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16 pages, 2056 KiB

Open AccessArticle

Chenodeoxycholic Acid Has Non-Thermogenic, Mitodynamic Anti-Obesity Effects in an In Vitro CRISPR/Cas9 Model of Bile Acid Receptor TGR5 Knockdown

by João S. Teodoro, Ivo F. Machado, Ana C. Castela, João A. Amorim, Ivana Jarak, Rui A. Carvalho, Carlos M. Palmeira and Anabela P. Rolo

Int. J. Mol. Sci. 2021, 22(21), 11738; https://doi.org/10.3390/ijms222111738 - 29 Oct 2021

Cited by 7 | Viewed by 1927

Abstract

Bile acids (BA) have shown promising effects in animal models of obesity. However, the said effects are thought to rely on a thermogenic effect, which is questionably present in humans. A previous work has shown that the BA chenodeoxycholic acid (CDCA) can revert [...] Read more.

Bile acids (BA) have shown promising effects in animal models of obesity. However, the said effects are thought to rely on a thermogenic effect, which is questionably present in humans. A previous work has shown that the BA chenodeoxycholic acid (CDCA) can revert obesity and accelerate metabolism in animal and cell culture models. Thus, the aim of this study was to understand if this obesity reduction is indeed thermogenically-dependent. A CRISPR/Cas9 model of TGR5 (BA receptor) knockdown in 3T3-L1 adipocytes was developed to diminish thermogenic effects. Various parameters were assessed, including mitochondrial bioenergetics by Seahorse flux analysis, oxidative stress and membrane potential by fluorometry, intermediary metabolism by NMR, protein content assessment by Western Blot, gene expression by qPCR, and confocal microscopy evaluation of mitophagy. CDCA was still capable, for the most part, of reversing the harmful effects of cellular obesity, elevating mitophagy and leading to the reduction of harmed mitochondria within the cells, boosting mitochondrial activity, and thus energy consumption. In summary, CDCA has a non-thermogenic, obesity reducing capacity that hinges on a healthy mitochondrial population, explaining at least some of these effects and opening avenues of human treatment for metabolic diseases. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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16 pages, 3703 KiB

Open AccessArticle

Butyrate Feeding Reverses CypD-Related Mitoflash Phenotypes in Mouse Myofibers

by Ang Li, Xuejun Li, Jianxun Yi, Jianjie Ma and Jingsong Zhou

Int. J. Mol. Sci. 2021, 22(14), 7412; https://doi.org/10.3390/ijms22147412 - 10 Jul 2021

Cited by 5 | Viewed by 2585

Abstract

Mitoflashes are spontaneous transients of the biosensor mt-cpYFP. In cardiomyocytes, mitoflashes are associated with the cyclophilin D (CypD) mediated opening of mitochondrial permeability transition pore (mPTP), while in skeletal muscle they are considered hallmarks of mitochondrial respiration burst under physiological conditions. Here, we [...] Read more.

Mitoflashes are spontaneous transients of the biosensor mt-cpYFP. In cardiomyocytes, mitoflashes are associated with the cyclophilin D (CypD) mediated opening of mitochondrial permeability transition pore (mPTP), while in skeletal muscle they are considered hallmarks of mitochondrial respiration burst under physiological conditions. Here, we evaluated the potential association between mitoflashes and the mPTP opening at different CypD levels and phosphorylation status by generating three CypD derived fusion constructs with a red shifted, pH stable Ca²⁺ sensor jRCaMP1b. We observed perinuclear mitochondrial Ca²⁺ efflux accompanying mitoflashes in CypD and CypDS42A (a phosphor-resistant mutation at Serine 42) overexpressed myofibers but not the control myofibers expressing the mitochondria-targeting sequence of CypD (CypDN30). Assisted by a newly developed analysis program, we identified shorter, more frequent mitoflash activities occurring over larger areas in CypD and CypDS42A overexpressed myofibers than the control CypDN30 myofibers. These observations provide an association between the elevated CypD expression and increased mitoflash activities in hindlimb muscles in an amyotrophic lateral sclerosis (ALS) mouse model previously observed. More importantly, feeding the mice with sodium butyrate reversed the CypD-associated mitoflash phenotypes and protected against ectopic upregulation of CypD, unveiling a novel molecular mechanism underlying butyrate mediated alleviation of ALS progression in the mouse model. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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21 pages, 3183 KiB

Open AccessArticle

Western Diet Decreases the Liver Mitochondrial Oxidative Flux of Succinate: Insight from a Murine NAFLD Model

by Pavla Staňková, Otto Kučera, Eva Peterová, Moustafa Elkalaf, David Rychtrmoc, Jan Melek, Miroslav Podhola, Veronika Zubáňová and Zuzana Červinková

Int. J. Mol. Sci. 2021, 22(13), 6908; https://doi.org/10.3390/ijms22136908 - 27 Jun 2021

Cited by 12 | Viewed by 3508

Abstract

Mitochondria play an essential role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Previously, we found that succinate-activated respiration was the most affected mitochondrial parameter in mice with mild NAFLD. In this study, we focused on the role of succinate dehydrogenase (SDH) [...] Read more.

Mitochondria play an essential role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Previously, we found that succinate-activated respiration was the most affected mitochondrial parameter in mice with mild NAFLD. In this study, we focused on the role of succinate dehydrogenase (SDH) in NAFLD pathogenesis. To induce the progression of NAFLD to nonalcoholic steatohepatitis (NASH), C57BL/6J mice were fed a Western-style diet (WD) or control diet for 30 weeks. NAFLD severity was evaluated histologically and the expression of selected proteins and genes was assessed. Mitochondrial respiration was measured by high-resolution respirometry. Liver redox status was assessed using glutathione, malondialdehyde, and mitochondrial production of reactive oxygen species (ROS). Metabolomic analysis was performed by GC/MS. WD consumption for 30 weeks led to reduced succinate-activated respiration. We also observed decreased SDH activity, decreased expression of the SDH activator sirtuin 3, decreased gene expression of SDH subunits, and increased levels of hepatic succinate, an important signaling molecule. Succinate receptor 1 (SUCNR1) gene and protein expression were reduced in the livers of WD-fed mice. We did not observe signs of oxidative damage compared to the control group. The changes observed in WD-fed mice appear to be adaptive to prevent mitochondrial respiratory chain overload and massive ROS production. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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24 pages, 7488 KiB

Open AccessArticle

The Alterations of Mitochondrial Function during NAFLD Progression—An Independent Effect of Mitochondrial ROS Production

by Inês C. M. Simões, Ricardo Amorim, José Teixeira, Agnieszka Karkucinska-Wieckowska, Adriana Carvalho, Susana P. Pereira, Rui F. Simões, Sylwia Szymanska, Michał Dąbrowski, Justyna Janikiewicz, Agnieszka Dobrzyń, Paulo J. Oliveira, Yaiza Potes and Mariusz R. Wieckowski

Int. J. Mol. Sci. 2021, 22(13), 6848; https://doi.org/10.3390/ijms22136848 - 25 Jun 2021

Cited by 24 | Viewed by 3781

Abstract

The progression of non-alcoholic fatty liver (NAFL) into non-alcoholic steatohepatitis implicates multiple mechanisms, chief of which is mitochondrial dysfunction. However, the sequence of events underlying mitochondrial failure are still poorly clarified. In this work, male C57BL/6J mice were fed with a high-fat plus [...] Read more.

The progression of non-alcoholic fatty liver (NAFL) into non-alcoholic steatohepatitis implicates multiple mechanisms, chief of which is mitochondrial dysfunction. However, the sequence of events underlying mitochondrial failure are still poorly clarified. In this work, male C57BL/6J mice were fed with a high-fat plus high-sucrose diet for 16, 20, 22, and 24 weeks to induce NAFL. Up to the 20th week, an early mitochondrial remodeling with increased OXPHOS subunits levels and higher mitochondrial respiration occurred. Interestingly, a progressive loss of mitochondrial respiration along “Western diet” feeding was identified, accompanied by higher susceptibility to mitochondrial permeability transition pore opening. Importantly, our findings prove that mitochondrial alterations and subsequent impairment are independent of an excessive mitochondrial reactive oxygen species (ROS) generation, which was found to be progressively diminished along with disease progression. Instead, increased peroxisomal abundance and peroxisomal fatty acid oxidation-related pathway suggest that peroxisomes may contribute to hepatic ROS generation and oxidative damage, which may accelerate hepatic injury and disease progression. We show here for the first time the sequential events of mitochondrial alterations involved in non-alcoholic fatty liver disease (NAFLD) progression and demonstrate that mitochondrial ROS are not one of the first hits that cause NAFLD progression. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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19 pages, 2709 KiB

Open AccessArticle

TAT-Conjugated NDUFS8 Can Be Transduced into Mitochondria in a Membrane-Potential-Independent Manner and Rescue Complex I Deficiency

by Bo-Yu Lin, Gui-Teng Zheng, Kai-Wen Teng, Juan-Yu Chang, Chao-Chang Lee, Pin-Chao Liao and Mou-Chieh Kao

Int. J. Mol. Sci. 2021, 22(12), 6524; https://doi.org/10.3390/ijms22126524 - 17 Jun 2021

Cited by 5 | Viewed by 2429

Abstract

NADH dehydrogenase (ubiquinone) Fe-S protein 8 (NDUFS8) is a nuclear-encoded core subunit of human mitochondrial complex I. Defects in NDUFS8 are associated with Leigh syndrome and encephalomyopathy. Cell-penetrating peptide derived from the HIV-1 transactivator of transcription protein (TAT) has been successfully applied as [...] Read more.

NADH dehydrogenase (ubiquinone) Fe-S protein 8 (NDUFS8) is a nuclear-encoded core subunit of human mitochondrial complex I. Defects in NDUFS8 are associated with Leigh syndrome and encephalomyopathy. Cell-penetrating peptide derived from the HIV-1 transactivator of transcription protein (TAT) has been successfully applied as a carrier to bring fusion proteins into cells without compromising the biological function of the cargoes. In this study, we developed a TAT-mediated protein transduction system to rescue complex I deficiency caused by NDUFS8 defects. Two fusion proteins (TAT-NDUFS8 and NDUFS8-TAT) were exogenously expressed and purified from Escherichia coli for transduction of human cells. In addition, similar constructs were generated and used in transfection studies for comparison. The results showed that both exogenous TAT-NDUFS8 and NDUFS8-TAT were delivered into mitochondria and correctly processed. Interestingly, the mitochondrial import of TAT-containing NDUFS8 was independent of mitochondrial membrane potential. Treatment with TAT-NDUFS8 not only significantly improved the assembly of complex I in an NDUFS8-deficient cell line, but also partially rescued complex I functions both in the in-gel activity assay and the oxygen consumption assay. Our current findings suggest the considerable potential of applying the TAT-mediated protein transduction system for treatment of complex I deficiency. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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26 pages, 14572 KiB

Open AccessArticle

Quantifying Mitochondrial Dynamics in Patient Fibroblasts with Multiple Developmental Defects and Mitochondrial Disorders

by Ajibola B. Bakare, Julienne Daniel, Joshua Stabach, Anapaula Rojas, Austin Bell, Brooke Henry and Shilpa Iyer

Int. J. Mol. Sci. 2021, 22(12), 6263; https://doi.org/10.3390/ijms22126263 - 10 Jun 2021

Cited by 14 | Viewed by 4178

Abstract

Mitochondria are dynamic organelles that undergo rounds of fission and fusion and exhibit a wide range of morphologies that contribute to the regulation of different signaling pathways and various cellular functions. It is important to understand the differences between mitochondrial structure in health [...] Read more.

Mitochondria are dynamic organelles that undergo rounds of fission and fusion and exhibit a wide range of morphologies that contribute to the regulation of different signaling pathways and various cellular functions. It is important to understand the differences between mitochondrial structure in health and disease so that therapies can be developed to maintain the homeostatic balance of mitochondrial dynamics. Mitochondrial disorders are multisystemic and characterized by complex and variable clinical pathologies. The dynamics of mitochondria in mitochondrial disorders is thus worthy of investigation. Therefore, in this study, we performed a comprehensive analysis of mitochondrial dynamics in ten patient-derived fibroblasts containing different mutations and deletions associated with various mitochondrial disorders. Our results suggest that the most predominant morphological signature for mitochondria in the diseased state is fragmentation, with eight out of the ten cell lines exhibiting characteristics consistent with fragmented mitochondria. To our knowledge, this is the first comprehensive study that quantifies mitochondrial dynamics in cell lines with a wide array of developmental and mitochondrial disorders. A more thorough analysis of the correlations between mitochondrial dynamics, mitochondrial genome perturbations, and bioenergetic dysfunction will aid in identifying unique morphological signatures of various mitochondrial disorders in the future. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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19 pages, 5285 KiB

Open AccessArticle

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function

by Rob C. I. Wüst, Bram F. Coolen, Ntsiki M. Held, Mariah R. R. Daal, Vida Alizadeh Tazehkandi, Luciënne Baks-te Bulte, Marit Wiersma, Diederik W. D. Kuster, Bianca J. J. M. Brundel, Michel van Weeghel, Gustav J. Strijkers and Riekelt H. Houtkooper

Int. J. Mol. Sci. 2021, 22(8), 4100; https://doi.org/10.3390/ijms22084100 - 15 Apr 2021

Cited by 19 | Viewed by 4791

Abstract

Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline—which belongs to the tetracycline class—reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in Drosophila and [...] Read more.

Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline—which belongs to the tetracycline class—reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in Drosophila and in mice. Ampicillin and carbenicillin were used as control antibiotics since these do not interfere with mitochondrial translation. In line with its specific inhibitory effect on mitochondrial translation, doxycycline caused a mitonuclear protein imbalance in doxycycline-treated H9C2 cells, reduced maximal mitochondrial respiration, particularly with complex I substrates, and mitochondria appeared fragmented. Flux measurements using stable isotope tracers showed a shift away from OXPHOS towards glycolysis after doxycycline exposure. Cardiac contractility measurements in adult cardiomyocytes and Drosophila melanogaster hearts showed an increased diastolic calcium concentration, and a higher arrhythmicity index. Systolic and diastolic dysfunction were observed after exposure to doxycycline. Mice treated with doxycycline showed mitochondrial complex I dysfunction, reduced OXPHOS capacity and impaired diastolic function. Doxycycline exacerbated diastolic dysfunction and reduced ejection fraction in a diabetes mouse model vulnerable for metabolic derangements. We therefore conclude that doxycycline impairs mitochondrial function and causes cardiac dysfunction. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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14 pages, 2820 KiB

Open AccessArticle

p43, a Truncated Form of Thyroid Hormone Receptor α, Regulates Maturation of Pancreatic β Cells

by Emilie Blanchet, Laurence Pessemesse, Christine Feillet-Coudray, Charles Coudray, Chantal Cabello, Christelle Bertrand-Gaday and François Casas

Int. J. Mol. Sci. 2021, 22(5), 2489; https://doi.org/10.3390/ijms22052489 - 02 Mar 2021

Cited by 2 | Viewed by 2045

Abstract

P43 is a truncated form of thyroid hormone receptor α localized in mitochondria, which stimulates mitochondrial respiratory chain activity. Previously, we showed that deletion of p43 led to reduction of pancreatic islet density and a loss of glucose-stimulated insulin secretion in adult mice. [...] Read more.

P43 is a truncated form of thyroid hormone receptor α localized in mitochondria, which stimulates mitochondrial respiratory chain activity. Previously, we showed that deletion of p43 led to reduction of pancreatic islet density and a loss of glucose-stimulated insulin secretion in adult mice. The present study was designed to determine whether p43 was involved in the processes of β cell development and maturation. We used neonatal, juvenile, and adult p43-/- mice, and we analyzed the development of β cells in the pancreas. Here, we show that p43 deletion affected only slightly β cell proliferation during the postnatal period. However, we found a dramatic fall in p43-/- mice of MafA expression (V-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog A), a key transcription factor of beta-cell maturation. Analysis of the expression of antioxidant enzymes in pancreatic islet and 4-hydroxynonenal (4-HNE) (a specific marker of lipid peroxidation) staining revealed that oxidative stress occurred in mice lacking p43. Lastly, administration of antioxidants cocktail to p43-/- pregnant mice restored a normal islet density but failed to ensure an insulin secretion in response to glucose. Our findings demonstrated that p43 drives the maturation of β cells via its induction of transcription factor MafA during the critical postnatal window. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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Review

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34 pages, 3055 KiB

Open AccessReview

Mitochondria Matter: Systemic Aspects of Nonalcoholic Fatty Liver Disease (NAFLD) and Diagnostic Assessment of Liver Function by Stable Isotope Dynamic Breath Tests

by Agostino Di Ciaula, Giuseppe Calamita, Harshitha Shanmugam, Mohamad Khalil, Leonilde Bonfrate, David Q.-H. Wang, Gyorgy Baffy and Piero Portincasa

Int. J. Mol. Sci. 2021, 22(14), 7702; https://doi.org/10.3390/ijms22147702 - 19 Jul 2021

Cited by 16 | Viewed by 5202

Abstract

The liver plays a key role in systemic metabolic processes, which include detoxification, synthesis, storage, and export of carbohydrates, lipids, and proteins. The raising trends of obesity and metabolic disorders worldwide is often associated with the nonalcoholic fatty liver disease (NAFLD), which has [...] Read more.

The liver plays a key role in systemic metabolic processes, which include detoxification, synthesis, storage, and export of carbohydrates, lipids, and proteins. The raising trends of obesity and metabolic disorders worldwide is often associated with the nonalcoholic fatty liver disease (NAFLD), which has become the most frequent type of chronic liver disorder with risk of progression to cirrhosis and hepatocellular carcinoma. Liver mitochondria play a key role in degrading the pathways of carbohydrates, proteins, lipids, and xenobiotics, and to provide energy for the body cells. The morphological and functional integrity of mitochondria guarantee the proper functioning of β-oxidation of free fatty acids and of the tricarboxylic acid cycle. Evaluation of the liver in clinical medicine needs to be accurate in NAFLD patients and includes history, physical exam, imaging, and laboratory assays. Evaluation of mitochondrial function in chronic liver disease and NAFLD is now possible by novel diagnostic tools. “Dynamic” liver function tests include the breath test (BT) based on the use of substrates marked with the non-radioactive, naturally occurring stable isotope ¹³C. Hepatocellular metabolization of the substrate will generate ¹³CO₂, which is excreted in breath and measured by mass spectrometry or infrared spectroscopy. Breath levels of ¹³CO₂ are biomarkers of specific metabolic processes occurring in the hepatocyte cytosol, microsomes, and mitochondria. ¹³C-BTs explore distinct chronic liver diseases including simple liver steatosis, non-alcoholic steatohepatitis, liver fibrosis, cirrhosis, hepatocellular carcinoma, drug, and alcohol effects. In NAFLD, ¹³C-BT use substrates such as α-ketoisocaproic acid, methionine, and octanoic acid to assess mitochondrial oxidation capacity which can be impaired at an early stage of disease. ¹³C-BTs represent an indirect, cost-effective, and easy method to evaluate dynamic liver function. Further applications are expected in clinical medicine. In this review, we discuss the involvement of liver mitochondria in the progression of NAFLD, together with the role of ¹³C-BT in assessing mitochondrial function and its potential use in the prevention and management of NAFLD. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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18 pages, 1540 KiB

Open AccessReview

Targeting Mitochondria in Diabetes

by Nina Krako Jakovljevic, Kasja Pavlovic, Aleksandra Jotic, Katarina Lalic, Milica Stoiljkovic, Ljiljana Lukic, Tanja Milicic, Marija Macesic, Jelena Stanarcic Gajovic and Nebojsa M. Lalic

Int. J. Mol. Sci. 2021, 22(12), 6642; https://doi.org/10.3390/ijms22126642 - 21 Jun 2021

Cited by 47 | Viewed by 6910

Abstract

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy [...] Read more.

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy metabolism, are involved in the mechanisms of IR and T2D. Mitochondrial function is affected by insulin resistance in different tissues, among which skeletal muscle and liver have the highest impact on whole-body glucose homeostasis. This review focuses on human studies that assess mitochondrial function in liver, muscle and blood cells in the context of T2D. Furthermore, different interventions targeting mitochondria in IR and T2D are listed, with a selection of studies using respirometry as a measure of mitochondrial function, for better data comparison. Altogether, mitochondrial respiratory capacity appears to be a metabolic indicator since it decreases as the disease progresses but increases after lifestyle (exercise) and pharmacological interventions, together with the improvement in metabolic health. Finally, novel therapeutics developed to target mitochondria have potential for a more integrative therapeutic approach, treating both causative and secondary defects of diabetes. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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23 pages, 1512 KiB

Open AccessReview

The Muscle-Brain Axis and Neurodegenerative Diseases: The Key Role of Mitochondria in Exercise-Induced Neuroprotection

by Johannes Burtscher, Grégoire P. Millet, Nicolas Place, Bengt Kayser and Nadège Zanou

Int. J. Mol. Sci. 2021, 22(12), 6479; https://doi.org/10.3390/ijms22126479 - 17 Jun 2021

Cited by 51 | Viewed by 31170

Abstract

Regular exercise is associated with pronounced health benefits. The molecular processes involved in physiological adaptations to exercise are best understood in skeletal muscle. Enhanced mitochondrial functions in muscle are central to exercise-induced adaptations. However, regular exercise also benefits the brain and is a [...] Read more.

Regular exercise is associated with pronounced health benefits. The molecular processes involved in physiological adaptations to exercise are best understood in skeletal muscle. Enhanced mitochondrial functions in muscle are central to exercise-induced adaptations. However, regular exercise also benefits the brain and is a major protective factor against neurodegenerative diseases, such as the most common age-related form of dementia, Alzheimer’s disease, or the most common neurodegenerative motor disorder, Parkinson’s disease. While there is evidence that exercise induces signalling from skeletal muscle to the brain, the mechanistic understanding of the crosstalk along the muscle–brain axis is incompletely understood. Mitochondria in both organs, however, seem to be central players. Here, we provide an overview on the central role of mitochondria in exercise-induced communication routes from muscle to the brain. These routes include circulating factors, such as myokines, the release of which often depends on mitochondria, and possibly direct mitochondrial transfer. On this basis, we examine the reported effects of different modes of exercise on mitochondrial features and highlight their expected benefits with regard to neurodegeneration prevention or mitigation. In addition, knowledge gaps in our current understanding related to the muscle–brain axis in neurodegenerative diseases are outlined. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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35 pages, 23173 KiB

Open AccessReview

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

by Miriam Longo, Erika Paolini, Marica Meroni and Paola Dongiovanni

Int. J. Mol. Sci. 2021, 22(8), 4173; https://doi.org/10.3390/ijms22084173 - 17 Apr 2021

Cited by 25 | Viewed by 4999

Abstract

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis, thus becoming the main cause of [...] Read more.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis, thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles that may adapt in response to environment, genetics and epigenetics in the liver (“mitochondrial plasticity”). Mounting evidence highlights that mitochondrial dysfunction due to loss of mitochondrial flexibility may arise before overt NAFLD, and from the early stages of liver injury. Mitochondrial failure promotes not only hepatocellular damage, but also release signals (mito-DAMPs), which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by the remodeling of glucidic–lipidic metabolism combined with the reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research and for the development of potential preventive or curative strategies. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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