scholarly journals Mitochondria, calcium homeostasis and calcium signaling

2016 ◽  
Vol 62 (3) ◽  
pp. 311-317 ◽  
Author(s):  
I.B. Zavodnik
Keyword(s):  
Calcium Signaling ◽  
Molecular Targets ◽  
Permeability Transition ◽  
Good Evidence ◽  
Cellular Functions ◽  
Pathological Conditions ◽  
Intracellular Signal ◽  
Permeability Transition Pores ◽  
And Control ◽  
Functional Mechanisms

Са2+ is a very important and versatile intracellular signal which controls numerous biochemical and physiological (pathophysiological) processes in the cell. Good evidence exists that mitochondria are sensors, decoders and regulators of calcium signaling. Precise regulation of calcium signaling in the cell involves numerous molecular targets, which induce and decode changes of Са2+ concentrations in the cell (pumps, channels, Са2+-binding proteins, Са2+-dependent enzymes, localized in the cytoplasm and organelles). Mitochondrial Са2+ uniporter accumulates excess of Са2+ in mitochondria, while Na+/Са2+- and H+/Са2+-antiporters extrude Са2+ in the cytoplasm. Mitochondrial Са2+ overloading results in formation of mitochondria permeability transition pores which play an important role in cell death under many pathological conditions. Mitochondria regulate Са2+ homeostasis and control important cellular functions such as metabolism, proliferation, survival. Identification of cellular and mitochondrial Ca2+ transporters and understanding their functional mechanisms open up new prospects for their using as therapeutic targets

scholarly journals Mitochondrial permeability transition pores: The role in heart energy metabolism.

2020 ◽  
Author(s):  
Miroslav Ferko ◽  
Natália Andelová
Keyword(s):  
Energy Metabolism ◽  
Acute Phase ◽  
Myocardial Function ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Energy Metabolism ◽  
Mitochondrial Permeability ◽  
Pathological Conditions ◽  
Protective Processes ◽  
Permeability Transition Pores

Substantial evidence has revealed that mitochondrial permeability transition pores (mPTPs) are associated with signaling pathway of cardioprotective models and seem to be an end-effector of cardioprotection. Experimental streptozotocin-induced diabetes mellitus (D) was shown to provide sufficient protection to the myocardium via compensatory mechanisms enabling mitochondria to produce energy under pathological conditions during the acute phase. The hypothesized involvement of mPTPs in these processes prompted us to use liquid chromatography and mass spectrometry-based proteomic analysis to investigate the effects of the acute-phase D condition on the structural and regulatory components of this multienzyme complex and the changes caused by compensation events. We detected ADT1, ATP5H, ATPA, and ATPB as the most abundant mPTP proteins. The between-group differences in protein abundance of the mPTP complex as a whole were significantly upregulated in the D group when compared with the control (C) group (p = 0.0106), but fold changes in individual protein expression levels were not significantly altered except for ATP5H, ATP5J, and KCRS. However, none of them passed the criterion of a 1.5-fold change in differential expression for biologically meaningful change. Visualization of the (dis-)similarity between the C and D groups and pairwise correlations revealed different patterns of protein interactions under the C and D conditions which may be linked to endogenous protective processes, of which beneficial effects on myocardial function were previously confirmed. Our results point to the involvement of mPTP proteins in the endogenous protective processes leading to the preservation of myocardial function under pathological conditions. Proteomic studies with respect to the correlation of mPTP proteins were shown to be one of the most promising options for the advancement of mPTP regulation mechanisms. Subtle changes in mPTP protein expressions, as well as mutual relationships between proteins, may be sufficient to contribute to preserving mitochondrial energy metabolism under the increased energy load represented by experimental D.

scholarly journals Role of ROS and RNS Sources in Physiological and Pathological Conditions

2016 ◽  
Vol 2016 ◽  
pp. 1-44 ◽  
Author(s):  
Sergio Di Meo ◽  
Tanea T. Reed ◽  
Paola Venditti ◽  
Victor Manuel Victor
Keyword(s):  
Oxidative Damage ◽  
Stress Responses ◽  
Significant Contribution ◽  
Permeability Transition ◽  
Significant Evidence ◽  
Pathological Conditions ◽  
Permeability Transition Pores ◽  
Molecular Signals ◽  
Stimulation Of

There is significant evidence that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. Mitochondria have been thought to both play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including stimulation of opening of permeability transition pores. Until recently, the functional significance of ROS sources different from mitochondria has received lesser attention. However, the most recent data, besides confirming the mitochondrial role in tissue oxidative stress and protection, show interplay between mitochondria and other ROS cellular sources, so that activation of one can lead to activation of other sources. Thus, it is currently accepted that in various conditions all cellular sources of ROS provide significant contribution to processes that oxidatively damage tissues and assure their survival, through mechanisms such as autophagy and apoptosis.

scholarly journals Tetrandrine alleviates silicosis by inhibiting canonical and non-canonical NLRP3 inflammasome activation in lung macrophages

2021 ◽  
Author(s):  
Mei-yue Song ◽  
Jia-xin Wang ◽  
You-liang Sun ◽  
Zhi-fa Han ◽  
Yi-tian Zhou ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Therapeutic Strategy ◽  
Molecular Targets ◽  
Mechanisms Of Action ◽  
Inflammasome Activation ◽  
Lung Macrophages ◽  
Nlrp3 Inflammasome Activation ◽  
Function Test ◽  
And Control ◽  
Therapeutic Administration

AbstractSilicosis caused by inhalation of silica particles leads to more than ten thousand new occupational exposure-related deaths yearly. Exacerbating this issue, there are currently few drugs reported to effectively treat silicosis. Tetrandrine is the only drug approved for silicosis treatment in China, and despite more than decades of use, its efficacy and mechanisms of action remain largely unknown. Here, in this study, we established silicosis mouse models to investigate the effectiveness of tetrandrine of early and late therapeutic administration. To this end, we used multiple cardiopulmonary function test, as well as markers for inflammation and fibrosis. Moreover, using single cell RNA sequencing and transcriptomics of lung tissue and quantitative microarray analysis of serum from silicosis and control mice, our results provide a novel description of the target pathways for tetrandrine. Specifically, we found that tetrandrine attenuated silicosis by inhibiting both the canonical and non-canonical NLRP3 inflammasome pathways in lung macrophages. Taken together, our work showed that tetrandrine yielded promising results against silicosis-associated inflammation and fibrosis and further lied the groundwork for understanding its molecular targets. Our results also facilitated the wider adoption and development of tetrandirne, potentially accelerating a globally accepted therapeutic strategy for silicosis.

scholarly journals The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 489
Author(s):  
Hilary Y. Liu ◽  
Jenna R. Gale ◽  
Ian J. Reynolds ◽  
John H. Weiss ◽  
Elias Aizenman
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Neuronal Damage ◽  
Mitochondrial Fission ◽  
Permeability Transition ◽  
High Energy ◽  
Atp Depletion ◽  
Ros Generation ◽  
Cellular Functions ◽  
Calcium Deregulation ◽  
Energy Demands

Zinc is a highly abundant cation in the brain, essential for cellular functions, including transcription, enzymatic activity, and cell signaling. However, zinc can also trigger injurious cascades in neurons, contributing to the pathology of neurodegenerative diseases. Mitochondria, critical for meeting the high energy demands of the central nervous system (CNS), are a principal target of the deleterious actions of zinc. An increasing body of work suggests that intracellular zinc can, under certain circumstances, contribute to neuronal damage by inhibiting mitochondrial energy processes, including dissipation of the mitochondrial membrane potential (MMP), leading to ATP depletion. Additional consequences of zinc-mediated mitochondrial damage include reactive oxygen species (ROS) generation, mitochondrial permeability transition, and excitotoxic calcium deregulation. Zinc can also induce mitochondrial fission, resulting in mitochondrial fragmentation, as well as inhibition of mitochondrial motility. Here, we review the known mechanisms responsible for the deleterious actions of zinc on the organelle, within the context of neuronal injury associated with neurodegenerative processes. Elucidating the critical contributions of zinc-induced mitochondrial defects to neurotoxicity and neurodegeneration may provide insight into novel therapeutic targets in the clinical setting.

scholarly journals Systemic metabolite profiling reveals sexual dimorphism of AIBP control of metabolism in mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0248964
Author(s):  
Jun-dae Kim ◽  
Lingping Zhu ◽  
Quan Sun ◽  
Longhou Fang
Keyword(s):  
Sexual Dimorphism ◽  
Knockout Mice ◽  
Metabolite Profiling ◽  
Krebs Cycle ◽  
Leigh Syndrome ◽  
Metabolite Profile ◽  
Cellular Functions ◽  
Metabolic Basis ◽  
And Control ◽  
Cellular Cholesterol Efflux

Emerging studies indicate that APOA-I binding protein (AIBP) is a secreted protein and functions extracellularly to promote cellular cholesterol efflux, thereby disrupting lipid rafts on the plasma membrane. AIBP is also present in the mitochondria and acts as an epimerase, facilitating the repair of dysfunctional hydrated NAD(P)H, known as NAD(P)H(X). Importantly, AIBP deficiency contributes to lethal neurometabolic disorder, reminiscent of the Leigh syndrome in humans. Whereas cyclic NADPHX production is proposed to be the underlying cause, we hypothesize that an unbiased metabolic profiling may: 1) reveal new clues for the lethality, e.g., changes of mitochondrial metabolites., and 2) identify metabolites associated with new AIBP functions. To this end, we performed unbiased and profound metabolic studies of plasma obtained from adult AIBP knockout mice and control littermates of both genders. Our systemic metabolite profiling, encompassing 9 super pathways, identified a total of 640 compounds. Our studies demonstrate a surprising sexual dimorphism of metabolites affected by AIBP deletion, with more statistically significant changes in the AIBP knockout female vs male when compared with the corresponding controls. AIBP knockout trends to reduce cholesterol but increase the bile acid precursor 7-HOCA in female but not male. Complex lipids, phospholipids, sphingomyelin and plasmalogens were reduced, while monoacylglycerol, fatty acids and the lipid soluble vitamins E and carotene diol were elevated in AIBP knockout female but not male. NAD metabolites were not significantly different in AIBP knockout vs control mice but differed for male vs female mice. Metabolites associated with glycolysis and the Krebs cycle were unchanged by AIBP knockout. Importantly, polyamine spermidine, critical for many cellular functions including cerebral cortex synapses, was reduced in male but not female AIBP knockout. This is the first report of a systemic metabolite profile of plasma samples from AIBP knockout mice, and provides a metabolic basis for future studies of AIBP regulation of cellular metabolism and the pathophysiological presentation of AIBP deficiency in patients.

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