bims-midbra 2021-12-19 papers

bims-midbra

Biomed News

on Mitochondrial dynamics in brain cells

Issue of 2021‒12‒19
nine papers selected by
Ana Paula Mendonça
University of Padova

A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic tau mouse model of Alzheimer disease.
PINK1 signalling in neurodegenerative disease.
Cannabidiol activates PINK1-Parkin-dependent mitophagy and mitochondrial-derived vesicles.
Cristae junction as a fundamental switchboard for mitochondrial ion signaling and bioenergetics.
Mitochondria Dysfunction in Frontotemporal Dementia/Amyotrophic Lateral Sclerosis: Lessons From Drosophila Models.
Imaging of Mitophagy Enabled by an Acidity-Reporting Probe Anchored on the Mitochondrial Inner Membrane.
ZFP36 protects against oxygen-glucose deprivation/reoxygenation-induced mitochondrial fragmentation and neuronal apoptosis through inhibiting NOX4-DRP1 pathway.
Novel chemical inhibitor against SOD1 misfolding and aggregation protects neuron-loss and ameliorates disease symptoms in ALS mouse model.
Presynaptic Mitochondrial Volume and Packing Density Scale with Presynaptic Power Demand.

Hum Mol Genet. 2021 Dec 17. pii: ddab360. [Epub ahead of print]

A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic tau mouse model of Alzheimer disease.

Ramesh Kandimalla, Maria Manczak, Jangampalli Adi Pradeepkiran, Hallie Morton, P Hemachandra Reddy.

  The purpose of our study is to understand the impact of a partial dynamin-related protein 1 (Drp1) on cognitive behavior, mitophagy, autophagy, and mitochondrial and synaptic activities in transgenic Tau mice in Alzheimer's disease (ad). Our lab reported increased levels of Aβ and P-Tau, and abnormal interactions between Aβ and Drp1, P-Tau, and Drp1 induced increased mitochondrial fragmentation and reduced fusion and synaptic activities in ad. These abnormal interactions, result in the proliferation of dysfunctional mitochondria in ad neurons. Recent research on mitochondria revealed that fission protein Drp1 is largely implicated in mitochondrial dynamics in ad. To determine the impact of reduced Drp1 in ad, we recently crossed transgenic Tau mice with Drp1 heterozygote knockout (Drp1+/-) mice and generated double mutant (P301LDrp1+/-) mice. In the current study, we assessed cognitive behavior, mRNA and protein levels of mitophagy, autophagy, mitochondrial biogenesis, dynamics and synaptic genes, mitochondrial morphology & mitochondrial function, dendritic spines in Tau mice relative to double mutant mice. When compared to Tau mice, double mutant mice did better on Morris Maze (reduced latency to find hidden platform, increased swimming speed and time spent on quadrant) and rotarod (stayed a longer period of time) tests. Both mRNA and proteins levels autophagy, mitophagy, mitochondrial biogenesis and synaptic proteins were increased in double mutant mice compared to Tau (P301L) mice. Dendritic spines were significantly increased; mitochondrial number is reduced and length is increased in double mutant mice. Based on these observations, we conclude that reduced Drp1 is beneficial in a symptomatic-transgenic Tau (P301L) mice.

Keywords:  Mitochondria Alzheimer’s disease Mitophagy Autophagy Dynamin-related protein 1 Oxidative stress Mitochondrial biogenesis

DOI:  https://doi.org/10.1093/hmg/ddab360
Essays Biochem. 2021 Dec 13. pii: EBC20210036. [Epub ahead of print]

PINK1 signalling in neurodegenerative disease.

Daniel R Whiten, Dezerae Cox, Carolyn M Sue.

  PTEN-induced kinase 1 (PINK1) impacts cell health and human pathology through diverse pathways. The strict processing of full-length PINK1 on the outer mitochondrial membrane populates a cytoplasmic pool of cleaved PINK1 (cPINK1) that is constitutively degraded. However, despite rapid proteasomal clearance, cPINK1 still appears to exert quality control influence over the neuronal protein homeostasis network, including protein synthesis and degradation machineries. The cytoplasmic concentration and activity of this molecule is therefore a powerful sensor that coordinates aspects of mitochondrial and cellular health. In addition, full-length PINK1 is retained on the mitochondrial membrane following depolarisation, where it is a powerful inducer of multiple mitophagic pathways. This function is executed primarily through the phosphorylation of several ubiquitin ligases, including its most widely studied substrate Parkin. Furthermore, the phosphorylation of both pro- and anti-apoptotic proteins by mitochondrial PINK1 acts as a pro-cellular survival signal when faced with apoptotic stimuli. Through these varied roles PINK1 directly influences functions central to cell dysfunction in neurodegenerative disease.

Keywords:  Mitochondria; Mitophagy; Neurodegneration; PTEN induced putative kinase 1; Parkinsons disease

DOI:  https://doi.org/10.1042/EBC20210036
Eur J Cell Biol. 2021 Nov 14. pii: S0171-9335(21)00036-4. [Epub ahead of print]101(1): 151185

Cannabidiol activates PINK1-Parkin-dependent mitophagy and mitochondrial-derived vesicles.

Adrian Ramirez, William Old, David L Selwood, Xuedong Liu.

  The PINK1/Parkin pathway plays an important role in maintaining a healthy pool of mitochondria. Activation of this pathway can lead to apoptosis, mitophagy, or mitochondrial-derived vesicle formation, depending on the nature of mitochondrial damage. The signaling by which PINK/Parkin activation leads to these different mitochondrial outcomes remains understudied. Here we present evidence that cannabidiol (CBD) activates the PINK1-Parkin pathway in a unique manner. CBD stimulates PINK1-dependent Parkin mitochondrial recruitment similarly to other well-studied Parkin activators but with a distinctive shift in the temporal dynamics and mitochondrial fates. The mitochondrial permeability transition pore inhibitor cyclosporine A exclusively diminished the CBD-induced PINK1/Parkin activation and its associated mitochondrial effects. Unexpectedly, CBD treatment also induced elevated production of mitochondrial-derived vesicles (MDV), a potential quality control mechanism that may help repair partial damaged mitochondria. Our results suggest that CBD may engage the PINK1-Parkin pathway to produce MDV and repair mitochondrial lesions via mitochondrial permeability transition pore opening. This work uncovered a novel link between CBD and PINK1/Parkin-dependent MDV production in mitochondrial health regulation.

Keywords:  Cannabidiol; Mitochondrial quality control; Mitochondrial-derived vesicles (MDV); Mitophagy; PINK; Parkin

DOI:  https://doi.org/10.1016/j.ejcb.2021.151185
Cell Calcium. 2021 Dec 10. pii: S0143-4160(21)00171-8. [Epub ahead of print]101 102517

Cristae junction as a fundamental switchboard for mitochondrial ion signaling and bioenergetics.

Benjamin Gottschalk, Corina T Madreiter-Sokolowski, Wolfgang F Graier.

OPA1 and MICU1 are both involved in the regulation of mitochondrial Ca2+ uptake and the stabilization of the cristae junction, which separates the inner mitochondrial membrane into the interboundary membrane and the cristae membrane. In this mini-review, we focus on the synergetic control of OPA1 and MICU1 on the cristae junction that serves as a fundamental regulator of multiple mitochondrial functions. In particular, we point to the critical role of an adaptive cristae junction permeability in mitochondrial Ca2+ signaling, spatial H+ gradients and mitochondrial membrane potential, metabolic activity, and apoptosis. These characteristics bear on a distinct localization of the oxidative phosphorylation machinery, the FoF1-ATPase, and mitochondrial Ca2+uniporter (MCU) within sections of the inner mitochondrial membrane isolated by the cristae junction and regulated by proteins like OPA1 and MICU1. We specifically focus on the impact of MICU1-regulated cristae junction on the activity and distribution of MCU within the complex ultrastructure of mitochondria.

DOI: https://doi.org/10.1016/j.ceca.2021.102517
Front Neurosci. 2021 ;15 786076

Mitochondria Dysfunction in Frontotemporal Dementia/Amyotrophic Lateral Sclerosis: Lessons From Drosophila Models.

Sharifah Anoar, Nathaniel S Woodling, Teresa Niccoli.

  Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by declining motor and cognitive functions. Even though these diseases present with distinct sets of symptoms, FTD and ALS are two extremes of the same disease spectrum, as they show considerable overlap in genetic, clinical and neuropathological features. Among these overlapping features, mitochondrial dysfunction is associated with both FTD and ALS. Recent studies have shown that cells derived from patients' induced pluripotent stem cells (iPSC)s display mitochondrial abnormalities, and similar abnormalities have been observed in a number of animal disease models. Drosophila models have been widely used to study FTD and ALS because of their rapid generation time and extensive set of genetic tools. A wide array of fly models have been developed to elucidate the molecular mechanisms of toxicity for mutations associated with FTD/ALS. Fly models have been often instrumental in understanding the role of disease associated mutations in mitochondria biology. In this review, we discuss how mutations associated with FTD/ALS disrupt mitochondrial function, and we review how the use of Drosophila models has been pivotal to our current knowledge in this field.

Keywords:  ALS; Drosophila; FTD; mitochondria; neurodegeneration

DOI:  https://doi.org/10.3389/fnins.2021.786076
Anal Chem. 2021 Dec 12.

Imaging of Mitophagy Enabled by an Acidity-Reporting Probe Anchored on the Mitochondrial Inner Membrane.

Shixiong Wen, Xiao Hu, Yilong Shi, Jiahuai Han, Shoufa Han.

Classical chemical probes are prone to dissipation from stressed organelles, as evidenced by the incapability of mitochondrial dyes to image mitophagy linked to multiple diseases. We herein reported mitophagy imaging via covalent anchoring of a lysosomal probe to the mitochondrial inner membrane (CALM). Utilizing DBCORC-TPP, an azide-conjugatable probe with acidity-triggered fluorescence, CALM is operated via ΔΨm-promoted probe accumulation in mitochondria and thereby bioorthogonal ligation of the trapped probe with azido-choline (Azcholine) metabolically installed on the mitochondrial membrane. Overcoming the limitation of synthetic probes to dissipate from stressed organelles, CALM enables signal-on fluorescence imaging of mitophagy induced by starvation and is further employed to reveal mitophagy in ferroptosis. These results suggest the potential of CALM as a new tool to study mitophagy.

DOI: https://doi.org/10.1021/acs.analchem.1c03881
Brain Res Bull. 2021 Dec 09. pii: S0361-9230(21)00340-3. [Epub ahead of print]

ZFP36 protects against oxygen-glucose deprivation/reoxygenation-induced mitochondrial fragmentation and neuronal apoptosis through inhibiting NOX4-DRP1 pathway.

Hengjiang Guo, Yan Jiang, Zhiqing Gu, Lulu Ren, Change Zhu, Shenghua Yu, Rong Wei.

  The imbalance of mitochondrial dynamics plays an important role in the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Zinc-finger protein 36 (ZFP36) has been documented to have neuroprotective effects, however, whether ZFP36 is involved in the regulation of neuronal survival during cerebral I/R injury remains unknown. In this study, we found that the transcriptional and translational levels of ZFP36 were increased in immortalized hippocampal HT22 neuronal cells after oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. ZFP36 gene silencing exacerbated OGD/R-induced dynamin-related protein 1 (DRP1) activity, mitochondrial fragmentation, oxidative stress and neuronal apoptosis, whereas ZFP36 overexpression exhibited the opposite effects. Besides, we found that NADPH oxidase 4 (NOX4) was upregulated by OGD/R, and NOX4 inhibition remarkably attenuated OGD/R-instigated DRP1 activity, mitochondrial fragmentation and neuronal apoptosis. Further study demonstrated that ZFP36 targeted NOX4 mRNA directly by binding to the AU-rich elements (AREs) in the NOX4 3'-untranslated regions (3'-UTR) and inhibited NOX4 expression. Taken together, our data indicate that ZFP36 protects against OGD/R-induced neuronal injury by inhibiting NOX4-mediated DRP1 activation and excessive mitochondrial fission. Pharmacological targeting of ZFP36 to suppress excessive mitochondrial fission may provide new therapeutic strategies in the treatment of cerebral I/R injury.

Keywords:  DRP1; ZFP36; mitochondrial dysfunction; mitochondrial fission; neuronal apoptosis

DOI:  https://doi.org/10.1016/j.brainresbull.2021.12.003
Commun Biol. 2021 Dec 15. 4(1): 1397

Novel chemical inhibitor against SOD1 misfolding and aggregation protects neuron-loss and ameliorates disease symptoms in ALS mouse model.

Tae-Gyun Woo, Min-Ho Yoon, So-Mi Kang, Soyoung Park, Jung-Hyun Cho, Young Jun Hwang, Jinsook Ahn, Hyewon Jang, Yun-Jeong Shin, Eui-Man Jung, Nam-Chul Ha, Bae-Hoon Kim, Yonghoon Kwon, Bum-Joon Park.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective death of motor neurons. Mutations in Cu, Zn-superoxide dismutase (SOD1) causing the gain of its toxic property are the major culprit of familial ALS (fALS). The abnormal SOD1 aggregation in the motor neurons has been suggested as the major pathological hallmark of ALS patients. However, the development of pharmacological interventions against SOD1 still needs further investigation. In this study, using ELISA-based chemical screening with wild and mutant SOD1 proteins, we screened a new small molecule, PRG-A01, which could block the misfolding/aggregation of SOD1 or TDP-43. The drug rescued the cell death induced by mutant SOD1 in human neuroblastoma cell line. Administration of PRG-A01 into the ALS model mouse resulted in significant improvement of muscle strength, motor neuron viability and mobility with extended lifespan. These results suggest that SOD1 misfolding/aggregation is a potent therapeutic target for SOD1 related ALS.

DOI: https://doi.org/10.1038/s42003-021-02862-z
J Neurosci. 2021 Dec 10. pii: JN-RM-1236-21. [Epub ahead of print]

Presynaptic Mitochondrial Volume and Packing Density Scale with Presynaptic Power Demand.

Karlis A Justs, Zhongmin Lu, Amit K Chouhan, Jolanta A Borycz, Zhiyuan Lu, Ian A Meinertzhagen, Gregory T Macleod.

Stable neural function requires an energy supply that can meet the intense episodic power demands of neuronal activity. Neurons have presumably optimized the volume of their bioenergetic machinery to ensure these power demands are met, but the relationship between presynaptic power demands and the volume available to the bioenergetic machinery has never been quantified. Here we estimated the power demands of six motor nerve terminals in female Drosophila larvae through direct measurements of neurotransmitter release and Ca2+ entry, and via theoretical estimates of Na+ entry and power demands at rest. Electron microscopy revealed that terminals with the highest power demands contained the greatest volume of mitochondria, indicating that mitochondria are allocated according to presynaptic power demands. In addition, terminals with the greatest power demand-to-volume ratio (∼66 nmol·min-1·μL-1) harbor the largest mitochondria packed at the greatest density. If we assume sequential and complete oxidation of glucose by glycolysis and oxidative phosphorylation, then these mitochondria are required to produce ATP at a rate of 52 nmol·min-1·μL-1 at rest, rising to 963 during activity. Glycolysis would contribute ATP at 0.24 nmol·min-1·μL-1 of cytosol at rest, rising to 4.36 during activity. These data provide a quantitative framework for presynaptic bioenergetics in situ, and reveal that, beyond an immediate capacity to accelerate ATP output from glycolysis and oxidative phosphorylation, over longer time periods presynaptic terminals optimize mitochondrial volume and density to meet power demand.Significance StatementThe remarkable energy demands of the brain are supported by the complete oxidation of its fuel but debate continues regarding a division of labor between glycolysis and oxidative phosphorylation across different cell types. Here we exploit the neuromuscular synapse, a model for studying neurophysiology, to elucidate fundamental aspects of neuronal energy metabolism that ultimately constrain rates of neural processing. We quantified energy production rates required to sustain activity at individual nerve terminals and compared these with the volume capable of oxidative phosphorylation (mitochondria) and glycolysis (cytosol). We find strong support for oxidative phosphorylation playing a primary role in presynaptic terminals and provide the first in vivo estimates of energy production rates per unit volume of presynaptic mitochondria and cytosol.

DOI: https://doi.org/10.1523/JNEUROSCI.1236-21.2021