scholarly journals Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sahar Elouej ◽  
Karim Harhouri ◽  
Morgane Le Mao ◽  
Genevieve Baujat ◽  
Sheela Nampoothiri ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Premature Aging ◽  
Arterial Calcification ◽  
Nuclear Morphology ◽  
C Elegans ◽  
Primary Fibroblasts ◽  
Morphological Defects ◽  
Induced Apoptosis ◽  
And Function ◽  
Mandibuloacral Dysplasia

Abstract Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients’ primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients’ fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features.

scholarly journals Disruption of genes associated with Charcot-Marie-Tooth type 2 lead to common behavioural, cellular and molecular defects inCaenorhabditis elegans

2019 ◽  
Author(s):  
Ming S. Soh ◽  
Xinran Cheng ◽  
Jie Liu ◽  
Brent Neumann
Keyword(s):  
Sensory Neuropathy ◽  
Current Frequency ◽  
Charcot Marie Tooth ◽  
C Elegans ◽  
Muscle Structure ◽  
Electrophysiological Recordings ◽  
Morphological Defects ◽  
Underlying Mechanisms ◽  
And Function ◽  
Peripheral Motor

AbstractCharcot-Marie-Tooth (CMT) disease is an inherited peripheral motor and sensory neuropathy. The disease is divided into demyelinating (CMT1) and axonal (CMT2) neuropathies, and although we have gained molecular information into the details of CMT1 pathology, much less is known about CMT2. Due to its clinical and genetic heterogeneity, coupled with a lack of animal models, common underlying mechanisms remain elusive. In order to understand the biological importance of CMT2-casuative genes, we have studied the behavioural, cellular and molecular consequences of mutating nine different genes associated with CMT2 in the nematodeCaenorhabditis elegans(lin-41/TRIM2, dyn-1/DMN2, unc-116/KIF5A, fzo-1/MFN2, osm-9/TRPV4, cua-1/ATP7A, hsp-25/HSPB1, hint-1/HINT1, nep-2/MME). We show thatC. elegansdefective for these genes display debilitated movement in crawling and swimming assays. Severe morphological defects in cholinergic motors neurons are also evident in two of the mutants (dyn-1andunc-116). Furthermore, we establish novel methods for quantifying muscle morphology and use these to demonstrate striking loss of muscle structure across the mutants that correspond with reductions in muscle function. Finally, using electrophysiological recordings of neuromuscular junction (NMJ) activity, we uncover reductions in spontaneous postsynaptic current frequency inlin-41, dyn-1, unc-116andfzo-1mutants. By comparing the consequences of mutating numerous CMT2-related genes, this study reveals common deficits in muscle structure and function, as well as NMJ signalling when these genes are disrupted.

scholarly journals Author Correction: Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sahar Elouej ◽  
Karim Harhouri ◽  
Morgane Le Mao ◽  
Genevieve Baujat ◽  
Sheela Nampoothiri ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Nuclear Morphology ◽  
Correction Loss ◽  
Mandibuloacral Dysplasia

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cadmium directly induced mitochondrial dysfunction of human embryonic kidney cells

2010 ◽  
Vol 30 (8) ◽  
pp. 920-929 ◽  
Author(s):  
WP Mao ◽  
NN Zhang ◽  
FY Zhou ◽  
WX Li ◽  
HY Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Hek293 Cells ◽  
Human Embryonic Kidney Cells ◽  
Stress Markers ◽  
Mitochondria Pathway ◽  
Induced Apoptosis ◽  
And Function ◽  
Induced Changes ◽  
First Time

Cadmium (Cd) is the major component of polluted environment, which has numerous undesirable effects on health. Cd could induce apoptosis of HEK293 cells, and the mitochondria may play a key role. However, the mode of action is unclear. In the present study, we aimed to evaluate the ability of the Cd to induce dysfunction of mitochondria. We examined the effect of cadmium chloride (1, 5 and 10 μM) on mitochondrial membrane permeability and potential as well as oxidative stress markers in mitochondria isolated from HEK293 cells. We found that Cd could directly increase in permeability and decrease in membrane potential of mitochondria, even resulted in mitochondrial swelling, and that Cd could inhibit the activities of ATPase, lactate dehydrogenase (LDH), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), enhanced the levels of reactive oxygen species (ROS) and lipid peroxidation (LPO). On the whole, the results show that Cd can directly lead to mitochondrial dysfunction of HEK293 cells, including increased permeability, inhibiting respiration and evoking oxidative stress. Thus, for the first time, this paper makes an overall analysis of Cd-induced changes of structure and function of isolated mitochondria. Our findings may also have general implications in Cd-induced apoptosis by mitochondria pathway.

scholarly journals The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

2019 ◽  
Vol 10 (1) ◽  
pp. 199-210 ◽  
Author(s):  
Chuanman Zhou ◽  
Jintao Luo ◽  
Xiaohui He ◽  
Qian Zhou ◽  
Yunxia He ◽  
...  
Keyword(s):  
Plant Hormone ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Loss Of Function ◽  
Wild Type ◽  
C Elegans ◽  
Link Type ◽  
Complex Functions ◽  
And Function ◽  
Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

scholarly journals C. elegans germ granules require both assembly and localized regulators for mRNA repression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Scott Takeo Aoki ◽  
Tina R. Lynch ◽  
Sarah L. Crittenden ◽  
Craig A. Bingman ◽  
Marvin Wickens ◽  
...  
Keyword(s):  
Liquid Droplet ◽  
Scaffolding Protein ◽  
P Granules ◽  
C Elegans ◽  
Cytoplasmic Rna ◽  
And Function ◽  
Rnp Granules ◽  
Key Residues ◽  
Reporter Mrna

AbstractCytoplasmic RNA–protein (RNP) granules have diverse biophysical properties, from liquid to solid, and play enigmatic roles in RNA metabolism. Nematode P granules are paradigmatic liquid droplet granules and central to germ cell development. Here we analyze a key P granule scaffolding protein, PGL-1, to investigate the functional relationship between P granule assembly and function. Using a protein–RNA tethering assay, we find that reporter mRNA expression is repressed when recruited to PGL-1. We determine the crystal structure of the PGL-1 N-terminal region to 1.5 Å, discover its dimerization, and identify key residues at the dimer interface. Mutations of those interface residues prevent P granule assembly in vivo, de-repress PGL-1 tethered mRNA, and reduce fertility. Therefore, PGL-1 dimerization lies at the heart of both P granule assembly and function. Finally, we identify the P granule-associated Argonaute WAGO-1 as crucial for repression of PGL-1 tethered mRNA. We conclude that P granule function requires both assembly and localized regulators.

scholarly journals The Interplay between Mitochondrial Morphology and Myomitokines in Aging Sarcopenia

2020 ◽  
Vol 22 (1) ◽  
pp. 91
Author(s):  
Vanina Romanello
Keyword(s):  
Mitochondrial Dysfunction ◽  
Poor Quality ◽  
Whole Body ◽  
Fibroblast Growth Factor 21 ◽  
Mitochondrial Morphology ◽  
Mass Force ◽  
Major Mechanism ◽  
Muscle Aging ◽  
And Function

Sarcopenia is a chronic disease characterized by the progressive loss of skeletal muscle mass, force, and function during aging. It is an emerging public problem associated with poor quality of life, disability, frailty, and high mortality. A decline in mitochondria quality control pathways constitutes a major mechanism driving aging sarcopenia, causing abnormal organelle accumulation over a lifetime. The resulting mitochondrial dysfunction in sarcopenic muscles feedbacks systemically by releasing the myomitokines fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), influencing the whole-body homeostasis and dictating healthy or unhealthy aging. This review describes the principal pathways controlling mitochondrial quality, many of which are potential therapeutic targets against muscle aging, and the connection between mitochondrial dysfunction and the myomitokines FGF21 and GDF15 in the pathogenesis of aging sarcopenia.

scholarly journals Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1552
Author(s):  
Mariona Guitart-Mampel ◽  
Pedro Urquiza ◽  
Jordana I. Borges ◽  
Anastasios Lymperopoulos ◽  
Maria E. Solesio
Keyword(s):  
Mitochondrial Dysfunction ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Cellular Level ◽  
Cardiac Physiology ◽  
Failing Heart ◽  
Receptor Kinases ◽  
And Function ◽  
The Impact ◽  
G Protein Coupled

The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)—particularly βARs—play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.

Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy

2005 ◽  
Vol 23 (2) ◽  
pp. 150-158 ◽  
Author(s):  
Ilaria Filesi ◽  
Francesca Gullotta ◽  
Giovanna Lattanzi ◽  
Maria Rosaria D'Apice ◽  
Cristina Capanni ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Protein A ◽  
Nuclear Architecture ◽  
Mendelian Inheritance ◽  
Premature Aging ◽  
Lamin A ◽  
Lamin B ◽  
Lamin B Receptor ◽  
Epigenetic Events ◽  
Mandibuloacral Dysplasia

Autosomal recessive mandibuloacral dysplasia [mandibuloacral dysplasia type A (MADA); Online Mendelian Inheritance in Man (OMIM) no. 248370 ] is caused by a mutation in LMNA encoding lamin A/C. Here we show that this mutation causes accumulation of the lamin A precursor protein, a marked alteration of the nuclear architecture and, hence, chromatin disorganization. Heterochromatin domains are altered or completely lost in MADA nuclei, consistent with the finding that heterochromatin-associated protein HP1β and histone H3 methylated at lysine 9 and their nuclear envelope partner protein lamin B receptor (LBR) are delocalized and solubilized. Both accumulation of lamin A precursor and chromatin defects become more severe in older patients. These results strongly suggest that altered chromatin remodeling is a key event in the cascade of epigenetic events causing MADA and could be related to the premature-aging phenotype.

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