bims-midbra 2021-11-07 papers

bims-midbra

Biomed News

on Mitochondrial dynamics in brain cells

Issue of 2021–11–07
nine papers selected by
Ana Paula Mendonça, University of Padova

Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer's Disease.
The loss of enzymatic activity of the PHARC associated lipase ABHD12 results in increased phagocytosis that causes neuroinflammation.
Overexpression of SIRT3 Suppresses Oxidative Stress-induced Neurotoxicity and Mitochondrial Dysfunction in Dopaminergic Neuronal Cells.
Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease.
Resveratrol reduces DRP1-mediated mitochondrial dysfunction via the SIRT1-PGC1α signaling pathway in manganese-induced nerve damage in mice.
Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease: removing axonal debris.
Primary mitochondrial myopathies in childhood.
Disruption of mitochondrial complex I induces progressive parkinsonism.
Mitigating the pro-oxidant state and melanogenesis of Retinitis pigmentosa: by counteracting mitochondrial dysfunction.

Mol Neurobiol. 2021 Nov 02.

Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer's Disease.

Rishika Dhapola, Phulen Sarma, Bikash Medhi, Ajay Prakash, Dibbanti HariKrishna Reddy.

  Alzheimer's disease (AD) is a neurodegenerative disorder which leads to mental deterioration due to aberrant accretion of misfolded proteins in the brain. According to mitochondrial cascade hypothesis, mitochondrial dysfunction is majorly involved in the pathogenesis of AD. Many drugs targeting mitochondria to treat and prevent AD are in different phases of clinical trials for the evaluation of safety and efficacy as mitochondria are involved in various cellular and neuronal functions. Mitochondrial dynamics is regulated by fission and fusion processes mediated by dynamin-related protein (Drp1). Inner membrane fusion takes place by OPA1 and outer membrane fusion is facilitated by mitofusin1 and mitofusin2 (Mfn1/2). Excessive calcium release also impairs mitochondrial functions; to overcome this, calcium channel blockers like nilvadipine are used. Another process acting as a regulator of mitochondrial function is mitophagy which is involved in the removal of damaged and non-functional mitochondria however this process is also altered in AD due to mutations in Presenilin1 (PS1) and Amyloid Precursor Protein (APP) gene. Mitochondrial dynamics is altered in AD which led to the discovery of various fission protein (like Drp1) inhibitors and drugs that promote fusion. Modulations in AMPK, SIRT1 and Akt pathways can also come out to be better therapeutic strategies as these pathways regulate functions of mitochondria. Oxidative phosphorylation is major generator of Reactive Oxygen Species (ROS) leading to mitochondrial damage; therefore reduction in production of ROS by using antioxidants like MitoQ, Curcumin and Vitamin Eis quiteeffective.

Keywords:  Alzheimer’s disease; Drugs; Fusion-fission proteins; Mitochondrial dysfunction; Mitophagy

DOI:  https://doi.org/10.1007/s12035-021-02612-6
Eur J Neurosci. 2021 Nov 02.

The loss of enzymatic activity of the PHARC associated lipase ABHD12 results in increased phagocytosis that causes neuroinflammation.

Shubham Singh, Siddhesh S Kamat.

  Phagocytosis is an important evolutionary conserved process, essential for clearing pathogens and cellular debris in higher organisms, including humans. This well-orchestrated innate immunological response is intricately regulated by numerous cellular factors, important amongst which, are the immunomodulatory lysophosphatidylserines (lyso-PSs) and the pro-apoptotic oxidized phosphatidylserines (PSs) signaling lipids. Interestingly, in mammals, both these signaling lipids are physiologically regulated by the lipase ABHD12, mutations of which, cause the human neurological disorder PHARC. Despite the biomedical significance of this lipase, detailed mechanistic studies and the specific contribution of ABHD12 to innate processes like phagocytosis remain poorly understood. Here, by immunohistochemical and immunofluorescence approaches, using the murine model of PHARC, we show, that upon an inflammatory stimulus, activated microglial cells in the cerebellum of mice deficient in ABHD12 have an amoeboid morphology, increased soma size, and display heightened phagocytosis activity. We also report that upon an inflammatory stimulus, cerebellar levels of ABHD12 increase to possibly metabolize the heightened oxidized PS levels, temper phagocytosis and in turn control neuroinflammation during oxidative stress. Next, to complement these findings, using biochemical approaches in cultured microglial cells, we show that the pharmacological inhibition and/or genetic deletion of ABHD12 results in increased phagocytic uptake in a fluorescent bead uptake assay. Together, our studies provide compelling evidence that ABHD12 plays an important role in regulating phagocytosis in cerebellar microglial cells, and provides a possible explanation, as to why human PHARC subjects display neuroinflammation and atrophy in the cerebellum.

Keywords:  ABHD12; PHARC; cerebellum; lyso-PS; microglia; neuroinflammation; neurons; oxidized PS; phagocytosis

DOI:  https://doi.org/10.1111/ejn.15516
Exp Neurobiol. 2021 Oct 31. 30(5): 341-355

Overexpression of SIRT3 Suppresses Oxidative Stress-induced Neurotoxicity and Mitochondrial Dysfunction in Dopaminergic Neuronal Cells.

Shinrye Lee, Yu-Mi Jeon, Myungjin Jo, Hyung-Jun Kim.

  Sirtuin 3 (SIRT3), a well-known mitochondrial deacetylase, is involved in mitochondrial function and metabolism under various stress conditions. In this study, we found that the expression of SIRT3 was markedly increased by oxidative stress in dopaminergic neuronal cells. In addition, SIRT3 overexpression enhanced mitochondrial activity in differentiated SH-SY5Y cells. We also showed that SIRT3 overexpression attenuated rotenoneor H2O2-induced toxicity in differentiated SH-SY5Y cells (human dopaminergic cell line). We further found that knockdown of SIRT3 enhanced rotenone- or H2O2-induced toxicity in differentiated SH-SY5Y cells. Moreover, overexpression of SIRT3 mitigated cell death caused by LPS/IFN-γ stimulation in astrocytes. We also found that the rotenone treatment increases the level of SIRT3 in Drosophila brain. We observed that downregulation of sirt2 (Drosophila homologue of SIRT3) significantly accelerated the rotenone-induced toxicity in flies. Taken together, these findings suggest that the overexpression of SIRT3 mitigates oxidative stress-induced cell death and mitochondrial dysfunction in dopaminergic neurons and astrocytes.

Keywords:  Astrocyte/neuron coculture; Dopaminergic neuron; Mitochondrial dysfunction; Neurotoxicity; Oxidative stress; SIRT3

DOI:  https://doi.org/10.5607/en21021
Commun Biol. 2021 Nov 04. 4(1): 1262

Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease.

Aine Fairbrother-Browne, Aminah T Ali, Regina H Reynolds, Sonia Garcia-Ruiz, David Zhang, Zhongbo Chen, Mina Ryten, Alan Hodgkinson.

Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases. The mitochondrial genome encodes core respiratory chain proteins, but the vast majority of mitochondrial proteins are nuclear-encoded, making interactions between the two genomes vital for cell function. Here, we examine these relationships by comparing mitochondrial and nuclear gene expression across different regions of the human brain in healthy and disease cohorts. We find strong regional patterns that are modulated by cell-type and reflect functional specialisation. Nuclear genes causally implicated in sporadic Parkinson's and Alzheimer's disease (AD) show much stronger relationships with the mitochondrial genome than expected by chance, and mitochondrial-nuclear relationships are highly perturbed in AD cases, particularly through synaptic and lysosomal pathways, potentially implicating the regulation of energy balance and removal of dysfunction mitochondria in the etiology or progression of the disease. Finally, we present MitoNuclearCOEXPlorer, a tool to interrogate key mitochondria-nuclear relationships in multi-dimensional brain data.

DOI: https://doi.org/10.1038/s42003-021-02792-w
Environ Toxicol. 2021 Nov 05.

Resveratrol reduces DRP1-mediated mitochondrial dysfunction via the SIRT1-PGC1α signaling pathway in manganese-induced nerve damage in mice.

Meng-Yu Lei, Lin Cong, Zhi-Qi Liu, Zhuo-Fan Liu, Zhuo Ma, Kuan Liu, Jing Li, Yu Deng, Wei Liu, Bin Xu.

  Excessive manganese (Mn) exposure can cause nerve damage and mitochondrial dysfunction, which may involve defects in mitochondrial dynamics. Resveratrol (RSV) exerts a wide range of beneficial effects via activation of sirtuin 1 (SIRT1) and thus may positively impact Mn-induced mitochondrial damage through the regulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) by SIRT1. In this study, we investigated the molecular mechanisms by which RSV alleviates the nerve injury and mitochondrial fragmentation caused by Mn in C57 BL/6 mice. Our results demonstrated that RSV activated the deacetylase activity of SIRT1 and protected against the surge of mitochondrial reactive oxygen species, the loss of mitochondrial membrane potential, and the attenuation of ATP caused by Mn. RSV, therefore, inhibits mitochondrial fragmentation and safeguards neural cells. Increased deacetylase activity led to a reduction in the acetylation of PGC-1α, which directly regulates DRP1 expression by binding to the DRP1 promoter. The resultant attenuation of DRP1-mediated mitochondrial fragmentation in RSV-pretreated mice was abolished by the addition of the SIRT1 inhibitor EX527. Taken together, these findings indicate that RSV alleviates Mn-induced mitochondrial dysfunction mediated by DRP1 by modulating the SIRT1/PGC-1α signaling pathway.

Keywords:  dynamin-related protein 1; mitochondrial fragmentization; neurotoxicity; sirtuin1

DOI:  https://doi.org/10.1002/tox.23397
Transl Neurodegener. 2021 Nov 02. 10(1): 43

Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease: removing axonal debris.

Ingrid Morales, Ricardo Puertas-Avendaño, Alberto Sanchez, Adrian Perez-Barreto, Clara Rodriguez-Sabate, Manuel Rodriguez.

   OBJECTIVE: The dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%-5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson's disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia.
METHODS: Rats and mice were injected in the lateral ventricles with 6-hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images.
RESULTS: The selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α-synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons.
CONCLUSIONS: The present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.

Keywords:  Astrocyte; Dying-back degeneration; Medial forebrain bundle; Parkinson’s disease; Phagocytosis; Spheroid

DOI:  https://doi.org/10.1186/s40035-021-00262-1
Neuromuscul Disord. 2021 Oct;pii: S0960-8966(21)00607-6. [Epub ahead of print]31(10): 978-987

Primary mitochondrial myopathies in childhood.

Catarina Olimpio, May Yung Tiet, Rita Horvath.

  Primary mitochondrial myopathies are genetic metabolic disorders of mitochondrial dysfunction affecting mainly, but not exclusively, skeletal muscle. Although individually rare, they are the most common inherited metabolic disorders in childhood. They can be similar to other childhood muscle diseases such as congenital myopathies, dystrophies, myasthenic syndromes or metabolic myopathies and a muscle biopsy and genetic testing are important in the differential diagnosis. Mitochondrial myopathies can present at any age but typically childhood onset myopathies have more significant muscle involvement and are caused by genes encoded in the nuclear DNA. Mitochondrial myopathy in infants presents with hypotonia, muscle weakness and difficulty feeding. In toddlers and older children delayed motor development, exercise intolerance and premature fatigue are common. A number of nuclear DNA and mitochondrial DNA encoded genes are known to cause isolated myopathy in childhood and they are important in a range of mitochondrial functions such as oxidative phosphorylation, mitochondrial transcription/translation and mitochondrial fusion/fission. A rare cause of isolated myopathy in children, reversible infantile respiratory chain deficiency myopathy, is non-progressive and typically associated with spontaneous full recovery. Promising targeted treatments have been reported for a number or mitochondrial myopathies including riboflavin in ACAD9 and ETFDH-myopathies and deoxynucleoside for TK2-related disease.

Keywords:  Differential diagnosis; Mitochondria; Mitochondrial myopathy; Muscle; Next-generation sequencing; Treatment

DOI:  https://doi.org/10.1016/j.nmd.2021.08.005
Nature. 2021 Nov 03.

Disruption of mitochondrial complex I induces progressive parkinsonism.

Patricia González-Rodríguez, Enrico Zampese, Kristen A Stout, Jaime N Guzman, Ema Ilijic, Ben Yang, Tatiana Tkatch, Mihaela A Stavarache, David L Wokosin, Lin Gao, Michael G Kaplitt, José López-Barneo, Paul T Schumacker, D James Surmeier.

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease1. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm3,4.

DOI: https://doi.org/10.1038/s41586-021-04059-0
Cell Mol Life Sci. 2021 Oct 31.

Mitigating the pro-oxidant state and melanogenesis of Retinitis pigmentosa: by counteracting mitochondrial dysfunction.

Giovanni Pagano, Federico V Pallardó, Alex Lyakhovich, Luca Tiano, Marco Trifuoggi.

  Retinitis pigmentosa (RP) is a group of mitochondrial diseases characterized by progressive degeneration of rods and cones leading to retinal loss of light sensitivity and, consequently, to blindness. To date, no cure is available according to the clinical literature. As a disease associated with pigmentation-related, pro-oxidant state, and mitochondrial dysfunction, RP may be viewed at the crossroads of different pathogenetic pathways involved in adverse health outcomes, where mitochondria play a preeminent role. RP has been investigated in a number of experimental and clinical studies aimed at delaying retinal hyperpigmentation by means of a number of natural and synthetic antioxidants, as well as mitochondrial cofactors, also termed mitochondrial nutrients (MNs), such as alpha-lipoic acid, coenzyme Q10 and carnitine. One should consider that each MN plays distinct-and indispensable-roles in mitochondrial function. Thus, a logical choice would imply the administration of MN combinations, instead of individual MNs, as performed in previous studies, and with limited, if any, positive outcomes. A rational study design aimed at comparing the protective effects of MNs, separately or in combinations, and in association with other antioxidants, might foresee the utilization of animal RP models. The results should verify a comparative optimization in preventing or effectively contrasting retinal oxidative stress in mouse RP models and, in prospect, in human RP cases.

Keywords:  Antioxidants; Mitochondrial cofactors; Mitochondrial disease; Oxidative stress; Reactive oxygen species

DOI:  https://doi.org/10.1007/s00018-021-04007-1