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New Insights into the Role of Mitochondrial Dysfunction in Diseases

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Endocrinology & Metabolism".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 29707

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Special Issue Editors

Dr. Antonella Cormio

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Guest Editor

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy
Interests: mitochondrial biogenesis; mitochondrial dynamics; mithophagy, mtDNA alterations; mitochondrial proteases, mitochondrial dysfunctions in bladder cancer, mitochondrial dysfunctions in endometrial cancer, mitochondrial dysfunctions in ovarian cancer

Dr. Clara Musicco

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Guest Editor

CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), 70126 Bari, Italy
Interests: mitochondrial proteome in aging; muscle unloading; cancer; mitochondrial biogenesis; mitochondrial antioxidant proteins; mitochondrial DNA-binding proteins; mitochondrial dynamics; metabolomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria are essential organelles in all eukaryotic cells. They provide ATP via the oxidative phosphorylation system, thus functioning as the fulcrum of metabolic pathways, primary sources of reactive oxygen species (ROS), buffers of intracellular calcium, and regulators of apoptosis as well as of signal transduction.

To ensure maximal mitochondrial function, mitochondrial quality control systems protect mitochondria from damage at the protein and DNA level by activating antioxidant systems, mitochondrial proteases, and mtDNA repair machinery. Moreover, at the organelle level, damaged mitochondria are removed through mitophagy and functional mitochondria are maintained through enhancing mitochondrial biogenesis and modulating mitochondrial dynamics.

A flaw in these systems may lead to mitochondrial dysfunctions such as mtDNA alterations (mutations and altered mtDNA content), mitochondrial respiratory chain activity defects, and altered mitochondrial morphology.

The aim of this Special Issue is to collect novel findings in the field of mitochondrial dysfunctions in diseases including but not limited to cancer, neurodegenerative disorders, and diabetes.

We cordially invite scientists involved in base research as well as in translational studies to submit their original researches or review manuscripts to this Special Issue.

Dr. Antonella Cormio
Dr. Clara Musicco
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. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly 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 2600 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

MtDNA alterations (deletions, point mutations, and mtDNA copy number)
Mitochondrial biogenesis
Mitochondrial respiration
Mitophagy
Mitochondrial dynamics
Mitochondrial antioxidant systems
Mitochondrial proteases
Alteration of mitochondrial proteome
mtDNA repair machinery
Cancer
Neurodegenerative diseases
Mitochondrial diseases
Diabetes

Published Papers (7 papers)

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Research

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21 pages, 7621 KiB

Open AccessArticle

Impaired Mitochondrial Morphology and Functionality in Lonp1^wt/− Mice

by Anna De Gaetano, Lara Gibellini, Elena Bianchini, Rebecca Borella, Sara De Biasi, Milena Nasi, Federica Boraldi, Andrea Cossarizza and Marcello Pinti

J. Clin. Med. 2020, 9(6), 1783; https://doi.org/10.3390/jcm9061783 - 08 Jun 2020

Cited by 11 | Viewed by 3294

Abstract

LONP1 is a nuclear-encoded mitochondrial protease crucial for organelle homeostasis; mutations of LONP1 have been associated with Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies (CODAS) syndrome. To clarify the role of LONP1 in vivo, we generated a mouse model in which Lonp1 was ablated. The homozygous Lonp^−/− mouse was not vital, while the heterozygous Lonp1^wt/− showed similar growth rate, weight, length, life-span and histologic features as wild type. Conversely, ultrastructural analysis of heterozygous enterocytes evidenced profound morphological alterations of mitochondria, which appeared increased in number, swollen and larger, with a lower complexity. Embryonic fibroblasts (MEFs) from Lonp1^wt/− mice showed a reduced expression of Lonp1 and Tfam, whose expression is regulated by LONP1. Mitochondrial DNA was also reduced, and mitochondria were swollen and larger, albeit at a lesser extent than enterocytes, with a perinuclear distribution. From the functional point of view, mitochondria from heterozygous MEF showed a lower oxygen consumption rate in basal conditions, either in the presence of glucose or galactose, and a reduced expression of mitochondrial complexes than wild type. In conclusion, the presence of one functional copy of the Lonp1 gene leads to impairment of mitochondrial ultrastructure and functions in vivo. Full article

(This article belongs to the Special Issue New Insights into the Role of Mitochondrial Dysfunction in Diseases)

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19 pages, 3815 KiB

Open AccessArticle

The Anti-Diabetic Drug Metformin Rescues Aberrant Mitochondrial Activity and Restrains Oxidative Stress in a Female Mouse Model of Rett Syndrome

by Ilaria Zuliani, Chiara Urbinati, Daniela Valenti, Maria Cristina Quattrini, Vanessa Medici, Livia Cosentino, Donatella Pietraforte, Fabio Di Domenico, Marzia Perluigi, Rosa Anna Vacca and Bianca De Filippis

J. Clin. Med. 2020, 9(6), 1669; https://doi.org/10.3390/jcm9061669 - 01 Jun 2020

Cited by 15 | Viewed by 3528

Abstract

Metformin is the first-line therapy for diabetes, even in children, and a promising attractive candidate for drug repurposing. Mitochondria are emerging as crucial targets of metformin action both in the periphery and in the brain. The present study evaluated whether treatment with metformin may rescue brain mitochondrial alterations and contrast the increased oxidative stress in a validated mouse model of Rett syndrome (RTT), a rare neurologic disorder of monogenic origin characterized by severe behavioral and physiological symptoms. No cure for RTT is available. In fully symptomatic RTT mice (12 months old MeCP2-308 heterozygous female mice), systemic treatment with metformin (100 mg/kg ip for 10 days) normalized the reduced mitochondrial ATP production and ATP levels in the whole-brain, reduced brain oxidative damage, and rescued the increased production of reactive oxidizing species in blood. A 10-day long treatment with metformin also boosted pathways related to mitochondrial biogenesis and antioxidant defense in the brain of metformin-treated RTT mice. This treatment regimen did not improve general health status and motor dysfunction in RTT mice at an advanced stage of the disease. Present results provide evidence that systemic treatment with metformin may represent a novel, repurposable therapeutic strategy for RTT. Full article

(This article belongs to the Special Issue New Insights into the Role of Mitochondrial Dysfunction in Diseases)

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18 pages, 1459 KiB

Open AccessArticle

Mitochondrial Dysfunction: A Common Hallmark Underlying Comorbidity between sIBM and Other Degenerative and Age-Related Diseases

by Marc Catalán-García, Francesc Josep García-García, Pedro J. Moreno-Lozano, Gema Alcarraz-Vizán, Adrià Tort-Merino, José César Milisenda, Judith Cantó-Santos, Tamara Barcos-Rodríguez, Francesc Cardellach, Albert Lladó, Anna Novials, Glòria Garrabou and Josep M. Grau-Junyent

J. Clin. Med. 2020, 9(5), 1446; https://doi.org/10.3390/jcm9051446 - 13 May 2020

Cited by 4 | Viewed by 2838

Abstract

Sporadic inclusion body myositis (sIBM) is an inflammatory myopathy associated, among others, with mitochondrial dysfunction. Similar molecular features are found in Alzheimer’s disease (AD) and Type 2 Diabetes Mellitus (T2DM), underlying potential comorbidity. This study aims to evaluate common clinical and molecular hallmarks among sIBM, AD, and T2DM. Comorbidity with AD was assessed in n = 14 sIBM patients by performing neuropsychological and cognitive tests, cranial magnetic resonance imaging, AD cerebrospinal fluid biomarkers (levels of amyloid beta, total tau, and phosphorylated tau at threonine-181), and genetic apolipoprotein E genotyping. In the same sIBM cohort, comorbidity with T2DM was assessed by collecting anthropometric measures and performing an oral glucose tolerance test and insulin determinations. Results were compared to the standard population and other myositis (n = 7 dermatomyositis and n = 7 polymyositis). Mitochondrial contribution into disease was tested by measurement of oxidative/anaerobic and oxidant/antioxidant balances, respiration fluxes, and enzymatic activities in sIBM fibroblasts subjected to different glucose levels. Comorbidity of sIBM with AD was not detected. Clinically, sIBM patients showed signs of misbalanced glucose homeostasis, similar to other myositis. Such misbalance was further confirmed at the molecular level by the metabolic inability of sIBM fibroblasts to adapt to different glucose conditions. Under the standard condition, sIBM fibroblasts showed decreased respiration (0.71 ± 0.08 vs. 1.06 ± 0.04 nmols O₂/min; p = 0.024) and increased anaerobic metabolism (5.76 ± 0.52 vs. 3.79 ± 0.35 mM lactate; p = 0.052). Moreover, when glucose conditions were changed, sIBM fibroblasts presented decreased fold change in mitochondrial enzymatic activities (−12.13 ± 21.86 vs. 199.22 ± 62.52 cytochrome c oxidase/citrate synthase ratio; p = 0.017) and increased oxidative stress per mitochondrial activity (203.76 ± 82.77 vs. −69.55 ± 21.00; p = 0.047), underlying scarce metabolic plasticity. These findings do not demonstrate higher prevalence of AD in sIBM patients, but evidences of prediabetogenic conditions were found. Glucose deregulation in myositis suggests the contribution of lifestyle conditions, such as restricted mobility. Additionally, molecular evidences from sIBM fibroblasts confirm that mitochondrial dysfunction may play a role. Monitoring T2DM development and mitochondrial contribution to disease in myositis patients could set a path for novel therapeutic options. Full article

(This article belongs to the Special Issue New Insights into the Role of Mitochondrial Dysfunction in Diseases)

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11 pages, 600 KiB

Open AccessCommunication

Altered Sphingolipids Metabolism Damaged Mitochondrial Functions: Lessons Learned From Gaucher and Fabry Diseases

by Margarita Ivanova

J. Clin. Med. 2020, 9(4), 1116; https://doi.org/10.3390/jcm9041116 - 14 Apr 2020

Cited by 27 | Viewed by 4583

Abstract

Sphingolipids represent a class of bioactive lipids that modulate the biophysical properties of biological membranes and play a critical role in cell signal transduction. Multiple studies have demonstrated that sphingolipids control crucial cellular functions such as the cell cycle, senescence, autophagy, apoptosis, cell migration, and inflammation. Sphingolipid metabolism is highly compartmentalized within the subcellular locations. However, the majority of steps of sphingolipids metabolism occur in lysosomes. Altered sphingolipid metabolism with an accumulation of undigested substrates in lysosomes due to lysosomal enzyme deficiency is linked to lysosomal storage disorders (LSD). Trapping of sphingolipids and their metabolites in the lysosomes inhibits lipid recycling, which has a direct effect on the lipid composition of cellular membranes, including the inner mitochondrial membrane. Additionally, lysosomes are not only the house of digestive enzymes, but are also responsible for trafficking organelles, sensing nutrients, and repairing mitochondria. However, lysosomal abnormalities lead to alteration of autophagy and disturb the energy balance and mitochondrial function. In this review, an overview of mitochondrial function in cells with altered sphingolipid metabolism will be discussed focusing on the two most common sphingolipid disorders, Gaucher and Fabry diseases. The review highlights the status of mitochondrial energy metabolism and the regulation of mitochondria–autophagy–lysosome crosstalk. Full article

(This article belongs to the Special Issue New Insights into the Role of Mitochondrial Dysfunction in Diseases)

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15 pages, 3228 KiB

Open AccessArticle

Preeclampsia with Intrauterine Growth Restriction Generates Morphological Changes in Endothelial Cells Associated with Mitochondrial Swelling—An In Vitro Study

by Dorota Formanowicz, Agnieszka Malińska, Marcin Nowicki, Katarzyna Kowalska, Karolina Gruca-Stryjak, Grzegorz Bręborowicz and Katarzyna Korybalska

J. Clin. Med. 2019, 8(11), 1994; https://doi.org/10.3390/jcm8111994 - 15 Nov 2019

Cited by 11 | Viewed by 2794

Abstract

Pregnancy complicated by preeclampsia (PE) and intrauterine growth restriction (IUGR) promotes endothelial cell (EC) dysfunction. Our in vitro study aimed to evaluate the endothelial cell morphology after acute and chronic exposition to medium supplemented with serum taken from healthy pregnant women and women with IUGR and IUGR with PE. In the same condition, ECs viability, proliferation, reactive oxygen species (ROS) production, and serum concentration of vascular endothelial growth factor (VEGF) were also measured. Pregnant women with IUGR and IUGR with PE-delivered babies with reduced body mass and were characterized in elevated blood pressure, urine protein loss, and reduced level of VEGF. The 24 hours of exposition did not exert any morphological changes in ECs, except the reduction in cell viability, but prolonged exposition resulted in significant morphological changes concerning mostly the swelling of mitochondria with accompanying ROS production, cell autophagy, reduced cell viability, and proliferation only in complicated pregnancies. In conclusion, the sera taken from women with IUGR and IUGR with PE show a detrimental effect on ECs, reducing their viability, proliferation, and generating oxidative stress due to dysfunctional mitochondria. This multidirectional effect might have an adverse impact on the cardiovascular system in women with IUGR and PE. Full article

(This article belongs to the Special Issue New Insights into the Role of Mitochondrial Dysfunction in Diseases)

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Review

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22 pages, 1019 KiB

Open AccessReview

Generation and Release of Mitochondrial-Derived Vesicles in Health, Aging and Disease

by Anna Picca, Flora Guerra, Riccardo Calvani, Hélio José Coelho-Junior, Maurizio Bossola, Francesco Landi, Roberto Bernabei, Cecilia Bucci and Emanuele Marzetti

J. Clin. Med. 2020, 9(5), 1440; https://doi.org/10.3390/jcm9051440 - 12 May 2020

Cited by 50 | Viewed by 8259

Abstract

Mitochondria are intracellular organelles involved in a myriad of activities. To safeguard their vital functions, mitochondrial quality control (MQC) systems are in place to support organelle plasticity as well as physical and functional connections with other cellular compartments. In particular, mitochondrial interactions with the endosomal compartment support the shuttle of ions and metabolites across organelles, while those with lysosomes ensure the recycling of obsolete materials. The extrusion of mitochondrial components via the generation and release of mitochondrial-derived vesicles (MDVs) has recently been described. MDV trafficking is now included among MQC pathways, possibly operating via mitochondrial–lysosomal contacts. Since mitochondrial dysfunction is acknowledged as a hallmark of aging and a major pathogenic factor of multiple age-associated conditions, the analysis of MDVs and, more generally, of extracellular vesicles (EVs) is recognized as a valuable research tool. The dissection of EV trafficking may help unravel new pathophysiological pathways of aging and diseases as well as novel biomarkers to be used in research and clinical settings. Here, we discuss (1) MQC pathways with a focus on mitophagy and MDV generation; (2) changes of MQC pathways during aging and their contribution to inflamm-aging and progeroid conditions; and (3) the relevance of MQC failure to several disorders, including neurodegenerative conditions (i.e., Parkinson’s disease, Alzheimer’s disease) and cardiovascular disease. Full article

(This article belongs to the Special Issue New Insights into the Role of Mitochondrial Dysfunction in Diseases)

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20 pages, 1752 KiB

Open AccessReview

New Insights into the Implication of Mitochondrial Dysfunction in Tissue, Peripheral Blood Mononuclear Cells, and Platelets during Lung Diseases

by Marianne Riou, Abrar Alfatni, Anne-Laure Charles, Emmanuel Andrès, Cristina Pistea, Anne Charloux and Bernard Geny

J. Clin. Med. 2020, 9(5), 1253; https://doi.org/10.3390/jcm9051253 - 26 Apr 2020

Cited by 11 | Viewed by 3841

Abstract

Lung diseases such as chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, or idiopathic pulmonary fibrosis are major causes of morbidity and mortality. Complex, their physiopathology is multifactorial and includes lung mitochondrial dysfunction and enhanced reactive oxygen species (ROS) release, which deserves increased attention. Further, and importantly, circulating blood cells (peripheral blood mononuclear cells-(PBMCs) and platelets) likely participate in these systemic diseases. This review presents the data published so far and shows that circulating blood cells mitochondrial oxidative capacity are likely to be reduced in chronic obstructive pulmonary disease (COPD), but enhanced in asthma and pulmonary arterial hypertension in a context of increased oxidative stress. Besides such PBMCs or platelets bioenergetics modifications, mitochondrial DNA (mtDNA) changes have also been observed in patients. These new insights open exciting challenges to determine their role as biomarkers or potential guide to a new therapeutic approach in lung diseases. Full article

(This article belongs to the Special Issue New Insights into the Role of Mitochondrial Dysfunction in Diseases)

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