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Mitochondria at the Heart of Metabolic Disorders

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (20 March 2023) | Viewed by 29879

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Dr. Mora Murri

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Guest Editor

1. Biomedical Research Institute of Malaga and Nanomedicine Platform (IBIMA Plataforma BIONAND), 29590 Málaga, Spain
2. Heart Area, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
3. Clinical Management Unit of Endocrinology and Nutrition, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
4. Biomedical Research Network Center for the Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
Interests: obesity; heart failure; mitochondria; exercise; sex dimorphism
Special Issues, Collections and Topics in MDPI journals

Dr. Hamid Azzouzi

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Co-Guest Editor

Department of Cardiology, University Medical Centre Utrecht, Utrecht University, 3584CX Utrecht, The Netherlands
Interests: mitochondrial homeostasis; RNA biology; cardiac regeneration; cardiovascular disease

Dr. Gustavo Silva

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Co-Guest Editor

Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, PB 4956 Nydalen, NO-0424 Oslo, Norway
Interests: microRNAs; heart failure; animal model; myocardial infarction

Special Issue Information

Dear Colleagues,

Metabolic disorders are defined as a group of diseases in which normal metabolic processes are disrupted, due to the accumulation of large amounts of one or more metabolites, or a deficiency in one or more metabolites. Metabolic disorders can be inherited or acquired during an individual’s lifetime. Inherited metabolic diseases result from a genetic defect in the functioning of an intermediate metabolic pathway, while acquired disorders result from external factors, with lifestyle factors being the main causes. Acquired metabolic disorders have dramatically increased worldwide, with obesity and overweight being the main disorders, affecting more than 2.1 billion people.

Mitochondria are the major energy producers within a cell, providing energy for physiological functions. In addition, mitochondria participate in the regulation of other cellular events, including apoptosis, calcium homeostasis, production of reactive oxygen species, and biosynthesis of steroid hormones. The essential functions of mitochondria in numerous features of metabolic regulation position them at the core of global energy homeostasis control. Mitochondrial metabolism is both the origin and target of numerous nutrient signals. This central position of mitochondria in metabolism makes them vulnerable to damage. A metabolic imbalance of nutrient signal input, energy production, and/or oxidative respiration results in “mitochondrial dysfunction”, with consequential effects on metabolism, leading to metabolic disorders.

In this Special Issue, we welcome submissions of original research and review articles that present novel insights into the interplay between mitochondrial dysfunction and metabolic disorders.

Dr. Mora Murri
Dr. Hamid Azzouzi
Dr. Gustavo Silva
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

metabolic disorders
metabolism
mitochondria
obesity
diabetes
metabolic syndrome

Published Papers (9 papers)

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Research

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12 pages, 1539 KiB

Open AccessArticle

Mitoregulin Contributes to Creatine Shuttling and Cardiolipin Protection in Mice Muscle

by Olga A. Averina, Oleg A. Permyakov, Mariia A. Emelianova, Olga O. Grigoryeva, Maxim L. Lovat, Anna E. Egorova, Andrei V. Grinchenko, Vadim V. Kumeiko, Maria V. Marey, Vasily N. Manskikh, Olga A. Dontsova, Mikhail Yu. Vysokikh and Petr V. Sergiev

Int. J. Mol. Sci. 2023, 24(8), 7589; https://doi.org/10.3390/ijms24087589 - 20 Apr 2023

Cited by 2 | Viewed by 1670

Abstract

Small peptides compose a large share of the mitochondrial proteome. Mitoregulin (Mtln) is a mitochondrial peptide known to contribute to the respiratory complex I functioning and other processes in mitochondria. In our previous studies, we demonstrated that Mtln knockout mice develop obesity and accumulate triglycerides and other oxidation substrates in serum, concomitant with an exhaustion of tricarboxylic acids cycle intermediates. Here we examined the functional role of Mtln in skeletal muscles, one of the major energy consuming tissues. We observed reduced muscle strength for Mtln knockout mice. Decrease of the mitochondrial cardiolipin and concomitant increase in monolysocardiolipin concentration upon Mtln inactivation is likely to be a consequence of imbalance between oxidative damage and remodeling of cardiolipin. It is accompanied by the mitochondrial creatine kinase octamer dissociation and suboptimal respiratory chain performance in Mtln knockout mice. Full article

(This article belongs to the Special Issue Mitochondria at the Heart of Metabolic Disorders)

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13 pages, 1840 KiB

Open AccessArticle

Renal Denervation Helps Preserve the Ejection Fraction by Preserving Endocardial-Endothelial Function during Heart Failure

by Sathnur Pushpakumar, Mahavir Singh, Yuting Zheng, Oluwaseun E. Akinterinwa, Sri Prakash L. Mokshagundam, Utpal Sen, Dinesh K. Kalra and Suresh C. Tyagi

Int. J. Mol. Sci. 2023, 24(8), 7302; https://doi.org/10.3390/ijms24087302 - 15 Apr 2023

Cited by 2 | Viewed by 2439

Abstract

Renal denervation (RDN) protects against hypertension, hypertrophy, and heart failure (HF); however, it is not clear whether RDN preserves ejection fraction (EF) during heart failure (HFpEF). To test this hypothesis, we simulated a chronic congestive cardiopulmonary heart failure (CHF) phenotype by creating an aorta-vena cava fistula (AVF) in the C57BL/6J wild type (WT) mice. Briefly, there are four ways to create an experimental CHF: (1) myocardial infarction (MI), which is basically ligating the coronary artery by instrumenting and injuring the heart; (2) trans-aortic constriction (TAC) method, which mimics the systematic hypertension, but again constricts the aorta on top of the heart and, in fact, exposes the heart; (3) acquired CHF condition, promoted by dietary factors, diabetes, salt, diet, etc., but is multifactorial in nature; and finally, (4) the AVF, which remains the only one wherein AVF is created ~1 cm below the kidneys in which the aorta and vena cava share the common middle-wall. By creating the AVF fistula, the red blood contents enter the vena cava without an injury to the cardiac tissue. This model mimics or simulates the CHF phenotype, for example, during aging wherein with advancing age, the preload volume keeps increasing beyond the level that the aging heart can pump out due to the weakened cardiac myocytes. Furthermore, this procedure also involves the right ventricle to lung to left ventricle flow, thus creating an ideal condition for congestion. The heart in AVF transitions from preserved to reduced EF (i.e., HFpEF to HFrEF). In fact, there are more models of volume overload, such as the pacing-induced and mitral valve regurgitation, but these are also injurious models in nature. Our laboratory is one of the first laboratories to create and study the AVF phenotype in the animals. The RDN was created by treating the cleaned bilateral renal artery. After 6 weeks, blood, heart, and renal samples were analyzed for exosome, cardiac regeneration markers, and the renal cortex proteinases. Cardiac function was analyzed by echocardiogram (ECHO) procedure. The fibrosis was analyzed with a trichrome staining method. The results suggested that there was a robust increase in the exosomes’ level in AVF blood, suggesting a compensatory systemic response during AVF-CHF. During AVF, there was no change in the cardiac eNOS, Wnt1, or β-catenin; however, during RDN, there were robust increases in the levels of eNOS, Wnt1, and β-catenin compared to the sham group. As expected in HFpEF, there was perivascular fibrosis, hypertrophy, and pEF. Interestingly, increased levels of eNOS suggested that despite fibrosis, the NO generation was higher and that it most likely contributed to pEF during HF. The RDN intervention revealed an increase in renal cortical caspase 8 and a decrease in caspase 9. Since caspase 8 is protective and caspase 9 is apoptotic, we suggest that RDN protects against the renal stress and apoptosis. It should be noted that others have demonstrated a role of vascular endothelium in preserving the ejection by cell therapy intervention. In the light of foregoing evidence, our findings also suggest that RDN is cardioprotective during HFpEF via preservation of the eNOS and accompanied endocardial-endothelial function. Full article

(This article belongs to the Special Issue Mitochondria at the Heart of Metabolic Disorders)

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20 pages, 3342 KiB

Open AccessArticle

Molecular Mechanisms Underlying TNFα-Induced Mitochondrial Biogenesis in Human Airway Smooth Muscle

by Debanjali Dasgupta, Sanjana Mahadev Bhat, Alexis L. Price, Philippe Delmotte and Gary C. Sieck

Int. J. Mol. Sci. 2023, 24(6), 5788; https://doi.org/10.3390/ijms24065788 - 17 Mar 2023

Cited by 8 | Viewed by 2179

Abstract

Proinflammatory cytokines such as TNFα mediate airway inflammation. Previously, we showed that TNFα increases mitochondrial biogenesis in human ASM (hASM) cells, which is associated with increased PGC1α expression. We hypothesized that TNFα induces CREB and ATF1 phosphorylation (pCREB^S133 and pATF1^S63), which transcriptionally co-activate PGC1α expression. Primary hASM cells were dissociated from bronchiolar tissue obtained from patients undergoing lung resection, cultured (one–three passages), and then differentiated by serum deprivation (48 h). hASM cells from the same patient were divided into two groups: TNFα (20 ng/mL) treated for 6 h and untreated controls. Mitochondria were labeled using MitoTracker green and imaged using 3D confocal microscopy to determine mitochondrial volume density. Mitochondrial biogenesis was assessed based on relative mitochondrial DNA (mtDNA) copy number determined by quantitative real-time PCR (qPCR). Gene and/or protein expression of pCREB^S133, pATF1^S63, PCG1α, and downstream signaling molecules (NRFs, TFAM) that regulate transcription and replication of the mitochondrial genome, were determined by qPCR and/or Western blot. TNFα increased mitochondrial volume density and mitochondrial biogenesis in hASM cells, which was associated with an increase in pCREB^S133, pATF1^S63 and PCG1α expression, with downstream transcriptional activation of NRF1, NRF2, and TFAM. We conclude that TNFα increases mitochondrial volume density in hASM cells via a pCREB^S133/pATF1^S63/PCG1α-mediated pathway. Full article

(This article belongs to the Special Issue Mitochondria at the Heart of Metabolic Disorders)

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10 pages, 2887 KiB

Open AccessCommunication

Exercise Induces an Augmented Skeletal Muscle Mitochondrial Unfolded Protein Response in a Mouse Model of Obesity Produced by a High-Fat Diet

by Pía Apablaza, Juan Carlos Bórquez, Rodrigo Mendoza, Mónica Silva, Gladys Tapia, Alejandra Espinosa, Rodrigo Troncoso, Luis A. Videla, Nevenka Juretić and Andrea del Campo

Int. J. Mol. Sci. 2023, 24(6), 5654; https://doi.org/10.3390/ijms24065654 - 16 Mar 2023

Cited by 2 | Viewed by 2024

Abstract

Increase in body fat contributes to loss of function and changes in skeletal muscle, accelerating sarcopenia, a phenomenon known as sarco-obesity or sarcopenic obesity. Studies suggest that obesity decreases the skeletal muscle (SM)’s ability to oxidize glucose, increases fatty acid oxidation and reactive oxygen species production, due to mitochondrial dysfunction. Exercise improves mitochondrial dysfunction in obesity; however, it is not known if exercise regulates the mitochondrial unfolded protein response (UPRmt) in the SM. Our study aimed to determine the mito-nuclear UPRmt in response to exercise in a model of obesity, and how this response is associated with the improvement in SM functioning after exercise training. C57BL/6 mice were fed a normal diet and high-fat diet (HFD) for 12 weeks. After 8 weeks, animals were subdivided into sedentary and exercised for the remaining 4 weeks. Grip strength and maximal velocity of mice submitted to HFD improved after training. Our results show an increase in the activation of UPRmt after exercise while in obese mice, proteostasis is basally decreased but shows a more pronounced increase with exercise. These results correlate with improvement in the circulating triglycerides, suggesting mitochondrial proteostasis could be protective and could be related to mitochondrial fuel utilization in SM. Full article

(This article belongs to the Special Issue Mitochondria at the Heart of Metabolic Disorders)

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20 pages, 5163 KiB

Open AccessArticle

Nicotinamide Mononucleotide Supplementation Improves Mitochondrial Dysfunction and Rescues Cellular Senescence by NAD⁺/Sirt3 Pathway in Mesenchymal Stem Cells

by Huan Wang, Yanan Sun, Chenchen Pi, Xiao Yu, Xingyu Gao, Chang Zhang, Hui Sun, Haiying Zhang, Yingai Shi and Xu He

Int. J. Mol. Sci. 2022, 23(23), 14739; https://doi.org/10.3390/ijms232314739 - 25 Nov 2022

Cited by 15 | Viewed by 4764

Abstract

In vitro expansion-mediated replicative senescence has severely limited the clinical applications of mesenchymal stem cells (MSCs). Accumulating studies manifested that nicotinamide adenine dinucleotide (NAD⁺) depletion is closely related to stem cell senescence and mitochondrial metabolism disorder. Promoting NAD⁺ level is considered as an effective way to delay aging. Previously, we have confirmed that nicotinamide mononucleotide (NMN), a precursor of NAD⁺, can alleviate NAD⁺ deficiency-induced MSC senescence. However, whether NMN can attenuate MSC senescence and its underlying mechanisms are still incompletely clear. The present study herein showed that late passage (LP) MSCs displayed lower NAD⁺ content, reduced Sirt3 expression and mitochondrial dysfunction. NMN supplementation leads to significant increase in intracellular NAD⁺ level, NAD⁺/ NADH ratio, Sirt3 expression, as well as ameliorated mitochondrial function and rescued senescent MSCs. Additionally, Sirt3 over-expression relieved mitochondrial dysfunction, and retrieved senescence-associated phenotypic features in LP MSCs. Conversely, inhibition of Sirt3 activity via a selective Sirt3 inhibitor 3-TYP in early passage (EP) MSCs resulted in aggravated cellular senescence and abnormal mitochondrial function. Furthermore, NMN administration also improves 3-TYP-induced disordered mitochondrial function and cellular senescence in EP MSCs. Collectively, NMN replenishment alleviates mitochondrial dysfunction and rescues MSC senescence through mediating NAD⁺/Sirt3 pathway, possibly providing a novel mechanism for MSC senescence and a promising strategy for anti-aging pharmaceuticals. Full article

(This article belongs to the Special Issue Mitochondria at the Heart of Metabolic Disorders)

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19 pages, 3451 KiB

Open AccessArticle

Quantitative Proteomics Analysis Reveals That Cyclooxygenase-2 Modulates Mitochondrial Respiratory Chain Complex IV in Cardiomyocytes

by Maria Soledad Alvarez, Estefanía Núñez, Marina Fuertes-Agudo, Carme Cucarella, Maria Fernandez-Velasco, Lisardo Boscá, Jesús Vázquez, Rodrigue Rossignol, Paloma Martin-Sanz and Marta Casado

Int. J. Mol. Sci. 2022, 23(21), 13476; https://doi.org/10.3390/ijms232113476 - 3 Nov 2022

Cited by 1 | Viewed by 1890

Abstract

The biochemical mechanisms of cell injury and myocardial cell death after myocardial infarction remain unresolved. Cyclooxygenase 2 (COX-2), a key enzyme in prostanoid synthesis, is expressed in human ischemic myocardium and dilated cardiomyopathy, but it is absent in healthy hearts. To assess the role of COX-2 in cardiovascular physiopathology, we developed transgenic mice that constitutively express functional human COX-2 in cardiomyocytes under the control of the α-myosin heavy chain promoter. These animals had no apparent phenotype but were protected against ischemia-reperfusion injury in isolated hearts, with enhanced functional recovery and diminished cellular necrosis. To further explore the phenotype of this animal model, we carried out a differential proteome analysis of wild-type vs. transgenic cardiomyocytes. The results revealed a tissue-specific proteomic profile dominated by mitochondrial proteins. In particular, an increased expression of respiratory chain complex IV proteins was observed. This correlated with increased catalytic activity, enhanced respiratory capacity, and increased ATP levels in the heart of COX-2 transgenic mice. These data suggest a new link between COX-2 and mitochondria, which might contribute to the protective cardiac effects of COX-2 against ischemia-reperfusion injury. Full article

(This article belongs to the Special Issue Mitochondria at the Heart of Metabolic Disorders)

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17 pages, 1794 KiB

Open AccessArticle

Cardiac Mitochondria Dysfunction in Dyslipidemic Mice

by Alicja Braczko, Barbara Kutryb-Zajac, Agata Jedrzejewska, Oliwia Krol, Paulina Mierzejewska, Magdalena Zabielska-Kaczorowska, Ewa M. Slominska and Ryszard T. Smolenski

Int. J. Mol. Sci. 2022, 23(19), 11488; https://doi.org/10.3390/ijms231911488 - 29 Sep 2022

Cited by 5 | Viewed by 2125

Abstract

Dyslipidemia triggers many severe pathologies, including atherosclerosis and chronic inflammation. Several lines of evidence, including our studies, have suggested direct effects of dyslipidemia on cardiac energy metabolism, but details of these effects are not clear. This study aimed to investigate how mild dyslipidemia affects cardiac mitochondria function and vascular nucleotide metabolism. The analyses were performed in 3- and 6-month-old knock-out mice for low-density lipoprotein receptor (Ldlr−/−) and compared to wild-type C57Bl/6J mice (WT). Cardiac isolated mitochondria function was analyzed using Seahorse metabolic flux analyzer. The mechanical function of the heart was measured using echocardiography. The levels of fusion, fission, and mitochondrial biogenesis proteins were determined by ELISA kits, while the cardiac intracellular nucleotide concentration and vascular pattern of nucleotide metabolism ecto-enzymes were analyzed using reverse-phase high-performance liquid chromatography. We revealed the downregulation of mitochondrial complex I, together with a decreased activity of citrate synthase (CS), reduced levels of nuclear respiratory factor 1 and mitochondrial fission 1 protein, as well as lower intracellular adenosine and guanosine triphosphates’ pool in the hearts of 6-month Ldlr−/− mice vs. age-matched WT. The analysis of vascular ecto-enzyme pattern revealed decreased rate of extracellular adenosine monophosphate hydrolysis and increased ecto-adenosine deaminase activity (eADA) in 6-month Ldlr−/− vs. WT mice. No changes were observed in echocardiography parameters in both age groups of Ldlr−/− mice. Younger hyperlipidemic mice revealed no differences in cardiac mitochondria function, CS activity, intracellular nucleotides, mitochondrial biogenesis, and dynamics but exhibited minor changes in vascular eADA activity vs. WT. This study revealed that dysfunction of cardiac mitochondria develops during prolonged mild hyperlipidemia at the time point corresponding to the formation of early vascular alterations. Full article

(This article belongs to the Special Issue Mitochondria at the Heart of Metabolic Disorders)

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19 pages, 1606 KiB

Open AccessReview

The Effects of Exercise Training on Mitochondrial Function in Cardiovascular Diseases: A Systematic Review and Meta-Analysis

by Ai Yin Lim, Yi-Ching Chen, Chih-Chin Hsu, Tieh-Cheng Fu and Jong-Shyan Wang

Int. J. Mol. Sci. 2022, 23(20), 12559; https://doi.org/10.3390/ijms232012559 - 19 Oct 2022

Cited by 7 | Viewed by 4169

Abstract

Mitochondria dysfunction is implicated in the pathogenesis of cardiovascular diseases (CVD). Exercise training is potentially an effective non-pharmacological strategy to restore mitochondrial health in CVD. However, how exercise modifies mitochondrial functionality is inconclusive. We conducted a systematic review using the PubMed; Scopus and Web of Science databases to investigate the effect of exercise training on mitochondrial function in CVD patients. Search terms included “mitochondria”, “exercise”, “aerobic capacity”, and “cardiovascular disease” in varied combination. The search yielded 821 records for abstract screening, of which 20 articles met the inclusion criteria. We summarized the effect of exercise training on mitochondrial morphology, biogenesis, dynamics, oxidative capacity, antioxidant capacity, and quality. Amongst these parameters, only oxidative capacity was suitable for a meta-analysis, which demonstrated a significant effect size of exercise in improving mitochondrial oxidative capacity in CVD patients (SMD = 4.78; CI = 2.99 to 6.57; p < 0.01), but with high heterogeneity among the studies (I² = 75%, p = 0.003). Notably, aerobic exercise enhanced succinate-involved oxidative phosphorylation. The majority of the results suggested that exercise improves morphology and biogenesis, whereas findings on dynamic, antioxidant capacity, and quality, were inadequate or inconclusive. A further randomized controlled trial is clearly required to explain how exercise modifies the pathway of mitochondrial quantity and quality in CVD patients. Full article

(This article belongs to the Special Issue Mitochondria at the Heart of Metabolic Disorders)

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20 pages, 928 KiB

Open AccessReview

Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease

by Raghu Ramanathan, Ahmad Hassan Ali and Jamal A. Ibdah

Int. J. Mol. Sci. 2022, 23(13), 7280; https://doi.org/10.3390/ijms23137280 - 30 Jun 2022

Cited by 49 | Viewed by 6973

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a global pandemic that affects one-quarter of the world’s population. NAFLD includes a spectrum of progressive liver disease from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis and can be complicated by hepatocellular carcinoma. It is strongly associated with metabolic syndromes, obesity, and type 2 diabetes, and it has been shown that metabolic dysregulation is central to its pathogenesis. Recently, it has been suggested that metabolic- (dysfunction) associated fatty liver disease (MAFLD) is a more appropriate term to describe the disease than NAFLD, which puts increased emphasis on the important role of metabolic dysfunction in its pathogenesis. There is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Impaired mitochondrial fatty acid oxidation and, more recently, a reduction in mitochondrial quality, have been suggested to play a major role in NAFLD development and progression. In this review, we provide an overview of our current understanding of NAFLD and highlight how mitochondrial dysfunction contributes to its pathogenesis in both animal models and human subjects. Further we discuss evidence that the modification of mitochondrial function modulates NAFLD and that targeting mitochondria is a promising new avenue for drug development to treat NAFLD/NASH. Full article

(This article belongs to the Special Issue Mitochondria at the Heart of Metabolic Disorders)

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