Journal of Clinical Medicine

Editorial

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8 pages, 375 KiB

Open AccessEditorial

Mitochondria at the Crossroads of Physiology and Pathology

by Loredana Moro

J. Clin. Med. 2020, 9(6), 1971; https://doi.org/10.3390/jcm9061971 - 24 Jun 2020

Cited by 17 | Viewed by 3828

Abstract

Mitochondria play a crucial role in cell life and death by regulating bioenergetic and biosynthetic pathways. They are able to adapt rapidly to different microenvironmental stressors by accommodating the metabolic and biosynthetic needs of the cell. Mounting evidence places mitochondrial dysfunction at the [...] Read more.

Mitochondria play a crucial role in cell life and death by regulating bioenergetic and biosynthetic pathways. They are able to adapt rapidly to different microenvironmental stressors by accommodating the metabolic and biosynthetic needs of the cell. Mounting evidence places mitochondrial dysfunction at the core of several diseases, notably in the context of pathologies of the cardiovascular and central nervous system. In addition, mutations in some mitochondrial proteins are bona fide cancer drivers. Better understanding of the functions of these multifaceted organelles and their components may finetune our knowledge on the molecular bases of certain diseases and suggest new therapeutic avenues. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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Research

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23 pages, 1871 KiB

Open AccessArticle

Novel Insights into the Role of UBE3A in Regulating Apoptosis and Proliferation

by Lilach Simchi, Julia Panov, Olla Morsy, Yonatan Feuermann and Hanoch Kaphzan

J. Clin. Med. 2020, 9(5), 1573; https://doi.org/10.3390/jcm9051573 - 22 May 2020

Cited by 16 | Viewed by 5607

Abstract

The UBE3A gene codes for a protein with two known functions, a ubiquitin E3-ligase which catalyzes ubiquitin binding to substrate proteins and a steroid hormone receptor coactivator. UBE3A is most famous for its critical role in neuronal functioning. Lack of UBE3A protein expression [...] Read more.

The UBE3A gene codes for a protein with two known functions, a ubiquitin E3-ligase which catalyzes ubiquitin binding to substrate proteins and a steroid hormone receptor coactivator. UBE3A is most famous for its critical role in neuronal functioning. Lack of UBE3A protein expression leads to Angelman syndrome (AS), while its overexpression is associated with autism. In spite of extensive research, our understanding of UBE3A roles is still limited. We investigated the cellular and molecular effects of Ube3a deletion in mouse embryonic fibroblasts (MEFs) and Angelman syndrome (AS) mouse model hippocampi. Cell cultures of MEFs exhibited enhanced proliferation together with reduced apoptosis when Ube3a was deleted. These findings were supported by transcriptome and proteome analyses. Furthermore, transcriptome analyses revealed alterations in mitochondria-related genes. Moreover, an analysis of adult AS model mice hippocampi also found alterations in the expression of apoptosis- and proliferation-associated genes. Our findings emphasize the role UBE3A plays in regulating proliferation and apoptosis and sheds light into the possible effects UBE3A has on mitochondrial involvement in governing this balance. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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15 pages, 1856 KiB

Open AccessArticle

Mitochondrial Signatures in Circulating Extracellular Vesicles of Older Adults with Parkinson’s Disease: Results from the EXosomes in PArkiNson’s Disease (EXPAND) Study

by Anna Picca, Flora Guerra, Riccardo Calvani, Federico Marini, Alessandra Biancolillo, Giovanni Landi, Raffaella Beli, Francesco Landi, Roberto Bernabei, Anna Rita Bentivoglio, Maria Rita Lo Monaco, Cecilia Bucci and Emanuele Marzetti

J. Clin. Med. 2020, 9(2), 504; https://doi.org/10.3390/jcm9020504 - 12 Feb 2020

Cited by 108 | Viewed by 7192

Abstract

Systemic inflammation and mitochondrial dysfunction are involved in neurodegeneration in Parkinson’s disease (PD). Extracellular vesicle (EV) trafficking may link inflammation and mitochondrial dysfunction. In the present study, circulating small EVs (sEVs) from 16 older adults with PD and 12 non-PD controls were purified [...] Read more.

Systemic inflammation and mitochondrial dysfunction are involved in neurodegeneration in Parkinson’s disease (PD). Extracellular vesicle (EV) trafficking may link inflammation and mitochondrial dysfunction. In the present study, circulating small EVs (sEVs) from 16 older adults with PD and 12 non-PD controls were purified and characterized. A panel of serum inflammatory biomolecules was measured by multiplex immunoassay. Protein levels of three tetraspanins (CD9, CD63, and CD81) and selected mitochondrial markers (adenosine triphosphate 5A (ATP5A), mitochondrial cytochrome C oxidase subunit I (MTCOI), nicotinamide adenine dinucleotide reduced form (NADH):ubiquinone oxidoreductase subunit B8 (NDUFB8), NADH:ubiquinone oxidoreductase subunit S3 (NDUFS3), succinate dehydrogenase complex iron sulfur subunit B (SDHB), and ubiquinol-cytochrome C reductase core protein 2 (UQCRC2)) were quantified in purified sEVs by immunoblotting. Relative to controls, PD participants showed a greater amount of circulating sEVs. Levels of CD9 and CD63 were lower in the sEV fraction of PD participants, whereas those of CD81 were similar between groups. Lower levels of ATP5A, NDUFS3, and SDHB were detected in sEVs from PD participants. No signal was retrieved for UQCRC2, MTCOI, or NDUFB8 in either participant group. To identify a molecular signature in circulating sEVs in relationship to systemic inflammation, a low level-fused (multi-platform) partial least squares discriminant analysis was applied. The model correctly classified 94.2% ± 6.1% PD participants and 66.7% ± 5.4% controls, and identified seven biomolecules as relevant (CD9, NDUFS3, C-reactive protein, fibroblast growth factor 21, interleukin 9, macrophage inflammatory protein 1β, and tumor necrosis factor alpha). In conclusion, a mitochondrial signature was identified in circulating sEVs from older adults with PD, in association with a specific inflammatory profile. In-depth characterization of sEV trafficking may allow identifying new biomarkers for PD and possible targets for personalized interventions. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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18 pages, 7268 KiB

Open AccessArticle

Variants in Miro1 Cause Alterations of ER-Mitochondria Contact Sites in Fibroblasts from Parkinson’s Disease Patients

by Clara Berenguer-Escuder, Dajana Grossmann, Franҫois Massart, Paul Antony, Lena F. Burbulla, Enrico Glaab, Sophie Imhoff, Joanne Trinh, Philip Seibler, Anne Grünewald and Rejko Krüger

J. Clin. Med. 2019, 8(12), 2226; https://doi.org/10.3390/jcm8122226 - 16 Dec 2019

Cited by 40 | Viewed by 7464

Abstract

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD-associated proteins are involved in mitochondrial quality control, [...] Read more.

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD-associated proteins are involved in mitochondrial quality control, e.g., PINK1, Parkin, and LRRK2, which were recently identified as regulators of mitochondrial-endoplasmic reticulum (ER) contact sites (MERCs) linking mitochondrial homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly recognized to play a role in PD pathology. Recently, we identified the first PD patients carrying mutations in RHOT1, the gene coding for Miro1. Here, we describe two novel RHOT1 mutations identified in two PD patients and the characterization of the cellular phenotypes. Methods: Using whole exome sequencing we identified two PD patients carrying heterozygous mutations leading to the amino acid exchanges T351A and T610A in Miro1. We analyzed calcium homeostasis and MERCs in detail by live cell imaging and immunocytochemistry in patient-derived fibroblasts. Results: We show that fibroblasts expressing mutant T351A or T610A Miro1 display impaired calcium homeostasis and a reduced amount of MERCs. All fibroblast lines from patients with pathogenic variants in Miro1, revealed alterations of the structure of MERCs. Conclusion: Our data suggest that Miro1 is important for the regulation of the structure and function of MERCs. Moreover, our study supports the role of MERCs in the pathogenesis of PD and further establishes variants in RHOT1 as rare genetic risk factors for neurodegeneration. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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14 pages, 1119 KiB

Open AccessArticle

Altered Bioenergetics of Blood Cell Sub-Populations in Acute Pancreatitis Patients

by Jack C. Morton, Jane A. Armstrong, Ajay Sud, Alexei V. Tepikin, Robert Sutton and David N. Criddle

J. Clin. Med. 2019, 8(12), 2201; https://doi.org/10.3390/jcm8122201 - 13 Dec 2019

Cited by 5 | Viewed by 4226

Abstract

Acute pancreatitis (AP) is a debilitating, sometimes fatal disease, marked by local injury and systemic inflammation. Mitochondrial dysfunction is a central feature of pancreatic damage in AP, however, its involvement in circulating blood cell subtypes is unknown. This study compared mitochondrial bioenergetics in [...] Read more.

Acute pancreatitis (AP) is a debilitating, sometimes fatal disease, marked by local injury and systemic inflammation. Mitochondrial dysfunction is a central feature of pancreatic damage in AP, however, its involvement in circulating blood cell subtypes is unknown. This study compared mitochondrial bioenergetics in circulating leukocytes from AP patients and healthy volunteers: 15 patients with mild to severe AP were compared to 10 healthy controls. Monocytes, lymphocytes and neutrophils were isolated using magnetic activated cell sorting and mitochondrial bioenergetics profiles of the cell populations determined using a Seahorse XF24 flux analyser. Rates of oxygen consumption (OCR) and extracellular acidification (ECAR) under conditions of electron transport chain (ETC) inhibition (“stress” test) informed respiratory and glycolytic parameters, respectively. Phorbol ester stimulation was used to trigger the oxidative burst. Basal OCR in all blood cell subtypes was similar in AP patients and controls. However, maximal respiration and spare respiratory capacity of AP patient lymphocytes were decreased, indicating impairment of functional capacity. A diminished oxidative burst occurred in neutrophils from AP patients, compared to controls, whereas this was enhanced in both monocytes and lymphocytes. The data demonstrate important early alterations of bioenergetics in blood cell sub-populations from AP patients, which imply functional alterations linked to clinical disease progression. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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14 pages, 2262 KiB

Open AccessArticle

A Humanized Bone Niche Model Reveals Bone Tissue Preservation Upon Targeting Mitochondrial Complex I in Pseudo-Orthotopic Osteosarcoma

by Ivana Kurelac, Ander Abarrategi, Moira Ragazzi, Luisa Iommarini, Nikkitha Umesh Ganesh, Thomas Snoeks, Dominique Bonnet, Anna Maria Porcelli, Ilaria Malanchi and Giuseppe Gasparre

J. Clin. Med. 2019, 8(12), 2184; https://doi.org/10.3390/jcm8122184 - 11 Dec 2019

Cited by 11 | Viewed by 4301

Abstract

A cogent issue in cancer research is how to account for the effects of tumor microenvironment (TME) on the response to therapy, warranting the need to adopt adequate in vitro and in vivo models. This is particularly relevant in the development of strategies [...] Read more.

A cogent issue in cancer research is how to account for the effects of tumor microenvironment (TME) on the response to therapy, warranting the need to adopt adequate in vitro and in vivo models. This is particularly relevant in the development of strategies targeting cancer metabolism, as they will inevitably have systemic effects. For example, inhibition of mitochondrial complex I (CI), despite showing promising results as an anticancer approach, triggers TME-mediated survival mechanisms in subcutaneous osteosarcoma xenografts, a response that may vary according to whether the tumors are induced via subcutaneous injection or by intrabone orthotopic transplantation. Thus, with the aim to characterize the TME of CI-deficient tumors in a model that more faithfully represents osteosarcoma development, we set up a humanized bone niche ectopic graft. A prominent involvement of TME was revealed in CI-deficient tumors, characterized by the abundance of cancer associated fibroblasts, tumor associated macrophages and preservation of osteocytes and osteoblasts in the mineralized bone matrix. The pseudo-orthotopic approach allowed investigation of osteosarcoma progression in a bone-like microenvironment setting, without being invasive as the intrabone cell transplantation. Additionally, establishing osteosarcomas in a humanized bone niche model identified a peculiar association between targeting CI and bone tissue preservation. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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29 pages, 10920 KiB

Open AccessArticle

FAD/NADH Dependent Oxidoreductases: From Different Amino Acid Sequences to Similar Protein Shapes for Playing an Ancient Function

by Lucia Trisolini, Nicola Gambacorta, Ruggiero Gorgoglione, Michele Montaruli, Luna Laera, Francesco Colella, Mariateresa Volpicella, Anna De Grassi and Ciro Leonardo Pierri

J. Clin. Med. 2019, 8(12), 2117; https://doi.org/10.3390/jcm8122117 - 2 Dec 2019

Cited by 50 | Viewed by 8744

Abstract

Flavoprotein oxidoreductases are members of a large protein family of specialized dehydrogenases, which include type II NADH dehydrogenase, pyridine nucleotide-disulphide oxidoreductases, ferredoxin-NAD+ reductases, NADH oxidases, and NADH peroxidases, playing a crucial role in the metabolism of several prokaryotes and eukaryotes. Although several studies [...] Read more.

Flavoprotein oxidoreductases are members of a large protein family of specialized dehydrogenases, which include type II NADH dehydrogenase, pyridine nucleotide-disulphide oxidoreductases, ferredoxin-NAD+ reductases, NADH oxidases, and NADH peroxidases, playing a crucial role in the metabolism of several prokaryotes and eukaryotes. Although several studies have been performed on single members or protein subgroups of flavoprotein oxidoreductases, a comprehensive analysis on structure–function relationships among the different members and subgroups of this great dehydrogenase family is still missing. Here, we present a structural comparative analysis showing that the investigated flavoprotein oxidoreductases have a highly similar overall structure, although the investigated dehydrogenases are quite different in functional annotations and global amino acid composition. The different functional annotation is ascribed to their participation in species-specific metabolic pathways based on the same biochemical reaction, i.e., the oxidation of specific cofactors, like NADH and FADH₂. Notably, the performed comparative analysis sheds light on conserved sequence features that reflect very similar oxidation mechanisms, conserved among flavoprotein oxidoreductases belonging to phylogenetically distant species, as the bacterial type II NADH dehydrogenases and the mammalian apoptosis-inducing factor protein, until now retained as unique protein entities in Bacteria/Fungi or Animals, respectively. Furthermore, the presented computational analyses will allow consideration of FAD/NADH oxidoreductases as a possible target of new small molecules to be used as modulators of mitochondrial respiration for patients affected by rare diseases or cancer showing mitochondrial dysfunction, or antibiotics for treating bacterial/fungal/protista infections. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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11 pages, 3378 KiB

Open AccessArticle

Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants

by Rocio Rius, Nicole J. Van Bergen, Alison G. Compton, Lisa G. Riley, Maina P. Kava, Shanti Balasubramaniam, David J. Amor, Miriam Fanjul-Fernandez, Mark J. Cowley, Michael C. Fahey, Mary K. Koenig, Gregory M. Enns, Simon Sadedin, Meredith J. Wilson, Tiong Y. Tan, David R. Thorburn and John Christodoulou

J. Clin. Med. 2019, 8(11), 2020; https://doi.org/10.3390/jcm8112020 - 19 Nov 2019

Cited by 26 | Viewed by 6609

Abstract

PNPT1 (PNPase—polynucleotide phosphorylase) is involved in multiple RNA processing functions in the mitochondria. Bi-allelic pathogenic PNPT1 variants cause heterogeneous clinical phenotypes affecting multiple organs without any established genotype–phenotype correlations. Defects in PNPase can cause variable combined respiratory chain complex defects. Recently, it has [...] Read more.

PNPT1 (PNPase—polynucleotide phosphorylase) is involved in multiple RNA processing functions in the mitochondria. Bi-allelic pathogenic PNPT1 variants cause heterogeneous clinical phenotypes affecting multiple organs without any established genotype–phenotype correlations. Defects in PNPase can cause variable combined respiratory chain complex defects. Recently, it has been suggested that PNPase can lead to activation of an innate immune response. To better understand the clinical and molecular spectrum of patients with bi-allelic PNPT1 variants, we captured detailed clinical and molecular phenotypes of all 17 patients reported in the literature, plus seven new patients, including a 78-year-old male with the longest reported survival. A functional follow-up of genomic sequencing by cDNA studies confirmed a splicing defect in a novel, apparently synonymous, variant. Patient fibroblasts showed an accumulation of mitochondrial unprocessed PNPT1 transcripts, while blood showed an increased interferon response. Our findings suggest that functional analyses of the RNA processing function of PNPase are more sensitive than testing downstream defects in oxidative phosphorylation (OXPHPOS) enzyme activities. This research extends our knowledge of the clinical and functional consequences of bi-allelic pathogenic PNPT1 variants that may guide management and further efforts into understanding the pathophysiological mechanisms for therapeutic development. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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20 pages, 2079 KiB

Open AccessArticle

Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment

by Irene Bravo-Alonso, Rosa Navarrete, Ana Isabel Vega, Pedro Ruíz-Sala, María Teresa García Silva, Elena Martín-Hernández, Pilar Quijada-Fraile, Amaya Belanger-Quintana, Sinziana Stanescu, María Bueno, Isidro Vitoria, Laura Toledo, María Luz Couce, Inmaculada García-Jiménez, Ricardo Ramos-Ruiz, Miguel Ángel Martín, Lourdes R. Desviat, Magdalena Ugarte, Celia Pérez-Cerdá, Begoña Merinero, Belén Pérez and Pilar Rodríguez-Pombo Show full author list Hide full author list

J. Clin. Med. 2019, 8(11), 1811; https://doi.org/10.3390/jcm8111811 - 1 Nov 2019

Cited by 13 | Viewed by 5118

Abstract

Congenital lactic acidosis (CLA) is a rare condition in most instances due to a range of inborn errors of metabolism that result in defective mitochondrial function. Even though the implementation of next generation sequencing has been rapid, the diagnosis rate for this highly [...] Read more.

Congenital lactic acidosis (CLA) is a rare condition in most instances due to a range of inborn errors of metabolism that result in defective mitochondrial function. Even though the implementation of next generation sequencing has been rapid, the diagnosis rate for this highly heterogeneous allelic condition remains low. The present work reports our group’s experience of using a clinical/biochemical analysis system in conjunction with genetic findings that facilitates the taking of timely clinical decisions with minimum need for invasive procedures. The system’s workflow combines different metabolomics datasets and phenotypic information with the results of clinical exome sequencing and/or RNA analysis. The system’s use detected genetic variants in 64% of a cohort of 39 CLA-patients; these variants, 14 of which were novel, were found in 19 different nuclear and two mitochondrial genes. For patients with variants of unknown significance, the genetic analysis was combined with functional genetic and/or bioenergetics analyses in an attempt to detect pathogenicity. Our results warranted subsequent testing of antisense therapy to rescue the abnormal splicing in cultures of fibroblasts from a patient with a defective GFM1 gene. The discussed system facilitates the diagnosis of CLA by avoiding the need to use invasive techniques and increase our knowledge of the causes of this condition. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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26 pages, 2284 KiB

Open AccessArticle

Brain-Immune Alterations and Mitochondrial Dysfunctions in a Mouse Model of Paediatric Autoimmune Disorder Associated with Streptococcus: Exacerbation by Chronic Psychosocial Stress

by Maria Antonietta Ajmone-Cat, Chiara Spinello, Daniela Valenti, Francesca Franchi, Simone Macrì, Rosa Anna Vacca and Giovanni Laviola

J. Clin. Med. 2019, 8(10), 1514; https://doi.org/10.3390/jcm8101514 - 20 Sep 2019

Cited by 2 | Viewed by 5425

Abstract

Adverse psychosocial experiences have been shown to modulate individual responses to immune challenges and affect mitochondrial functions. The aim of this study was to investigate inflammation and immune responses as well as mitochondrial bioenergetics in an experimental model of Paediatric Autoimmune Neuropsychiatric Disorders [...] Read more.

Adverse psychosocial experiences have been shown to modulate individual responses to immune challenges and affect mitochondrial functions. The aim of this study was to investigate inflammation and immune responses as well as mitochondrial bioenergetics in an experimental model of Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). Starting in adolescence (postnatal day 28), male SJL/J mice were exposed to five injections (interspaced by two weeks) with Group-A beta-haemolytic streptococcus (GAS) homogenate. Mice were exposed to chronic psychosocial stress, in the form of protracted visual exposure to an aggressive conspecific, for four weeks. Our results indicate that psychosocial stress exacerbated individual response to GAS administrations whereby mice exposed to both treatments exhibited altered cytokine and immune-related enzyme expression in the hippocampus and hypothalamus. Additionally, they showed impaired mitochondrial respiratory chain complexes IV and V, and reduced adenosine triphosphate (ATP) production by mitochondria and ATP content. These brain abnormalities, observed in GAS-Stress mice, were associated with blunted titers of plasma corticosterone. Present data support the hypothesis that challenging environmental conditions, in terms of chronic psychosocial stress, may exacerbate the long-term consequences of exposure to GAS processes through the promotion of central immunomodulatory and oxidative stress. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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Review

Jump to: Editorial, Research

26 pages, 1863 KiB

Open AccessReview

Mitophagy in Cardiovascular Diseases

by Giampaolo Morciano, Simone Patergnani, Massimo Bonora, Gaia Pedriali, Anna Tarocco, Esmaa Bouhamida, Saverio Marchi, Gina Ancora, Gabriele Anania, Mariusz R. Wieckowski, Carlotta Giorgi and Paolo Pinton

J. Clin. Med. 2020, 9(3), 892; https://doi.org/10.3390/jcm9030892 - 24 Mar 2020

Cited by 87 | Viewed by 8190

Abstract

Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown that pharmacological or genetic targeting of mitochondria can ameliorate each stage of these pathologies, which are strongly associated with mitochondrial dysfunction. Removal of inefficient and dysfunctional mitochondria through the [...] Read more.

Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown that pharmacological or genetic targeting of mitochondria can ameliorate each stage of these pathologies, which are strongly associated with mitochondrial dysfunction. Removal of inefficient and dysfunctional mitochondria through the process of mitophagy has been reported to be essential for meeting the energetic requirements and maintaining the biochemical homeostasis of cells. This process is useful for counteracting the negative phenotypic changes that occur during cardiovascular diseases, and understanding the molecular players involved might be crucial for the development of potential therapies. Here, we summarize the current knowledge on mitophagy (and autophagy) mechanisms in the context of heart disease with an important focus on atherosclerosis, ischemic heart disease, cardiomyopathies, heart failure, hypertension, arrhythmia, congenital heart disease and peripheral vascular disease. We aim to provide a complete background on the mechanisms of action of this mitochondrial quality control process in cardiology and in cardiac surgery by also reviewing studies on the use of known compounds able to modulate mitophagy for cardioprotective purposes. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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25 pages, 2550 KiB

Open AccessReview

The Role of Mitochondria in Inflammation: From Cancer to Neurodegenerative Disorders

by Sonia Missiroli, Ilaria Genovese, Mariasole Perrone, Bianca Vezzani, Veronica A. M. Vitto and Carlotta Giorgi

J. Clin. Med. 2020, 9(3), 740; https://doi.org/10.3390/jcm9030740 - 9 Mar 2020

Cited by 167 | Viewed by 11367

Abstract

The main features that are commonly attributed to mitochondria consist of the regulation of cell proliferation, ATP generation, cell death and metabolism. However, recent scientific advances reveal that the intrinsic dynamicity of the mitochondrial compartment also plays a central role in proinflammatory signaling, [...] Read more.

The main features that are commonly attributed to mitochondria consist of the regulation of cell proliferation, ATP generation, cell death and metabolism. However, recent scientific advances reveal that the intrinsic dynamicity of the mitochondrial compartment also plays a central role in proinflammatory signaling, identifying these organelles as a central platform for the control of innate immunity and the inflammatory response. Thus, mitochondrial dysfunctions have been related to severe chronic inflammatory disorders. Strategies aimed at reestablishing normal mitochondrial physiology could represent both preventive and therapeutic interventions for various pathologies related to exacerbated inflammation. Here, we explore the current understanding of the intricate interplay between mitochondria and the innate immune response in specific inflammatory diseases, such as neurological disorders and cancer. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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18 pages, 2255 KiB

Open AccessReview

Rescue of TCA Cycle Dysfunction for Cancer Therapy

by Jubert Marquez, Jessa Flores, Amy Hyein Kim, Bayalagmaa Nyamaa, Anh Thi Tuyet Nguyen, Nammi Park and Jin Han

J. Clin. Med. 2019, 8(12), 2161; https://doi.org/10.3390/jcm8122161 - 6 Dec 2019

Cited by 36 | Viewed by 8205

Abstract

Mitochondrion, a maternally hereditary, subcellular organelle, is the site of the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and oxidative phosphorylation (OXPHOS)—the basic processes of ATP production. Mitochondrial function plays a pivotal role in the development and pathology of different cancers. Disruption [...] Read more.

Mitochondrion, a maternally hereditary, subcellular organelle, is the site of the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and oxidative phosphorylation (OXPHOS)—the basic processes of ATP production. Mitochondrial function plays a pivotal role in the development and pathology of different cancers. Disruption in its activity, like mutations in its TCA cycle enzymes, leads to physiological imbalances and metabolic shifts of the cell, which contributes to the progression of cancer. In this review, we explored the different significant mutations in the mitochondrial enzymes participating in the TCA cycle and the diseases, especially cancer types, that these malfunctions are closely associated with. In addition, this paper also discussed the different therapeutic approaches which are currently being developed to address these diseases caused by mitochondrial enzyme malfunction. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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14 pages, 775 KiB

Open AccessReview

The Rise of Mitochondria in Peripheral Arterial Disease Physiopathology: Experimental and Clinical Data

by Mégane Pizzimenti, Marianne Riou, Anne-Laure Charles, Samy Talha, Alain Meyer, Emmanuel Andres, Nabil Chakfé, Anne Lejay and Bernard Geny

J. Clin. Med. 2019, 8(12), 2125; https://doi.org/10.3390/jcm8122125 - 2 Dec 2019

Cited by 32 | Viewed by 4570

Abstract

Peripheral arterial disease (PAD) is a frequent and serious condition, potentially life-threatening and leading to lower-limb amputation. Its pathophysiology is generally related to ischemia-reperfusion cycles, secondary to reduction or interruption of the arterial blood flow followed by reperfusion episodes that are necessary but [...] Read more.

Peripheral arterial disease (PAD) is a frequent and serious condition, potentially life-threatening and leading to lower-limb amputation. Its pathophysiology is generally related to ischemia-reperfusion cycles, secondary to reduction or interruption of the arterial blood flow followed by reperfusion episodes that are necessary but also—per se—deleterious. Skeletal muscles alterations significantly participate in PAD injuries, and interestingly, muscle mitochondrial dysfunctions have been demonstrated to be key events and to have a prognosis value. Decreased oxidative capacity due to mitochondrial respiratory chain impairment is associated with increased release of reactive oxygen species and reduction of calcium retention capacity leading thus to enhanced apoptosis. Therefore, targeting mitochondria might be a promising therapeutic approach in PAD. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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15 pages, 562 KiB

Open AccessReview

Mitochondrial Dysfunction in Aging and Cancer

by Loredana Moro

J. Clin. Med. 2019, 8(11), 1983; https://doi.org/10.3390/jcm8111983 - 15 Nov 2019

Cited by 59 | Viewed by 6702

Abstract

Aging is a major risk factor for developing cancer, suggesting that these two events may represent two sides of the same coin. It is becoming clear that some mechanisms involved in the aging process are shared with tumorigenesis, through convergent or divergent pathways. [...] Read more.

Aging is a major risk factor for developing cancer, suggesting that these two events may represent two sides of the same coin. It is becoming clear that some mechanisms involved in the aging process are shared with tumorigenesis, through convergent or divergent pathways. Increasing evidence supports a role for mitochondrial dysfunction in promoting aging and in supporting tumorigenesis and cancer progression to a metastatic phenotype. Here, a summary of the current knowledge of three aspects of mitochondrial biology that link mitochondria to aging and cancer is presented. In particular, the focus is on mutations and changes in content of the mitochondrial genome, activation of mitochondria-to-nucleus signaling and the newly discovered mitochondria-telomere communication. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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29 pages, 1423 KiB

Open AccessReview

An Intriguing Involvement of Mitochondria in Cystic Fibrosis

by Maria Favia, Lidia de Bari, Antonella Bobba and Anna Atlante

J. Clin. Med. 2019, 8(11), 1890; https://doi.org/10.3390/jcm8111890 - 6 Nov 2019

Cited by 22 | Viewed by 10731

Abstract

Cystic fibrosis (CF) occurs when the cystic fibrosis transmembrane conductance regulator (CFTR) protein is not synthetized and folded correctly. The CFTR protein helps to maintain the balance of salt and water on many body surfaces, such as the lung surface. When the protein [...] Read more.

Cystic fibrosis (CF) occurs when the cystic fibrosis transmembrane conductance regulator (CFTR) protein is not synthetized and folded correctly. The CFTR protein helps to maintain the balance of salt and water on many body surfaces, such as the lung surface. When the protein is not working correctly, chloride becomes trapped in cells, then water cannot hydrate the cellular surface and the mucus covering the cells becomes thick and sticky. Furthermore, a defective CFTR appears to produce a redox imbalance in epithelial cells and extracellular fluids and to cause an abnormal generation of reactive oxygen species: as a consequence, oxidative stress has been implicated as a causative factor in the aetiology of the process. Moreover, massive evidences show that defective CFTR gives rise to extracellular GSH level decrease and elevated glucose concentrations in airway surface liquid (ASL), thus encouraging lung infection by pathogens in the CF advancement. Recent research in progress aims to rediscover a possible role of mitochondria in CF. Here the latest new and recent studies on mitochondrial bioenergetics are collected. Surprisingly, they have enabled us to ascertain that mitochondria have a leading role in opposing the high ASL glucose level as well as oxidative stress in CF. Full article

(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)

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