Integrated application of multi-omics strategies provides insights into the environmental hypoxia response in Pelteobagrus vachelli muscle

Abstract Increasing pressures on aquatic ecosystems due to pollutants, nutrient enrichment and global warming have severely depleted oxygen concentrations. This sudden and significant lack of oxygen has resulted in persistent increases fish mortality rates. Revealing the molecular mechanism of fish hypoxia adaptation will help researchers to find hypoxic markers for hypoxia induced by environmental stress. Here, we used a multi-omics approach to identify several hypoxia-associated miRNAs, mRNAs, proteins, and metabolites involved in diverse biological pathways in the muscles of Pelteobagrus vachelli. Our findings revealed significant hypoxia-associated changes in muscles over 4 h of hypoxia exposure and discrete tissue-specific patterns. We have previously reported that P. vachelli livers exhibit increased anaerobic glycolysis, heme synthesis, erythropoiesis, and inhibit apoptosis when exposed to hypoxia 4 h. However, the opposite was observed in muscles. According to our comprehensive analysis, fishes show an acute response to hypoxia, including activation of catabolic pathways to generate more energy, reduction of biosynthesis to decrease energy consumption, and shifting from aerobic to anaerobic metabolic contributions. Also we found that hypoxia induced muscle dysfunction by impairing mitochondrial function, activating inflammasomes, and apoptosis. The hypoxia-induced mitochondrial dysfunction enhanced oxidative stress, apoptosis, and further triggered IL-1β production via inflammasome activation. In turn, IL-1β further impaired mitochondrial function or apoptosis by suppressing downstream mitochondrial biosynthesis-related proteins, thus resulting in a vicious cycle of inflammasome activation and mitochondrial dysfunction. Our findings contribute meaningful insights into the molecular mechanisms of hypoxia, and the methods and study design can be utilized across different fish species.

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NADH Fluorescence Lifetime Imaging Microscopy Reveals Selective Mitochondrial Dysfunction in Neurons Overexpressing Alzheimer’s Disease–Related Proteins

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.671274 ◽

2021 ◽

Vol 8 ◽

Author(s):

Moritz A. Niederschweiberer ◽

Patrick M. Schaefer ◽

Larry N. Singh ◽

Ludwig Lausser ◽

Devyani Bhosale ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Single Cell ◽

Mitochondrial Function ◽

Primary Neurons ◽

Single Cell Level ◽

Cell Level ◽

Lifetime Imaging ◽

Highly Sensitive ◽

Related Proteins ◽

Subcellular Level

Alzheimer’s disease (AD), the most prevalent form of dementia, affects globally more than 30 million people suffering from cognitive deficits and neuropsychiatric symptoms. Substantial evidence for the involvement of mitochondrial dysfunction in the development and/or progression of AD has been shown in addition to the pathological hallmarks amyloid beta (Aβ) and tau. Still, the selective vulnerability and associated selective mitochondrial dysfunction cannot even be resolved to date. We aimed at optically quantifying mitochondrial function on a single-cell level in primary hippocampal neuron models of AD, unraveling differential involvement of cell and mitochondrial populations in amyloid precursor protein (APP)-associated mitochondrial dysfunction. NADH lifetime imaging is a highly sensitive marker-free method with high spatial resolution. However, deciphering cellular bioenergetics of complex cells like primary neurons has still not succeeded yet. To achieve this, we combined highly sensitive NADH lifetime imaging with respiratory inhibitor treatment, allowing characterization of mitochondrial function down to even the subcellular level in primary neurons. Measuring NADH lifetime of the same neuron before and after respiratory treatment reveals the metabolic delta, which can be taken as a surrogate for cellular redox capacity. Correlating NADH lifetime delta with overexpression strength of Aβ-related proteins on the single-cell level, we could verify the important role of intracellular Aβ-mediated mitochondrial toxicity. Subcellularly, we could demonstrate a higher respiration in neuronal somata in general than dendrites, but a similar impairment of somatic and dendritic mitochondria in our AD models. This illustrates the power of NADH lifetime imaging in revealing mitochondrial function on a single and even subcellular level and its potential to shed light into bioenergetic alterations in neuropsychiatric diseases and beyond.

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Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2–AMPK–PGC1α signaling pathway

Biochemistry and Cell Biology ◽

10.1139/bcb-2018-0310 ◽

2019 ◽

Vol 97 (4) ◽

pp. 397-405 ◽

Cited By ~ 8

Author(s):

Bing Liu ◽

Jiangbo Jin ◽

Ziyu Zhang ◽

Li Zuo ◽

Meixiu Jiang ◽

...

Keyword(s):

Oxidative Stress ◽

Hepatocellular Carcinoma ◽

Antitumor Activity ◽

Mitochondrial Dysfunction ◽

Signaling Pathway ◽

Mitochondrial Function ◽

Molecular Mechanisms ◽

Tricarboxylic Acid Cycle ◽

Dependent Manner ◽

Promising Therapeutic Approach

Shikonin, a naphthoquinone derivative isolated from the root of Lithospermum erythrorhizon, exhibits broad-spectrum antitumor activity via different molecular mechanisms. In this study, we investigated the effect of shikonin on mitochondrial dysfunction in hepatocellular carcinoma (HCC). Our results showed that shikonin inhibited the proliferation, migration, and invasiveness of HCCLM3 cells, and promoted cell apoptosis in a dose-dependent manner. More importantly, shikonin affected mitochondrial function by disrupting mitochondrial membrane potential and oxidative stress (OS) status. Furthermore, shikonin decreased the oxygen consumption rate of HCCLM3 cells, as well as the levels of ATP and metabolites involved in the tricarboxylic acid cycle (TCA cycle). We also investigated the molecular mechanisms underlying the regulation of mitochondrial function by shikonin as an inhibitor of PKM2. Shikonin decreased the expression of PKM2 in the mitochondria and affected other metabolic pathways (AMPK and PGC1α pathways), which aggravated the oxidative stress and nutrient deficiency. Our results indicate a novel role of shikonin in triggering mitochondria dysfunction via the PKM2–AMPK–PGC1α signaling pathway and provide a promising therapeutic approach for the treatment of HCC.

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Weaning differentially affects mitochondrial function, oxidative stress, inflammation and apoptosis in normal and low birth weight piglets

PLoS ONE ◽

10.1371/journal.pone.0247188 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0247188

Author(s):

Aliny K. Novais ◽

Karine Deschêne ◽

Yan Martel-Kennes ◽

Caroline Roy ◽

Jean-Paul Laforest ◽

...

Keyword(s):

Oxidative Stress ◽

Birth Weight ◽

Low Birth Weight ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Molecular Mechanisms ◽

Target Genes ◽

Antioxidant Defenses ◽

Inflammatory Status ◽

And Oxidative Stress

Weaning is associated with increased occurrence of infections and diseases in piglets. Recent findings indicate that weaning induces mitochondrial dysfunction and oxidative stress conditions that more severely impact smaller piglets. The objective of this study was to characterize the molecular mechanisms underlying these physiological consequences and the relation with systemic inflammatory status in both normal and low birth weight (NBW and LBW) piglets throughout the peri-weaning period. To conduct the study, 30 sows were inseminated, and specific piglets from their litters were assigned to one of two experimental groups: NBW (n = 60, 1.73 ± 0.01 kg,) and LBW piglets weighing less than 1.2 kg (n = 60, 1.01 ± 0.01 kg). Then, 10 piglets from each group were selected at 14, 21 (weaning), 23, 25, 29 and 35 days of age to collect organ and plasma samples. Specific porcine RT2 Profiler™ PCR Arrays related to mitochondrial function, oxidative stress, inflammation and apoptosis processes were first used to target genes that are modulated after weaning in NBW piglets (d 23 and d 35 vs. d 14). Expression of selected genes was evaluated by quantitative PCR. These analyses revealed that expression of inflammatory genes CXCL10 and CCL19 increased after weaning in intestinal mucosa, while expression of genes encoding subunits of the mitochondrial respiratory chain was downregulated in liver and kidney of both groups. Interestingly, major modulators of mitophagy (BNIP3), cell survival (BCL2A1) and antioxidant defense system (TXNRD2, GPx3, HMOX1) were found to be highly expressed in NBW piglets. The systemic levels of TNF-α and IL1-β significantly increased following weaning and were higher in NBW piglets. These results provide novel information about the molecular origin of mitochondrial dysfunction and oxidative stress observed in weaned piglets and suggest that clearance of dysfunctional mitochondria, antioxidant defenses and inflammatory response are compromised in LBW piglets.

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Mitochondrial Structure and Function in the Metabolic Myopathy Accompanying Patients with Critical Limb Ischemia

Cells ◽

10.3390/cells9030570 ◽

2020 ◽

Vol 9 (3) ◽

pp. 570 ◽

Cited By ~ 2

Author(s):

Thomas Groennebaek ◽

Tine Borum Billeskov ◽

Camilla Tvede Schytz ◽

Nichlas Riise Jespersen ◽

Hans Erik Bøtker ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Critical Limb Ischemia ◽

Mitochondrial Respiration ◽

Molecular Mechanisms ◽

Limb Ischemia ◽

Fiber Types ◽

Metabolic Myopathy ◽

Mitochondrial Content ◽

Altered Expression ◽

Related Proteins

Mitochondrial dysfunction has been implicated as a central mechanism in the metabolic myopathy accompanying critical limb ischemia (CLI). However, whether mitochondrial dysfunction is directly related to lower extremity ischemia and the structural and molecular mechanisms underpinning mitochondrial dysfunction in CLI patients is not understood. Here, we aimed to study whether mitochondrial dysfunction is a distinctive characteristic of CLI myopathy by assessing mitochondrial respiration in gastrocnemius muscle from 14 CLI patients (65.3 ± 7.8 y) and 15 matched control patients (CON) with a similar comorbidity risk profile and medication regimen but without peripheral ischemia (67.4 ± 7.4 y). Furthermore, we studied potential structural and molecular mechanisms of mitochondrial dysfunction by measuring total, sub-population, and fiber-type-specific mitochondrial volumetric content and cristae density with transmission electron microscopy and by assessing mitophagy and fission/fusion-related protein expression. Finally, we asked whether commonly used biomarkers of mitochondrial content are valid in patients with cardiovascular disease. CLI patients exhibited inferior mitochondrial respiration compared to CON. This respiratory deficit was not related to lower whole-muscle mitochondrial content or cristae density. However, stratification for fiber types revealed ultrastructural mitochondrial alterations in CLI patients compared to CON. CLI patients exhibited an altered expression of mitophagy-related proteins but not fission/fusion-related proteins compared to CON. Citrate synthase, cytochrome c oxidase subunit IV (COXIV), and 3-hydroxyacyl-CoA dehydrogenase (β-HAD) could not predict mitochondrial content. Mitochondrial dysfunction is a distinctive characteristic of CLI myopathy and is not related to altered organelle content or cristae density. Our results link this intrinsic mitochondrial deficit to dysregulation of the mitochondrial quality control system, which has implications for the development of therapeutic strategies.

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Correlation between Mitochondrial Dysfunction, Cardiovascular Diseases, and Traditional Chinese Medicine

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/2902136 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Li Zhu ◽

Zhigang Chen ◽

Keli Han ◽

Yilin Zhao ◽

Yan Li ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Regulatory Effect ◽

Stress Regulation ◽

Dna Mutations ◽

Mitochondrial Biosynthesis ◽

Antioxidant Stress ◽

The Relationship

Cardiovascular disease (CVD) is the number one threat that seriously endangers human health. However, the mechanism of their occurrence is not completely clear. Increasing studies showed that mitochondrial dysfunction is closely related to CVD. Possible causes of mitochondrial dysfunction include oxidative stress, Ca2+ disorder, mitochondrial DNA mutations, and reduction of mitochondrial biosynthesis, all of which are closely related to the development of CVD. At present, traditional Chinese medicine (TCM) is widely used in the treatment of CVD. TCM has the therapeutic characteristics of multitargets and multipathways. Studies have shown that TCM can treat CVD by protecting mitochondrial function. Via systematic literature review, the results show that the specific mechanisms include antioxidant stress, regulation of calcium homeostasis, antiapoptosis, and regulation of mitochondrial biosynthesis. This article describes the relationship between mitochondrial dysfunction and CVD, summarizes the TCM commonly used for the treatment of CVD in recent years, and focuses on the regulatory effect of TCM on mitochondrial function.

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Mitochondrial Dysfunction and Cellular Senescence Due to Aging Contributes to Prostatic Fibrosis

Innovation in Aging ◽

10.1093/geroni/igaa057.439 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 133-134

Author(s):

Teresa Liu ◽

Emily Ricke ◽

Donald DeFranco ◽

William Ricke

Keyword(s):

Mitochondrial Dysfunction ◽

Cellular Senescence ◽

Mitochondrial Function ◽

Complex I ◽

Molecular Mechanisms ◽

Selective Inhibition ◽

Urinary Symptoms ◽

Lower Urinary Tract Dysfunction ◽

Mitochondrial Complex I ◽

Mitochondrial Complex

Abstract Aging is the single largest risk factor for many common diseases that burden public health. This is especially true in the prostate; as men age, the prostate undergoes a prototypical aging change, fibrosis. The aged fibrotic prostate causes urinary symptoms which will afflict nearly every man if they live long enough. However, the molecular mechanisms responsible for the aging-dependent promotion of fibrosis are largely unknown and understudied. In this study, we sought to reveal the contribution of mitochondrial dysfunction to fibrosis in the aging prostate, ultimately leading to prostate dysfunction, urinary symptoms, and overall poor health. The demise of mitochondrial function is well established in other aging-associated diseases but has not been investigated in the prostate. Our analysis revealed an increase in cellular senescence and mitochondrial dysfunction in BPH patient tissue compared to normal prostates. Furthermore, selective inhibition of mitochondrial complex I by rotenone in cultured human prostate fibroblasts led to myofibroblast phenoconversion as characterized by increased expression of Col1a1, Col3a1, and ACTA2. To determine the contribution of mitochondrial dysfunction on fibrosis and lower urinary tract dysfunction (LUTD), we examined the prostate lobes in both aging and steroid-induced LUTD in mice. These models have been extensively characterized and exhibit an age-mediated increase in LUTD and fibrosis. We observed a decrease in mitochondrial function and an increase in cellular senescence corresponding to an increase in fibrosis and LUTD. This suggests that normal aging-dependent reductions in mitochondrial complex I function in the prostate may promote fibrosis and contribute to urinary dysfunction.

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Mitochondrial Dysfunction Increases Arrhythmic Triggers and Substrates; Potential Anti-arrhythmic Pharmacological Targets

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.646932 ◽

2021 ◽

Vol 8 ◽

Author(s):

Khalil Saadeh ◽

Ibrahim Talal Fazmin

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Molecular Mechanisms ◽

Cardiac Fibrosis ◽

Ionic Currents ◽

Pharmacological Interventions ◽

Age Related ◽

Pharmacological Targets ◽

Cellular Ca ◽

Sodium And Potassium

Incidence of cardiac arrhythmias increases significantly with age. In order to effectively stratify arrhythmic risk in the aging population it is crucial to elucidate the relevant underlying molecular mechanisms. The changes underlying age-related electrophysiological disruption appear to be closely associated with mitochondrial dysfunction. Thus, the present review examines the mechanisms by which age-related mitochondrial dysfunction promotes arrhythmic triggers and substrate. Namely, via alterations in plasmalemmal ionic currents (both sodium and potassium), gap junctions, cellular Ca2+ homeostasis, and cardiac fibrosis. Stratification of patients' mitochondrial function status permits application of appropriate anti-arrhythmic therapies. Here, we discuss novel potential anti-arrhythmic pharmacological interventions that specifically target upstream mitochondrial function and hence ameliorates the need for therapies targeting downstream changes which have constituted traditional antiarrhythmic therapy.

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Melatonin As a Modulator of Degenerative and Regenerative Signaling Pathways in Injured Retinal Ganglion Cells

Current Pharmaceutical Design ◽

10.2174/1381612825666190829151314 ◽

2019 ◽

Vol 25 (28) ◽

pp. 3057-3073 ◽

Cited By ~ 6

Author(s):

Kobra B. Juybari ◽

Azam Hosseinzadeh ◽

Habib Ghaznavi ◽

Mahboobeh Kamali ◽

Ahad Sedaghat ◽

...

Keyword(s):

Optic Nerve ◽

Mitochondrial Dysfunction ◽

Signaling Pathways ◽

Retinal Ganglion Cells ◽

Molecular Mechanisms ◽

Nitrosative Stress ◽

Ganglion Cells ◽

Axon Growth ◽

Nerve Fibers ◽

Retinal Ganglion

Optic neuropathies refer to the dysfunction or degeneration of optic nerve fibers caused by any reasons including ischemia, inflammation, trauma, tumor, mitochondrial dysfunction, toxins, nutritional deficiency, inheritance, etc. Post-mitotic CNS neurons, including retinal ganglion cells (RGCs) intrinsically have a limited capacity for axon growth after either trauma or disease, leading to irreversible vision loss. In recent years, an increasing number of laboratory evidence has evaluated optic nerve injuries, focusing on molecular signaling pathways involved in RGC death. Trophic factor deprivation (TFD), inflammation, oxidative stress, mitochondrial dysfunction, glutamate-induced excitotoxicity, ischemia, hypoxia, etc. have been recognized as important molecular mechanisms leading to RGC apoptosis. Understanding these obstacles provides a better view to find out new strategies against retinal cell damage. Melatonin, as a wide-spectrum antioxidant and powerful freeradical scavenger, has the ability to protect RGCs or other cells against a variety of deleterious conditions such as oxidative/nitrosative stress, hypoxia/ischemia, inflammatory processes, and apoptosis. In this review, we primarily highlight the molecular regenerative and degenerative mechanisms involved in RGC survival/death and then summarize the possible protective effects of melatonin in the process of RGC death in some ocular diseases including optic neuropathies. Based on the information provided in this review, melatonin may act as a promising agent to reduce RGC death in various retinal pathologic conditions.

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Progress in understanding the role of lncRNA in programmed cell death

Cell Death Discovery ◽

10.1038/s41420-021-00407-1 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Na Jiang ◽

Xiaoyu Zhang ◽

Xuejun Gu ◽

Xiaozhuang Li ◽

Lei Shang

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Molecular Mechanisms ◽

Membrane Receptors ◽

Gene Expressions ◽

Apoptosis Pathway ◽

Stem Cell Pluripotency ◽

Extrinsic Apoptosis ◽

Related Proteins ◽

Cycle Regulation

AbstractLong non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides but not translated into proteins. LncRNAs regulate gene expressions at multiple levels, such as chromatin, transcription, and post-transcription. Further, lncRNAs participate in various biological processes such as cell differentiation, cell cycle regulation, and maintenance of stem cell pluripotency. We have previously reported that lncRNAs are closely related to programmed cell death (PCD), which includes apoptosis, autophagy, necroptosis, and ferroptosis. Overexpression of lncRNA can suppress the extrinsic apoptosis pathway by downregulating of membrane receptors and protect tumor cells by inhibiting the expression of necroptosis-related proteins. Some lncRNAs can also act as competitive endogenous RNA to prevent oxidation, thereby inhibiting ferroptosis, while some are known to activate autophagy. The relationship between lncRNA and PCD has promising implications in clinical research, and reports have highlighted this relationship in various cancers such as non-small cell lung cancer and gastric cancer. This review systematically summarizes the advances in the understanding of the molecular mechanisms through which lncRNAs impact PCD.

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Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

Antioxidants ◽

10.3390/antiox10010025 ◽

2020 ◽

Vol 10 (1) ◽

pp. 25

Author(s):

Lara Macchioni ◽

Davide Chiasserini ◽

Letizia Mezzasoma ◽

Magdalena Davidescu ◽

Pier Luigi Orvietani ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Age Related Macular Degeneration ◽

Inflammasome Activation ◽

Related Factor ◽

Nuclear Factor ◽

Rpe Cells ◽

Age Related ◽

Oxidative Insult

Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.

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