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Mitochondria: The Diseases' Cause and Cure
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Mitochondria: The Diseases' Cause and Cure

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Biochemistry and Molecular Biology".

Deadline for manuscript submissions: 30 November 2024 | Viewed by 14624

Special Issue Editors

Dr. Susana P. Pereira

E-Mail Website
Guest Editor
1. Laboratory of Metabolism and Exercise (LaMetEx), Research Center in Physical Activity, Health and Leisure (CIAFEL) and Laboratory for Integrative and Translational Research in Population Health (ITR), Faculty of Sports, University of Porto (FADEUP), 4200-450 Porto, Portugal
2. CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
3. IIIUC - Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
Interests: maternal nutrient reduction; fetal cardiac mitochondrial biology; fetal energy metabolism; utero; early life; metabolism; modulates diseases risk
Dr. Ludgero C. Tavares

E-Mail Website
Guest Editor
CIVG - Vasco da Gama Research Center, University School Vasco da Gama - EUVG, 3020-210 Coimbra, Portugal
Interests: metabolism; bioenergetics; nutrition; core metabolic pathways; nuclear magnetic resonance techniques; oncology; toxicology; hepatology; aquaculture; carbohydrate; lipid metabolism; pentose phosphate pathway (PPP)

Special Issue Information

Dear Colleagues,

Mitochondria plays a pivotal role in signaling, homeostasis and energy metabolism. Inherited mitochondrial diseases trigger major metabolic disruptions that may result in severe health impairments or even death. Nevertheless, the occurrence of inherited mitochondrial diseases is extremely rare and cannot justify most metabolic diseases. However, transient or chronic mitochondrial dysfunctions are fairly more common, as they can be caused by several factors or achieved (directly or indirectly) through a broad range of signaling pathways. In fact, reduced mitochondrial performance has been linked to and anticipated in the pathophysiology of several diseases, such as obesity, type 2 diabetes mellitus, cardiovascular diseases, hepatic and neurological disorders, cancer, and accelerated aging. Thus, recent research has begun to focus on mitochondria not only from the viewpoint of the disease mechanism and etiology but also as an ally for novel and/or improved therapeutic approaches. Several works describe the modulation of mitochondrial function in response to dietary approaches, exercise, and targeted and non-targeted compounds/drugs, rendering mitochondrial biology a central hub in the fate of disease progression.

This Special Issue aims to highlight state-of-the-art accomplishments regarding the role of mitochondria under pathophysiological conditions in various cells/animal models or human patients. We hope to foster the discussion of different approaches to modulate mitochondrial function and metabolism and lay new avenues in mitochondrial-targeted therapeutics. We kindly invite you to contribute to this Special Issue, providing novel scientific insights or sharing critical reviews that nurture new ideas into mitochondrial biology and how it drives metabolism under health and disease conditions or manuscripts on mitochondria as a promising target for metabolic modulation and treatment of a wide range of human pathological conditions.

Dr. Susana P. Pereira
Dr. Ludgero C. Tavares
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. Biology is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • pathology and clinical aspects of mitochondrial diseases

  • mitochondrial biology
  • metabolism
  • bioenergetic
  • biochemistry
  • energy production
  • disease
  • treatment
  • prevention
  • pharmacology

Published Papers (7 papers)

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Research

Jump to: Review

19 pages, 5932 KiB  
Article
Formoterol Acting via β2-Adrenoreceptor Restores Mitochondrial Dysfunction Caused by Parkinson’s Disease-Related UQCRC1 Mutation and Improves Mitochondrial Homeostasis Including Dynamic and Transport
by Jui-Chih Chang, Huei-Shin Chang, Yi-Chun Chao, Ching-Shan Huang, Chin-Hsien Lin, Zhong-Sheng Wu, Hui-Ju Chang, Chin-San Liu and Chieh-Sen Chuang
Biology 2024, 13(4), 231; https://doi.org/10.3390/biology13040231 - 30 Mar 2024
Viewed by 1017
Abstract
Formoterol, a β2-adrenergic receptor (β2AR) agonist, shows promise in various diseases, but its effectiveness in Parkinson’s disease (PD) is debated, with unclear regulation of mitochondrial homeostasis. This study employed a cell model featuring mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) variants associated [...] Read more.
Formoterol, a β2-adrenergic receptor (β2AR) agonist, shows promise in various diseases, but its effectiveness in Parkinson’s disease (PD) is debated, with unclear regulation of mitochondrial homeostasis. This study employed a cell model featuring mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) variants associated with familial parkinsonism, demonstrating mitochondrial dysfunction and dynamic imbalance, exploring the therapeutic effects and underlying mechanisms of formoterol. Results revealed that 24-h formoterol treatment enhanced cell proliferation, viability, and neuroprotection against oxidative stress. Mitochondrial function, encompassing DNA copy number, repatriation, and complex III-linked respiration, was comprehensively restored, along with the dynamic rebalance of fusion/fission events. Formoterol reduced extensive hypertubulation, in contrast to mitophagy, by significantly upregulating protein Drp-1, in contrast to fusion protein Mfn2, mitophagy-related protein Parkin. The upstream mechanism involved the restoration of ERK signaling and the inhibition of Akt overactivity, contingent on the activation of β2-adrenergic receptors. Formoterol additionally aided in segregating healthy mitochondria for distribution and transport, therefore normalizing mitochondrial arrangement in mutant cells. This study provides preliminary evidence that formoterol offers neuroprotection, acting as a mitochondrial dynamic balance regulator, making it a promising therapeutic candidate for PD. Full article
(This article belongs to the Special Issue Mitochondria: The Diseases' Cause and Cure)
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0 pages, 5331 KiB  
Article
The Cardiometabolic Impact of Rebaudioside A Exposure during the Reproductive Stage
by Isabella Bracchi, Juliana Morais, João Almeida Coelho, Ana Filipa Ferreira, Inês Alves, Cláudia Mendes, Beatriz Correia, Alexandre Gonçalves, João Tiago Guimarães, Inês Falcão-Pires, Elisa Keating and Rita Negrão
Biology 2024, 13(3), 163; https://doi.org/10.3390/biology13030163 - 2 Mar 2024
Viewed by 1442
Abstract
The consumption of non-sugar sweeteners (NSS) has increased during pregnancy. The European Food Safety Agency suggested that steviol glycosides, such as Rebaudioside A (RebA), the major sweetener component of stevia, are safe for humans up to a dose of 4 mg/kg body weight/day. [...] Read more.
The consumption of non-sugar sweeteners (NSS) has increased during pregnancy. The European Food Safety Agency suggested that steviol glycosides, such as Rebaudioside A (RebA), the major sweetener component of stevia, are safe for humans up to a dose of 4 mg/kg body weight/day. However, the World Health Organization recommended in 2023 the restraint of using NSS, including stevia, at any life stage, highlighting the need to study NSS safety in early periods of development. We aimed to study the mitochondrial and cardiometabolic effects of long-term RebA consumption during the reproductive stage of the life cycle. Female rats were exposed to RebA (4 mg steviol equivalents/kg body weight/day) in the drinking water from 4 weeks before mating until weaning. Morphometry, food and water consumption, glucose and lipid homeostasis, heart structure, function, and mitochondrial function were assessed. RebA showed an atrophic effect in the heart, decreasing cardiomyocyte cross-sectional area and myocardial fibrosis without repercussions on cardiac function. Mitochondrial and myofilamentary functions were not altered. Glucose tolerance and insulin sensitivity were not affected, but fasting glycemia and total plasma cholesterol decreased. This work suggests that this RebA dose is safe for female consumption during the reproductive stage, from a cardiometabolic perspective. However, studies on the effects of RebA exposure on the offspring are mandatory. Full article
(This article belongs to the Special Issue Mitochondria: The Diseases' Cause and Cure)
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23 pages, 3124 KiB  
Article
Phenotypic Characterization of Female Carrier Mice Heterozygous for Tafazzin Deletion
by Michelle V. Tomczewski, John Z. Chan, Duaa M. Al-Majmaie, Ming Rong Liu, Alex D. Cocco, Ken D. Stark, Douglas Strathdee and Robin E. Duncan
Biology 2023, 12(9), 1238; https://doi.org/10.3390/biology12091238 - 14 Sep 2023
Viewed by 1080
Abstract
Barth syndrome (BTHS) is caused by mutations in tafazzin resulting in deficits in cardiolipin remodeling that alter major metabolic processes. The tafazzin gene is encoded on the X chromosome, and therefore BTHS primarily affects males. Female carriers are typically considered asymptomatic, but age-related [...] Read more.
Barth syndrome (BTHS) is caused by mutations in tafazzin resulting in deficits in cardiolipin remodeling that alter major metabolic processes. The tafazzin gene is encoded on the X chromosome, and therefore BTHS primarily affects males. Female carriers are typically considered asymptomatic, but age-related changes have been reported in female carriers of other X-linked disorders. Therefore, we examined the phenotype of female mice heterozygous for deletion of the tafazzin gene (Taz-HET) at 3 and 12 months of age. Food intakes, body masses, lean tissue and adipose depot weights, daily activity levels, metabolic measures, and exercise capacity were assessed. Age-related changes in mice resulted in small but significant genotype-specific differences in Taz-HET mice compared with their female Wt littermates. By 12 months, Taz-HET mice weighed less than Wt controls and had smaller gonadal, retroperitoneal, and brown adipose depots and liver and brain masses, despite similar food consumption. Daily movement, respiratory exchange ratio, and total energy expenditure did not vary significantly between the age-matched genotypes. Taz-HET mice displayed improved glucose tolerance and insulin sensitivity at 12 months compared with their Wt littermates but had evidence of slightly reduced exercise capacity. Tafazzin mRNA levels were significantly reduced in the cardiac muscle of 12-month-old Taz-HET mice, which was associated with minor but significant alterations in the heart cardiolipin profile. This work is the first to report the characterization of a model of female carriers of heterozygous tafazzin deficiency and suggests that additional study, particularly with advancing age, is warranted. Full article
(This article belongs to the Special Issue Mitochondria: The Diseases' Cause and Cure)
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22 pages, 12937 KiB  
Article
Maternal Obesity Programs the Premature Aging of Rat Offspring Liver Mitochondrial Electron Transport Chain Genes in a Sex-Dependent Manner
by Consuelo Lomas-Soria, Guadalupe L. Rodríguez-González, Carlos A. Ibáñez, Luis A. Reyes-Castro, Peter W. Nathanielsz and Elena Zambrano
Biology 2023, 12(9), 1166; https://doi.org/10.3390/biology12091166 - 24 Aug 2023
Viewed by 1236
Abstract
We investigated whether maternal obesity affects the hepatic mitochondrial electron transport chain (ETC), sirtuins, and antioxidant enzymes in young (110 postnatal days (PND)) and old (650PND) male and female offspring in a sex- and age-related manner. Female Wistar rats ate a control (C) [...] Read more.
We investigated whether maternal obesity affects the hepatic mitochondrial electron transport chain (ETC), sirtuins, and antioxidant enzymes in young (110 postnatal days (PND)) and old (650PND) male and female offspring in a sex- and age-related manner. Female Wistar rats ate a control (C) or high-fat (MO) diet from weaning, through pregnancy and lactation. After weaning, the offspring ate the C diet and were euthanized at 110 and 650PND. The livers were collected for RNA-seq and immunohistochemistry. Male offspring livers had more differentially expressed genes (DEGs) down-regulated by both MO and natural aging than females. C-650PND vs. C-110PND and MO-110PND vs. C-110PND comparisons revealed 1477 DEGs in common for males (premature aging by MO) and 35 DEGs for females. Analysis to identify KEGG pathways enriched from genes in common showed changes in 511 and 3 KEGG pathways in the male and female livers, respectively. Mitochondrial function pathways showed ETC-related gene down-regulation. All ETC complexes, sirtuin2, sirtuin3, sod-1, and catalase, exhibited gene down-regulation and decreased protein expression at young and old ages in MO males vs. C males; meanwhile, MO females down-regulated only at 650PND. Conclusions: MO accelerates the age-associated down-regulation of ETC pathway gene expression in male offspring livers, thereby causing sex-dependent oxidative stress, premature aging, and metabolic dysfunction. Full article
(This article belongs to the Special Issue Mitochondria: The Diseases' Cause and Cure)
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Review

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34 pages, 2016 KiB  
Review
Mitochondrial Dysfunction in Endothelial Progenitor Cells: Unraveling Insights from Vascular Endothelial Cells
by Azra Kulovic-Sissawo, Carolina Tocantins, Mariana S. Diniz, Elisa Weiss, Andreas Steiner, Silvija Tokic, Corina T. Madreiter-Sokolowski, Susana P. Pereira and Ursula Hiden
Biology 2024, 13(2), 70; https://doi.org/10.3390/biology13020070 - 23 Jan 2024
Viewed by 2058
Abstract
Endothelial dysfunction is associated with several lifestyle-related diseases, including cardiovascular and neurodegenerative diseases, and it contributes significantly to the global health burden. Recent research indicates a link between cardiovascular risk factors (CVRFs), excessive production of reactive oxygen species (ROS), mitochondrial impairment, and endothelial [...] Read more.
Endothelial dysfunction is associated with several lifestyle-related diseases, including cardiovascular and neurodegenerative diseases, and it contributes significantly to the global health burden. Recent research indicates a link between cardiovascular risk factors (CVRFs), excessive production of reactive oxygen species (ROS), mitochondrial impairment, and endothelial dysfunction. Circulating endothelial progenitor cells (EPCs) are recruited into the vessel wall to maintain appropriate endothelial function, repair, and angiogenesis. After attachment, EPCs differentiate into mature endothelial cells (ECs). Like ECs, EPCs are also susceptible to CVRFs, including metabolic dysfunction and chronic inflammation. Therefore, mitochondrial dysfunction of EPCs may have long-term effects on the function of the mature ECs into which EPCs differentiate, particularly in the presence of endothelial damage. However, a link between CVRFs and impaired mitochondrial function in EPCs has hardly been investigated. In this review, we aim to consolidate existing knowledge on the development of mitochondrial and endothelial dysfunction in the vascular endothelium, place it in the context of recent studies investigating the consequences of CVRFs on EPCs, and discuss the role of mitochondrial dysfunction. Thus, we aim to gain a comprehensive understanding of mechanisms involved in EPC deterioration in relation to CVRFs and address potential therapeutic interventions targeting mitochondrial health to promote endothelial function. Full article
(This article belongs to the Special Issue Mitochondria: The Diseases' Cause and Cure)
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22 pages, 2027 KiB  
Review
Mitochondria Quality Control and Male Fertility
by José Costa, Patrícia C. Braga, Irene Rebelo, Pedro F. Oliveira and Marco G. Alves
Biology 2023, 12(6), 827; https://doi.org/10.3390/biology12060827 - 6 Jun 2023
Cited by 16 | Viewed by 3928
Abstract
Mitochondria are pivotal to cellular homeostasis, performing vital functions such as bioenergetics, biosynthesis, and cell signalling. Proper maintenance of these processes is crucial to prevent disease development and ensure optimal cell function. Mitochondrial dynamics, including fission, fusion, biogenesis, mitophagy, and apoptosis, maintain mitochondrial [...] Read more.
Mitochondria are pivotal to cellular homeostasis, performing vital functions such as bioenergetics, biosynthesis, and cell signalling. Proper maintenance of these processes is crucial to prevent disease development and ensure optimal cell function. Mitochondrial dynamics, including fission, fusion, biogenesis, mitophagy, and apoptosis, maintain mitochondrial quality control, which is essential for overall cell health. In male reproduction, mitochondria play a pivotal role in germ cell development and any defects in mitochondrial quality can have serious consequences on male fertility. Reactive oxygen species (ROS) also play a crucial role in sperm capacitation, but excessive ROS levels can trigger oxidative damage. Any imbalance between ROS and sperm quality control, caused by non-communicable diseases or environmental factors, can lead to an increase in oxidative stress, cell damage, and apoptosis, which in turn affect sperm concentration, quality, and motility. Therefore, assessing mitochondrial functionality and quality control is essential to gain valuable insights into male infertility. In sum, proper mitochondrial functionality is essential for overall health, and particularly important for male fertility. The assessment of mitochondrial functionality and quality control can provide crucial information for the study and management of male infertility and may lead to the development of new strategies for its management. Full article
(This article belongs to the Special Issue Mitochondria: The Diseases' Cause and Cure)
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21 pages, 2965 KiB  
Review
From Non-Alcoholic Fatty Liver to Hepatocellular Carcinoma: A Story of (Mal)Adapted Mitochondria
by Ricardo Amorim, Carina C. Magalhães, Fernanda Borges, Paulo J. Oliveira and José Teixeira
Biology 2023, 12(4), 595; https://doi.org/10.3390/biology12040595 - 14 Apr 2023
Cited by 7 | Viewed by 2959
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a global pandemic affecting 25% of the world’s population and is a serious health and economic concern worldwide. NAFLD is mainly the result of unhealthy dietary habits combined with sedentary lifestyle, although some genetic contributions to NAFLD [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a global pandemic affecting 25% of the world’s population and is a serious health and economic concern worldwide. NAFLD is mainly the result of unhealthy dietary habits combined with sedentary lifestyle, although some genetic contributions to NAFLD have been documented. NAFLD is characterized by the excessive accumulation of triglycerides (TGs) in hepatocytes and encompasses a spectrum of chronic liver abnormalities, ranging from simple steatosis (NAFL) to steatohepatitis (NASH), significant liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although the molecular mechanisms that cause the progression of steatosis to severe liver damage are not fully understood, metabolic-dysfunction-associated fatty liver disease is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Mitochondria are highly dynamic organelles that undergo functional and structural adaptations to meet the metabolic requirements of the cell. Alterations in nutrient availability or cellular energy needs can modify mitochondria formation through biogenesis or the opposite processes of fission and fusion and fragmentation. In NAFL, simple steatosis can be seen as an adaptive response to storing lipotoxic free fatty acids (FFAs) as inert TGs due to chronic perturbation in lipid metabolism and lipotoxic insults. However, when liver hepatocytes’ adaptive mechanisms are overburdened, lipotoxicity occurs, contributing to reactive oxygen species (ROS) formation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Impaired mitochondrial fatty acid oxidation, reduction in mitochondrial quality, and disrupted mitochondrial function are associated with a decrease in the energy levels and impaired redox balance and negatively affect mitochondria hepatocyte tolerance towards damaging hits. However, the sequence of events underlying mitochondrial failure from steatosis to hepatocarcinoma is still yet to be fully clarified. This review provides an overview of our understanding of mitochondrial adaptation in initial NAFLD stages and highlights how hepatic mitochondrial dysfunction and heterogeneity contribute to disease pathophysiology progression, from steatosis to hepatocellular carcinoma. Improving our understanding of different aspects of hepatocytes’ mitochondrial physiology in the context of disease development and progression is crucial to improving diagnosis, management, and therapy of NAFLD/NASH. Full article
(This article belongs to the Special Issue Mitochondria: The Diseases' Cause and Cure)
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