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17 pages, 2460 KiB

Open AccessArticle

Dose- and Time-Dependent Effects of Oleate on Mitochondrial Fusion/Fission Proteins and Cell Viability in HepG2 Cells: Comparison with Palmitate Effects

by Isy F. de Sousa, Vincenzo Migliaccio, Marilena Lepretti, Gaetana Paolella, Ilaria Di Gregorio, Ivana Caputo, Eliane Beraldi Ribeiro and Lillà Lionetti

Int. J. Mol. Sci. 2021, 22(18), 9812; https://doi.org/10.3390/ijms22189812 - 10 Sep 2021

Cited by 8 | Viewed by 2396

Abstract

Mitochondrial impairments in dynamic behavior (fusion/fission balance) associated with mitochondrial dysfunction play a key role in cell lipotoxicity and lipid-induced metabolic diseases. The present work aimed to evaluate dose- and time-dependent effects of the monounsaturated fatty acid oleate on mitochondrial fusion/fission proteins in [...] Read more.

Mitochondrial impairments in dynamic behavior (fusion/fission balance) associated with mitochondrial dysfunction play a key role in cell lipotoxicity and lipid-induced metabolic diseases. The present work aimed to evaluate dose- and time-dependent effects of the monounsaturated fatty acid oleate on mitochondrial fusion/fission proteins in comparison with the saturated fatty acid palmitate in hepatic cells. To this end, HepG-2 cells were treated with 0, 10 μM, 50 μM, 100 μM, 250 μM or 500 μM of either oleate or palmitate for 8 or 24 h. Cell viability and lipid accumulation were evaluated to assess lipotoxicity. Mitochondrial markers of fusion (mitofusin 2, MFN2) and fission (dynamin-related protein 1, DRP1) processes were evaluated by Western blot analysis. After 8 h, the highest dose of oleate induced a decrease in DRP1 content without changes in MFN2 content in association with cell viability maintenance, whereas palmitate induced a decrease in cell viability associated with a decrease mainly in MFN2 content. After 24 h, oleate induced MFN2 increase, whereas palmitate induced DRP1 increase associated with a higher decrease in cell viability with high doses compared to oleate. This finding could be useful to understand the role of mitochondria in the protective effects of oleate as a bioactive compound. Full article

(This article belongs to the Special Issue Targeted Protection of Bioactive Compounds to Mitochondria 2.0)

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15 pages, 1525 KiB

Open AccessArticle

Anti-Inflammatory and Antioxidant Properties of Dehydrated Potato-Derived Bioactive Compounds in Intestinal Cells

by Manuela Giovanna Basilicata, Giacomo Pepe, Shara Francesca Rapa, Fabrizio Merciai, Carmine Ostacolo, Michele Manfra, Veronica Di Sarno, Giuseppina Autore, Daniela De Vita, Stefania Marzocco and Pietro Campiglia

Int. J. Mol. Sci. 2019, 20(23), 6087; https://doi.org/10.3390/ijms20236087 - 03 Dec 2019

Cited by 21 | Viewed by 4279

Abstract

Inflammation and oxidative stress are always more recognized as responsible for chronic disease at the intestinal level. Currently, a growing interest is addressed to the discovery of diet-derived products which have anti-inflammatory and antioxidant properties. This work aims to characterize the pharmacological potential [...] Read more.

Inflammation and oxidative stress are always more recognized as responsible for chronic disease at the intestinal level. Currently, a growing interest is addressed to the discovery of diet-derived products which have anti-inflammatory and antioxidant properties. This work aims to characterize the pharmacological potential of dehydrated potatoes. For this purpose, a simulated gastrointestinal digestion was carried out. The bioaccessible peptides were fractionated on the basis of their molecular weight and tested on intestinal epithelial cells (IEC-6) under oxidative and inflammatory conditions. Our results demonstrate that the tested peptide fractions were able to significantly inhibit tumor necrosis factor-α release and cycloxygenase-2 and inducible nitric oxide synthase expression. The tested peptides also showed significant antioxidant activity, being able to both reduce reactive oxygen species (ROS) release, also from mitochondria, and nitrotyrosine formation, and increase the antioxidant response by heme oxygenase-1 and superoxide dismutase expression. Moreover, the peptide fractions were able to significantly increase the wound repair in IEC-6. The obtained results indicate the anti-inflammatory and antioxidant potential of dehydrated potatoes at the intestinal level. Full article

(This article belongs to the Special Issue Targeted Protection of Bioactive Compounds to Mitochondria)

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15 pages, 2468 KiB

Open AccessArticle

Adipose Tissue Mitochondrial Factors Profile after Dietary Bioactive Compound Weight Reduction Treatments in a Mice Obesity Model

by Anna Cassanye, Meritxell Martín-Gari, Manuel Portero-Otin and José CE Serrano

Int. J. Mol. Sci. 2019, 20(23), 5870; https://doi.org/10.3390/ijms20235870 - 22 Nov 2019

Cited by 1 | Viewed by 2535

Abstract

Prolonged caloric intake above energy needs disturbs the body’s ability to store and manage the excess of energy intake, leading to the onset of chronic degenerative diseases. This study aimed to compare the effect of three foods, which contain demonstrated bioactive compounds in [...] Read more.

Prolonged caloric intake above energy needs disturbs the body’s ability to store and manage the excess of energy intake, leading to the onset of chronic degenerative diseases. This study aimed to compare the effect of three foods, which contain demonstrated bioactive compounds in the treatment of obesity and as an adjuvant in obesity energy restriction treatments. In a mice obesity model induced through a high-fat diet; fish oil, soluble fibre, and soy were incorporated to evaluate its capacity to modulate metabolic factors in adipose tissue during a continued fat intake or weight reduction through a normocaloric diet. As a result, fish oil improved mitochondrial related, adipose tissue hormone expression, and oxidation products when high-fat diets are consumed; while soluble fibre improved glucose and inflammation pathways during high-fat diet intake. In weight reduction treatments few differential features, as a treatment adjuvant, were observed for fish oil and soy; while soluble fibre was able to improve the weight reduction effects induced by a normocaloric diet. As a conclusion, soluble fibre supplementation compared to an energy reduction program, was the only treatment able to induce a significant additional effect in the improvement of weight loss and adipose tissue metabolism. Full article

(This article belongs to the Special Issue Targeted Protection of Bioactive Compounds to Mitochondria)

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14 pages, 9252 KiB

Open AccessArticle

High-Fish Oil and High-Lard Diets Differently Affect Testicular Antioxidant Defense and Mitochondrial Fusion/Fission Balance in Male Wistar Rats: Potential Protective Effect of ω3 Polyunsaturated Fatty Acids Targeting Mitochondria Dynamics

by Vincenzo Migliaccio, Raffaella Sica, Ilaria Di Gregorio, Rosalba Putti and Lillà Lionetti

Int. J. Mol. Sci. 2019, 20(12), 3110; https://doi.org/10.3390/ijms20123110 - 25 Jun 2019

Cited by 13 | Viewed by 4482

Abstract

High-fat diets rich in fish oil (HFO diet, mainly ω3-PUFAs), in contrast to high-fat diets rich in lard (HL diet, mainly saturated fatty acids) have been shown to induce improvement in mitochondrial function and fusion processes associated with a reduction in reactive oxygen [...] Read more.

High-fat diets rich in fish oil (HFO diet, mainly ω3-PUFAs), in contrast to high-fat diets rich in lard (HL diet, mainly saturated fatty acids) have been shown to induce improvement in mitochondrial function and fusion processes associated with a reduction in reactive oxygen species production in both liver and skeletal muscle. High-fat diets may also impair testicular function, and mitochondria represent important cellular organelles with a pivotal role in reproductive function. Mitochondria are dynamic organelles that frequently undergo fission/fusion processes. A shift toward mitochondrial fusion process has been associated with improvement of mitochondrial function, as well as with ω3-PUFAs protective effects. The present study aimed to analyze the effect of chronic overfeeding (six weeks) with HFO or HL diet on testicular tissue histology, oxidative stress, antioxidant defenses, and mitochondrial fusion (mitofusin 2) and fission (dynamic related protein 1) protein. Our results showed that HFO diet induced less testicular histology impairment, oxidative stress, and apoptosis compared to a HL diet. This finding was associated with an increase in antioxidant activities and a shift toward mitochondrial fusion processes induced by HFO diet compared to HL diet, suggesting that ω3-PUFAs may act as bioactive compound targeting mitochondria dynamics to prevent testicular impairment. Full article

(This article belongs to the Special Issue Targeted Protection of Bioactive Compounds to Mitochondria)

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16 pages, 3386 KiB

Open AccessArticle

Mitochondrial Targeting of Antioxidants Alters Pancreatic Acinar Cell Bioenergetics and Determines Cell Fate

by Jane A. Armstrong, Nicole J. Cash, Jack C. Morton, Alexei V. Tepikin, Robert Sutton and David N. Criddle

Int. J. Mol. Sci. 2019, 20(7), 1700; https://doi.org/10.3390/ijms20071700 - 05 Apr 2019

Cited by 12 | Viewed by 3516

Abstract

Mitochondrial dysfunction is a core feature of acute pancreatitis, a severe disease in which oxidative stress is elevated. Mitochondrial targeting of antioxidants is a potential therapeutic strategy for this and other diseases, although thus far mixed results have been reported. We investigated the [...] Read more.

Mitochondrial dysfunction is a core feature of acute pancreatitis, a severe disease in which oxidative stress is elevated. Mitochondrial targeting of antioxidants is a potential therapeutic strategy for this and other diseases, although thus far mixed results have been reported. We investigated the effects of mitochondrial targeting with the antioxidant MitoQ on pancreatic acinar cell bioenergetics, adenosine triphosphate (ATP) production and cell fate, in comparison with the non-antioxidant control decyltriphenylphosphonium bromide (DecylTPP) and general antioxidant N-acetylcysteine (NAC). MitoQ (µM range) and NAC (mM range) caused sustained elevations of basal respiration and the inhibition of spare respiratory capacity, which was attributable to an antioxidant action since these effects were minimal with DecylTPP. Although MitoQ but not DecylTPP decreased cellular NADH levels, mitochondrial ATP turnover capacity and cellular ATP concentrations were markedly reduced by both MitoQ and DecylTPP, indicating a non-specific effect of mitochondrial targeting. All three compounds were associated with a compensatory elevation of glycolysis and concentration-dependent increases in acinar cell apoptosis and necrosis. These data suggest that reactive oxygen species (ROS) contribute a significant negative feedback control of basal cellular metabolism. Mitochondrial targeting using positively charged molecules that insert into the inner mitochondrial member appears to be deleterious in pancreatic acinar cells, as does an antioxidant strategy for the treatment of acute pancreatitis. Full article

(This article belongs to the Special Issue Targeted Protection of Bioactive Compounds to Mitochondria)

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Review

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16 pages, 1189 KiB

Open AccessReview

Natural Products Targeting ER Stress, and the Functional Link to Mitochondria

by Stefania Martucciello, Milena Masullo, Antonietta Cerulli and Sonia Piacente

Int. J. Mol. Sci. 2020, 21(6), 1905; https://doi.org/10.3390/ijms21061905 - 11 Mar 2020

Cited by 67 | Viewed by 5609

Abstract

The endoplasmic reticulum (ER) is a dynamic organelle essential for intracellular homeostasis maintenance, controlling synthesis, the folding of secreted and membrane-bound proteins, and transport of Ca²⁺. During cellular stress, ER dysfunction leads to the activation of unfolded protein response (UPR) due [...] Read more.

The endoplasmic reticulum (ER) is a dynamic organelle essential for intracellular homeostasis maintenance, controlling synthesis, the folding of secreted and membrane-bound proteins, and transport of Ca²⁺. During cellular stress, ER dysfunction leads to the activation of unfolded protein response (UPR) due to accumulated misfolded proteins in the ER. This condition is referred as ER stress. Mitochondria and ER form a site of close contact (the mitochondria-associated membrane, MAM) which is a major platform exerting important physiological roles in the regulation of intracellular Ca²⁺ homeostasis, lipid metabolism, mitochondrial fission, autophagosome formation, and apoptosis progression. Natural products have been receiving increasing attention for their ability to interfere with ER stress. Research works have focused on the capacity of these bioactive compounds to induce apoptosis by activating ER stress through the ER stress-mediated mitochondrial apoptotic pathway. In this review we discuss the role of natural products in the signaling communication between ER and mitochondria, focusing on the effects induced by ER stress including Ca²⁺ permeability transition and UPR signaling (protein kinase R-like ER kinase/mitofusin 2). Full article

(This article belongs to the Special Issue Targeted Protection of Bioactive Compounds to Mitochondria)

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13 pages, 1539 KiB

Open AccessReview

Impact of Glucoraphanin-Mediated Activation of Nrf2 on Non-Alcoholic Fatty Liver Disease with a Focus on Mitochondrial Dysfunction

by Liang Xu, Naoto Nagata and Tsuguhito Ota

Int. J. Mol. Sci. 2019, 20(23), 5920; https://doi.org/10.3390/ijms20235920 - 25 Nov 2019

Cited by 37 | Viewed by 7474

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common disease in Western nations and ranges in severity from steatosis to steatohepatitis (NASH). NAFLD is a genetic-environmental-metabolic stress-related disease of unclear pathogenesis. NAFLD is triggered by caloric overconsumption and physical inactivity, which lead to insulin [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a common disease in Western nations and ranges in severity from steatosis to steatohepatitis (NASH). NAFLD is a genetic-environmental-metabolic stress-related disease of unclear pathogenesis. NAFLD is triggered by caloric overconsumption and physical inactivity, which lead to insulin resistance and oxidative stress. A growing body of evidence indicates that mitochondrial dysfunction plays a critical role in the pathogenesis of NAFLD. Mitochondrial dysfunction not only promotes fat accumulation, but also leads to generation of reactive oxygen species (ROS) and lipid peroxidation, resulting in oxidative stress in hepatocytes. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important modulator of antioxidant signaling that serves as a primary cellular defense against the cytotoxic effects of oxidative stress. The pharmacological induction of Nrf2 ameliorates obesity-associated insulin resistance and NAFLD in a mouse model. Sulforaphane and its precursor glucoraphanin are derived from broccoli sprouts and are the most potent natural Nrf2 inducers—they may protect mitochondrial function, thus suppressing the development of NASH. In this review, we briefly describe the role of mitochondrial dysfunction in the pathogenesis of NASH and the effects of glucoraphanin on its development. Full article

(This article belongs to the Special Issue Targeted Protection of Bioactive Compounds to Mitochondria)

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31 pages, 2576 KiB

Open AccessReview

Mitochondria in Neuroprotection by Phytochemicals: Bioactive Polyphenols Modulate Mitochondrial Apoptosis System, Function and Structure

by Makoto Naoi, Yuqiu Wu, Masayo Shamoto-Nagai and Wakako Maruyama

Int. J. Mol. Sci. 2019, 20(10), 2451; https://doi.org/10.3390/ijms20102451 - 17 May 2019

Cited by 110 | Viewed by 10323

Abstract

In aging and neurodegenerative diseases, loss of distinct type of neurons characterizes disease-specific pathological and clinical features, and mitochondria play a pivotal role in neuronal survival and death. Mitochondria are now considered as the organelle to modulate cellular signal pathways and functions, not [...] Read more.

In aging and neurodegenerative diseases, loss of distinct type of neurons characterizes disease-specific pathological and clinical features, and mitochondria play a pivotal role in neuronal survival and death. Mitochondria are now considered as the organelle to modulate cellular signal pathways and functions, not only to produce energy and reactive oxygen species. Oxidative stress, deficit of neurotrophic factors, and multiple other factors impair mitochondrial function and induce cell death. Multi-functional plant polyphenols, major groups of phytochemicals, are proposed as one of most promising mitochondria-targeting medicine to preserve the activity and structure of mitochondria and neurons. Polyphenols can scavenge reactive oxygen and nitrogen species and activate redox-responsible transcription factors to regulate expression of genes, coding antioxidants, anti-apoptotic Bcl-2 protein family, and pro-survival neurotrophic factors. In mitochondria, polyphenols can directly regulate the mitochondrial apoptosis system either in preventing or promoting way. Polyphenols also modulate mitochondrial biogenesis, dynamics (fission and fusion), and autophagic degradation to keep the quality and number. This review presents the role of polyphenols in regulation of mitochondrial redox state, death signal system, and homeostasis. The dualistic redox properties of polyphenols are associated with controversial regulation of mitochondrial apoptosis system involved in the neuroprotective and anti-carcinogenic functions. Mitochondria-targeted phytochemical derivatives were synthesized based on the phenolic structure to develop a novel series of neuroprotective and anticancer compounds, which promote the bioavailability and effectiveness. Phytochemicals have shown the multiple beneficial effects in mitochondria, but further investigation is required for the clinical application. Full article

(This article belongs to the Special Issue Targeted Protection of Bioactive Compounds to Mitochondria)

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