neuronal 6 days in vitro (DIV), the inserts with SIPS-astrocytes were placed in the chamber and cocultured with neurons for 6 more days. The neuronal viability, the redox state [reduced glutathione/oxidized glutathione (GSH/GSSG)], the mitochondrial morphology, and the proteins and membrane potential were determined. Our results showed that the neuronal mitochondria functionality was altered after being cocultured with senescent astrocytes. In vivo, we found that old animals had diminished mitochondrial oxidative phosphorylation (OXPHOS) proteins, redox state, and senescence markers as compared to young rats, suggesting effects of the senescent astrocytes similar to the ones we observed in vitro. Overall, these results indicate that the microenvironment generated by senescent astrocytes can affect neuronal mitochondria and physiology.

Keywords:  aging; astrocyte; cellular senescence; mitochondria; redox state

DOI:  https://doi.org/10.3389/fnagi.2021.766306
Curr Issues Mol Biol. 2021 Dec 16. 43(3): 2238-2252

A Link between Mitochondrial Dysregulation and Idiopathic Autism Spectrum Disorder (ASD): Alterations in Mitochondrial Respiratory Capacity and Membrane Potential.

Hazirah Hassan, Fazaine Zakaria, Suzana Makpol, Norwahidah Abdul Karim.

  Autism spectrum disorder (ASD) is a neurological disorder triggered by various factors through complex mechanisms. Research has been done to elucidate the potential etiologic mechanisms in ASD, but no single cause has been confirmed. The involvement of oxidative stress is correlated with ASD and possibly affects mitochondrial function. This study aimed to elucidate the link between mitochondrial dysregulation and idiopathic ASD by focusing on mitochondrial respiratory capacity and membrane potential. Our findings showed that mitochondrial function in the energy metabolism pathway was significantly dysregulated in a lymphoblastoid cell line (LCL) derived from an autistic child (ALCL). Respiratory capacities of oxidative phosphorylation (OXPHOS), electron transfer of the Complex I and Complex II linked pathways, membrane potential, and Complex IV activity of the ALCL were analyzed and compared with control cell lines derived from a developmentally normal non-autistic sibling (NALCL). All experiments were performed using high-resolution respirometry. Respiratory capacities of OXPHOS, electron transfer of the Complex I- and Complex II-linked pathways, and Complex IV activity of the ALCL were significantly higher compared to healthy controls. Mitochondrial membrane potential was also significantly higher, measured in the Complex II-linked pathway during LEAK respiration and OXPHOS. These results indicate the abnormalities in mitochondrial respiratory control linking mitochondrial function with autism. Correlating mitochondrial dysfunction and autism is important for a better understanding of ASD pathogenesis in order to produce effective interventions.

Keywords:  autism; high-resolution respirometry; mitochondria; mitochondrial membrane potential; mitochondrial respiration; oxidative phosphorylation

DOI:  https://doi.org/10.3390/cimb43030157
Int J Mol Sci. 2021 Dec 14. pii: 13442. [Epub ahead of print]22(24):

Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons.

Guy C Brown.

  After stroke, there is a rapid necrosis of all cells in the infarct, followed by a delayed loss of neurons both in brain areas surrounding the infarct, known as 'selective neuronal loss', and in brain areas remote from, but connected to, the infarct, known as 'secondary neurodegeneration'. Here we review evidence indicating that this delayed loss of neurons after stroke is mediated by the microglial phagocytosis of stressed neurons. After a stroke, neurons are stressed by ongoing ischemia, excitotoxicity and/or inflammation and are known to: (i) release "find-me" signals such as ATP, (ii) expose "eat-me" signals such as phosphatidylserine, and (iii) bind to opsonins, such as complement components C1q and C3b, inducing microglia to phagocytose such neurons. Blocking these factors on neurons, or their phagocytic receptors on microglia, can prevent delayed neuronal loss and behavioral deficits in rodent models of ischemic stroke. Phagocytic receptors on microglia may be attractive treatment targets to prevent delayed neuronal loss after stroke due to the microglial phagocytosis of stressed neurons.

Keywords:  cell death; delayed neuronal death; ischemia; microglia; neuronal death; phagocytosis; phagoptosis; secondary neurodegeneration; selective neuronal loss; stroke

DOI:  https://doi.org/10.3390/ijms222413442
Brain. 2021 Dec 22. pii: awab473. [Epub ahead of print]

Distinct subcellular autophagy impairments in induced neurons from Huntington's disease patients.

Karolina Pircs, Janelle Drouin-Ouellet, Vivien Horváth, Jeovanis Gil, Melinda Rezeli, Raquel Garza, Daniela A Grassi, Yogita Sharma, Isabelle St-Amour, Kate Harris, Marie E Jönsson, Pia A Johansson, Romina Vuono, Shaline V Fazal, Thomas Stoker, Bob A Hersbach, Kritika Sharma, Jessica Lagerwall, Stina Lagerström, Petter Storm, Sébastien S Hébert, György Marko-Varga, Malin Parmar, Roger A Barker, Johan Jakobsson.

  Huntington's disease (HD) is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling Huntington's disease is challenging, as rodent and cellular models poorly recapitulate the disease as seen in aging humans. To address this, we generated induced neurons (iNs) through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics. HD-iNs displayed profound deficits in autophagy, characterised by reduced transport of late autophagic structures from the neurites to the soma. These neurite-specific alterations in autophagy resulted in shorter, thinner and fewer neurites specifically in HD-iNs. CRISPRi-mediated silencing of HTT did not rescue this phenotype but rather resulted in additional autophagy alterations in ctrl-iNs, highlighting the importance of wild type HTT in normal neuronal autophagy. In summary, our work identifies a distinct subcellular autophagy impairment in adult patient derived Huntington's disease neurons and provides a new rational for future development of autophagy activation therapies.

Keywords:  CRISPR interference; Huntington’s disease; autophagy; direct neural reprogramming; lentiviral vector

DOI:  https://doi.org/10.1093/brain/awab473
Cell Death Dis. 2021 Dec 20. 13(1): 14

BNIP3L/NIX-mediated mitophagy: molecular mechanisms and implications for human disease.

Yue Li, Wanqing Zheng, Yangyang Lu, Yanrong Zheng, Ling Pan, Xiaoli Wu, Yang Yuan, Zhe Shen, Shijia Ma, Xingxian Zhang, Jiaying Wu, Zhong Chen, Xiangnan Zhang.

Mitophagy is a highly conserved cellular process that maintains the mitochondrial quantity by eliminating dysfunctional or superfluous mitochondria through autophagy machinery. The mitochondrial outer membrane protein BNIP3L/Nix serves as a mitophagy receptor by recognizing autophagosomes. BNIP3L is initially known to clear the mitochondria during the development of reticulocytes. Recent studies indicated it also engages in a variety of physiological and pathological processes. In this review, we provide an overview of how BNIP3L induces mitophagy and discuss the biological functions of BNIP3L and its regulation at the molecular level. We further discuss current evidence indicating the involvement of BNIP3L-mediated mitophagy in human disease, particularly in cancer and neurological disorders.

DOI: https://doi.org/10.1038/s41419-021-04469-y
Antioxidants (Basel). 2021 Dec 18. pii: 2010. [Epub ahead of print]10(12):

AMPK-PINK1/Parkin Mediated Mitophagy Is Necessary for Alleviating Oxidative Stress-Induced Intestinal Epithelial Barrier Damage and Mitochondrial Energy Metabolism Dysfunction in IPEC-J2.

Shuting Cao, Hao Xiao, Xin Li, Jiang Zhu, Jingchun Gao, Li Wang, Caihong Hu.

  The imbalance of redox biology and oxidative stress leads to intestinal barrier injury and mitophagy. However, much uncertainty still exists about the role of mitophagy in oxidative stress and intestinal function. Here, we showed the effects of hydrogen peroxide (H2O2)-induced oxidative stress on intestinal epithelial cell oxidation balance, intestinal barrier function and mitochondrial energy metabolism and its underlying mechanism. In this study, we found that H2O2-induced oxidative stress activated adenosine monophosphate-activated protein kinase (AMPK) and enhanced mitophagy in intestinal porcine epithelial cells (IPEC-J2). While compound C (AMPK inhibitor) and mdivi-1 (mitophagy inhibitor) significantly reduced the activity of superoxide dismutase (SOD) and increased mitochondrial reactive oxygen species (ROS) levels in H2O2 treated cells. Moreover, compound C and mdivi-1 significantly reduced the trans-epithelium electrical resistant (TER) and increased the fluorescein isothiocyanate-dextran (FD4) flux in H2O2 treated IPEC-J2. Furthermore, compound C and mdivi-1 significantly reduced the activity of mitochondrial complex II. Seahorse XF96 data showed that compound C + mdivi-1+ H2O2 treatment significantly reduced maximum respiratory oxygen consumption and spare respiratory capacity. Additionally, compound C or mdivi-1 treatment reduced the formation of mitochondrial autophagosomes. These results unveiled that AMPK and PINK1/Parkin mediated mitophagy is necessary for alleviating oxidative stress induced intestinal epithelial barrier damage and mitochondrial energy metabolism dysfunction in IPEC-J2.

Keywords:  AMPK-PINK1/Parkin; intestinal barrier function; mitochondrial energy metabolism; mitophagy; oxidative stress

DOI:  https://doi.org/10.3390/antiox10122010