Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Mitochondria-Targeted Approaches in Health and Disease

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Related Special Issue
Published Papers

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

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 46225

Share This Special Issue

Special Issue Editor

Prof. Dr. Dmitry Zorov

E-Mail Website1 Website2
Guest Editor

Department of Functional Biochemistry of Biopolymers, A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
Interests: mitochondria; reactive oxygen species; oxidative stress; aging; ischemia; inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria are one of the most intriguing intracellular elements. Apart from their great contribution to cellular bioenergetics, they perform various unique functions (both synthetic and regulatory). Now, it has become clear that mitochondrial fitness is the prerequisite of a healthy cell. Inherited or acquired mitochondrial disfunction caused by changes in the genetic, lepidic, and proteinaceous content causing abnormal changes in structure and functions, can be detrimental or even fatal for a cell. The intrinsic mechanism of mitochondrial quality control realizes the detection of unfitted mitochondria or their elements with their elimination from the cell, ultimately performing clearing the system of abnormal mitochondrial structures. However, because of intrinsic and extrinsic challenges, this machinery misses the mitochondrial defects yielding the co-existance of normal and abnormal mitochondria within a single cell, which is a main index of diseases and aging. To avoid an unnecessary appearance of unhealthy mitochondrial population in the cell when intrinsic mechanisms of reparation are partially or completely failed, various approaches have been successfully developed. The goal of the proposed Special Issue, Mitochondria-Targeted Approaches in Health and Disease, is to collect all of the possible methods of intervention into mitochondrial functioning, so as to prevent or repair unwanted changes in the mitochondrial structure and function.

Prof. Dr. Dmitry B Zorov
Guest Editor

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

mitochondrial
membrane potential
DNA
ATP synthase
quality control
mitophagy
diseases
targeting
population analysis
death
cells
signaling
reactive oxygen species
radicals
damage
protection
structure
functions
respiratory chain
complexes

Related Special Issue

Mitochondria-Targeted Approaches in Health and Disease 2.0 in International Journal of Molecular Sciences (7 articles)

Published Papers (10 papers)

Download All Papers

Research

Jump to: Review

21 pages, 3426 KiB

Open AccessArticle

Involvement of Mitochondrial Mechanisms in the Cytostatic Effect of Desethylamiodarone in B16F10 Melanoma Cells

by Fadi H. J. Ramadan, Aliz Szabo, Dominika Kovacs, Aniko Takatsy, Rita Bognar, Ferenc Gallyas, Jr. and Zita Bognar

Int. J. Mol. Sci. 2020, 21(19), 7346; https://doi.org/10.3390/ijms21197346 - 05 Oct 2020

Cited by 2 | Viewed by 2765

Abstract

Previously, we showed that desethylamiodarone (DEA), a major metabolite of the widely used antiarrhythmic drug amiodarone, has direct mitochondrial effects. We hypothesized that these effects account for its observed cytotoxic properties and ability to limit in vivo metastasis. Accordingly, we examined DEA’s rapid (3–12 h) cytotoxicity and its early (3–6 h) effects on various mitochondrial processes in B16F10 melanoma cells. DEA did not affect cellular oxygen radical formation, as determined using two fluorescent dyes. However, it did decrease the mitochondrial transmembrane potential, as assessed by JC-1 dye and fluorescence microscopy. It also induced mitochondrial fragmentation, as visualized by confocal fluorescence microscopy. DEA decreased maximal respiration, ATP production, coupling efficiency, glycolysis, and non-mitochondrial oxygen consumption measured by a Seahorse cellular energy metabolism analyzer. In addition, it induced a cyclosporine A–independent mitochondrial permeability transition, as determined by Co²⁺-mediated calcein fluorescence quenching measured using a high-content imaging system. DEA also caused outer mitochondrial membrane permeabilization, as assessed by the immunoblot analysis of cytochrome C, apoptosis inducing factor, Akt, phospho-Akt, Bad, and phospho-Bad. All of these data supported our initial hypothesis. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease)

► Show Figures

Figure 1

21 pages, 6636 KiB

Open AccessArticle

Bioinformatics Analyses of the Transcriptome Reveal Ube3a-Dependent Effects on Mitochondrial-Related Pathways

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

Int. J. Mol. Sci. 2020, 21(11), 4156; https://doi.org/10.3390/ijms21114156 - 10 Jun 2020

Cited by 9 | Viewed by 3511

Abstract

The UBE3A gene encodes the ubiquitin E3-ligase protein, UBE3A, which is implicated in severe neurodevelopmental disorders. Lack of UBE3A expression results in Angelman syndrome, while UBE3A overexpression, due to genomic 15q duplication, results in autism. The cellular roles of UBE3A are not fully understood, yet a growing body of evidence indicates that these disorders involve mitochondrial dysfunction and increased oxidative stress. We utilized bioinformatics approaches to delineate the effects of murine Ube3a deletion on the expression of mitochondrial-related genes and pathways. For this, we generated an mRNA sequencing dataset from mouse embryonic fibroblasts (MEFs) in which both alleles of Ube3a gene were deleted and their wild-type controls. Since oxidative stress and mitochondrial dysregulation might not be exhibited in the resting baseline state, we also activated mitochondrial functioning in the cells of these two genotypes using TNFα application. Transcriptomes of the four groups of MEFs, Ube3a^+/+ and Ube3a^−/−, with or without the application of TNFα, were analyzed using various bioinformatics tools and machine learning approaches. Our results indicate that Ube3a deletion affects the gene expression profiles of mitochondrial-associated pathways. We further confirmed these results by analyzing other publicly available human transcriptome datasets of Angelman syndrome and 15q duplication syndrome. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease)

► Show Figures

Figure 1

23 pages, 2028 KiB

Open AccessArticle

Activation of Mitochondrial 2-Oxoglutarate Dehydrogenase by Cocarboxylase in Human Lung Adenocarcinoma Cells A549 Is p53/p21-Dependent and Impairs Cellular Redox State, Mimicking the Cisplatin Action

by Victoria I. Bunik, Vasily A. Aleshin, Xiaoshan Zhou, Vyacheslav Yu. Tabakov and Anna Karlsson

Int. J. Mol. Sci. 2020, 21(11), 3759; https://doi.org/10.3390/ijms21113759 - 26 May 2020

Cited by 6 | Viewed by 4781

Abstract

Genetic up-regulation of mitochondrial 2-oxoglutarate dehydrogenase is known to increase reactive oxygen species, being detrimental for cancer cells. Thiamine diphosphate (ThDP, cocarboxylase) is an essential activator of the enzyme and inhibits p53–DNA binding in cancer cells. We hypothesize that the pleiotropic regulator ThDP may be of importance for anticancer therapies. The hypothesis is tested in the present work on lung adenocarcinoma cells A549 possessing the p53–p21 pathway as fully functional or perturbed by p21 knockdown. Molecular mechanisms of ThDP action on cellular viability and their interplay with the cisplatin and p53–p21 pathways are characterized. Despite the well-known antioxidant properties of thiamine, A549 cells exhibit decreases in their reducing power and glutathione level after incubation with 5 mM ThDP, not observed in non-cancer epithelial cells Vero. Moreover, thiamine deficiency elevates glutathione in A549 cells. Viability of the thiamine deficient A549 cells is increased at a low (0.05 mM) ThDP. However, the increase is attenuated by 5 mM ThDP, p21 knockdown, specific inhibitor of the 2-oxoglutarate dehydrogenase complex (OGDHC), or cisplatin. Cellular levels of the catalytically competent ThDP·OGDHC holoenzyme are dysregulated by p21 knockdown and correlate negatively with the A549 viability. The inverse relationship between cellular glutathione and holo-OGDHC is corroborated by their comparison in the A549 and Vero cells. The similarity, non-additivity, and p21 dependence of the dual actions of ThDP and cisplatin on A549 cells manifest a common OGDHC-mediated mechanism of the viability decrease. High ThDP saturation of OGDHC compromises the redox state of A549 cells under the control of p53–p21 axes. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease)

► Show Figures

Graphical abstract

21 pages, 3622 KiB

Open AccessArticle

Nicotinamide Mononucleotide Administration Prevents Experimental Diabetes-Induced Cognitive Impairment and Loss of Hippocampal Neurons

by Krish Chandrasekaran, Joungil Choi, Muhammed Ikbal Arvas, Mohammad Salimian, Sujal Singh, Su Xu, Rao P Gullapalli, Tibor Kristian and James William Russell

Int. J. Mol. Sci. 2020, 21(11), 3756; https://doi.org/10.3390/ijms21113756 - 26 May 2020

Cited by 52 | Viewed by 5800

Abstract

Diabetes predisposes to cognitive decline leading to dementia and is associated with decreased brain NAD⁺ levels. This has triggered an intense interest in boosting nicotinamide adenine dinucleotide (NAD⁺) levels to prevent dementia. We tested if the administration of the precursor of NAD⁺, nicotinamide mononucleotide (NMN), can prevent diabetes-induced memory deficits. Diabetes was induced in Sprague-Dawley rats by the administration of streptozotocin (STZ). After 3 months of diabetes, hippocampal NAD⁺ levels were decreased (p = 0.011). In vivo localized high-resolution proton magnetic resonance spectroscopy (MRS) of the hippocampus showed an increase in the levels of glucose (p < 0.001), glutamate (p < 0.001), gamma aminobutyric acid (p = 0.018), myo-inositol (p = 0.018), and taurine (p < 0.001) and decreased levels of N-acetyl aspartate (p = 0.002) and glutathione (p < 0.001). There was a significant decrease in hippocampal CA1 neuronal volume (p < 0.001) and neuronal number (p < 0.001) in the Diabetic rats. Diabetic rats showed hippocampal related memory deficits. Intraperitoneal NMN (100 mg/kg) was given after induction and confirmation of diabetes and was provided on alternate days for 3 months. NMN increased brain NAD⁺ levels, normalized the levels of glutamate, taurine, N-acetyl aspartate (NAA), and glutathione. NMN-treatment prevented the loss of CA1 neurons and rescued the memory deficits despite having no significant effect on hyperglycemic or lipidemic control. In hippocampal protein extracts from Diabetic rats, SIRT1 and PGC-1α protein levels were decreased, and acetylation of proteins increased. NMN treatment prevented the diabetes-induced decrease in both SIRT1 and PGC-1α and promoted deacetylation of proteins. Our results indicate that NMN increased brain NAD⁺, activated the SIRT1 pathway, preserved mitochondrial oxidative phosphorylation (OXPHOS) function, prevented neuronal loss, and preserved cognition in Diabetic rats. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease)

► Show Figures

Figure 1

24 pages, 6945 KiB

Open AccessArticle

Bicalutamide Elicits Renal Damage by Causing Mitochondrial Dysfunction via ROS Damage and Upregulation of HIF-1

by Kuan-Chou Chen, Chang-Rong Chen, Chang-Yu Chen, Kai-Yi Tzou, Chiung-Chi Peng and Robert Y. Peng

Int. J. Mol. Sci. 2020, 21(9), 3400; https://doi.org/10.3390/ijms21093400 - 11 May 2020

Cited by 7 | Viewed by 3694

Abstract

Combined androgen blockade using bicalutamide (Bic) is a therapeutic choice for treating prostate cancer (PCa). However, even at regular clinical dosages, Bic frequently shows adverse effects associated with cardiovascular and renal damage. Previously, we found that Bic selectively damaged mesangial cells compared to tubular cells and in an in vivo rat model, we also found renal damage caused by Bic. In the present study, a rat mesangial cell model was used to further the investigation. Results indicated that Bic enhanced lactate dehydrogenase release, reactive oxygen species (ROS) production, lysosome population and kidney injury molecule-1 and decreased N-cadherin. Bic elicited mitochondrial swelling and reduced the mitochondrial potential, resulting in severe suppression of the oxygen consumption rate (OCR), maximum respiration and ATP production. The hypoxia-inducible factor (HIF)-1 transcriptional activity and messenger RNA were significantly upregulated in dose-dependent manners. The HIF-1 protein reached a peak value at 24 h then rapidly decayed. BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 and cleaved caspase-3 were dose-dependently upregulated by Bic (60 M) and that eventually led to cell apoptosis. It is suggested that Bic induces renal damage via ROS and modulates HIF-1 pathway and clinically, some protective agents like antioxidants are recommended for co-treatment. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease)

► Show Figures

Figure 1

14 pages, 2178 KiB

Open AccessArticle

miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase

by Anthea Di Rita, Teresa Maiorino, Krenare Bruqi, Floriana Volpicelli, Gian Carlo Bellenchi and Flavie Strappazzon

Int. J. Mol. Sci. 2020, 21(1), 355; https://doi.org/10.3390/ijms21010355 - 05 Jan 2020

Cited by 22 | Viewed by 4446

Abstract

The selective elimination of dysfunctional mitochondria through mitophagy is crucial for preserving mitochondrial quality and cellular homeostasis. The most described mitophagy pathway is regulated by a positive ubiquitylation feedback loop in which the PINK1 (PTEN induced kinase 1) kinase phosphorylates both ubiquitin and the E3 ubiquitin ligase PRKN (Parkin RBR E3 ubiquitin ligase), also known as PARKIN. This event recruits PRKN to the mitochondria, thus amplifying ubiquitylation signal. Here we report that miR-218 targets PRKN and negatively regulates PINK1/PRKN-mediated mitophagy. Overexpression of miR-218 reduces PRKN mRNA levels, thus also reducing protein content and deregulating the E3 ubiquitin ligase action. In fact, following miR-218 overexpression, mitochondria result less ubiquitylated and the autophagy machinery fails to proceed with correct mitochondrial clearance. Since mitophagy defects are associated with various human diseases, these results qualify miR-218 as a promising therapeutic target for human diseases. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease)

► Show Figures

Graphical abstract

Review

Jump to: Research

33 pages, 2183 KiB

Open AccessReview

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

by Jean Nakhle, Anne-Marie Rodriguez and Marie-Luce Vignais

Int. J. Mol. Sci. 2020, 21(12), 4405; https://doi.org/10.3390/ijms21124405 - 20 Jun 2020

Cited by 25 | Viewed by 5679

Abstract

Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease)

► Show Figures

Figure 1

27 pages, 3078 KiB

Open AccessReview

Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery

by Megan Noble, Qi-Tong Lin, Christian Sirko, Jacob A. Houpt, Matthew J. Novello and Peter B. Stathopulos

Int. J. Mol. Sci. 2020, 21(10), 3642; https://doi.org/10.3390/ijms21103642 - 21 May 2020

Cited by 6 | Viewed by 5360

Abstract

Calcium (Ca²⁺) is a universal signaling ion that is essential for the life and death processes of all eukaryotes. In humans, numerous cell stimulation pathways lead to the mobilization of sarco/endoplasmic reticulum (S/ER) stored Ca²⁺, resulting in the propagation of Ca²⁺ signals through the activation of processes, such as store-operated Ca²⁺ entry (SOCE). SOCE provides a sustained Ca²⁺ entry into the cytosol; moreover, the uptake of SOCE-mediated Ca²⁺ by mitochondria can shape cytosolic Ca²⁺ signals, function as a feedback signal for the SOCE molecular machinery, and drive numerous mitochondrial processes, including adenosine triphosphate (ATP) production and distinct cell death pathways. In recent years, tremendous progress has been made in identifying the proteins mediating these signaling pathways and elucidating molecular structures, invaluable for understanding the underlying mechanisms of function. Nevertheless, there remains a disconnect between using this accumulating protein structural knowledge and the design of new research tools and therapies. In this review, we provide an overview of the Ca²⁺ signaling pathways that are involved in mediating S/ER stored Ca²⁺ release, SOCE, and mitochondrial Ca²⁺ uptake, as well as pinpoint multiple levels of crosstalk between these pathways. Further, we highlight the significant protein structures elucidated in recent years controlling these Ca²⁺ signaling pathways. Finally, we describe a simple strategy that aimed at applying the protein structural data to initiating drug design. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease)

► Show Figures

Graphical abstract

30 pages, 3631 KiB

Open AccessReview

Regulation of Vascular Function and Inflammation via Cross Talk of Reactive Oxygen and Nitrogen Species from Mitochondria or NADPH Oxidase—Implications for Diabetes Progression

by Andreas Daiber, Sebastian Steven, Ksenija Vujacic-Mirski, Sanela Kalinovic, Matthias Oelze, Fabio Di Lisa and Thomas Münzel

Int. J. Mol. Sci. 2020, 21(10), 3405; https://doi.org/10.3390/ijms21103405 - 12 May 2020

Cited by 31 | Viewed by 4266

Abstract

Oxidative stress plays a key role for the development of cardiovascular, metabolic, and neurodegenerative disease. This concept has been proven by using the approach of genetic deletion of reactive oxygen and nitrogen species (RONS) producing, pro-oxidant enzymes as well as by the overexpression of RONS detoxifying, antioxidant enzymes leading to an amelioration of the severity of diseases. Vice versa, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of RONS detoxifying enzymes. We have previously identified cross talk mechanisms between different sources of RONS, which can amplify the oxidative stress-mediated damage. Here, the pathways and potential mechanisms leading to this cross talk are analyzed in detail and highlighted by selected examples from the current literature and own data including hypoxia, angiotensin II (AT-II)-induced hypertension, nitrate tolerance, aging, and others. The general concept of redox-based activation of RONS sources via “kindling radicals” and enzyme-specific “redox switches” as well as the interaction with redox-sensitive inflammatory pathways are discussed. Here, we present evidence for the existence of such cross talk mechanisms in the setting of diabetes and critically assess their contribution to the severity of diabetic complications. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease)

► Show Figures

Graphical abstract

25 pages, 1785 KiB

Open AccessReview

Mitochondrial Protection by PARP Inhibition

by Ferenc Gallyas Jr and Balazs Sumegi

Int. J. Mol. Sci. 2020, 21(8), 2767; https://doi.org/10.3390/ijms21082767 - 16 Apr 2020

Cited by 22 | Viewed by 5139

Abstract

Inhibitors of the nuclear DNA damage sensor and signalling enzyme poly(ADP-ribose) polymerase (PARP) have recently been introduced in the therapy of cancers deficient in double-strand DNA break repair systems, and ongoing clinical trials aim to extend their use from other forms of cancer non-responsive to conventional treatments. Additionally, PARP inhibitors were suggested to be repurposed for oxidative stress-associated non-oncological diseases resulting in a devastating outcome, or requiring acute treatment. Their well-documented mitochondria- and cytoprotective effects form the basis of PARP inhibitors’ therapeutic use for non-oncological diseases, yet can limit their efficacy in the treatment of cancers. A better understanding of the processes involved in their protective effects may improve the PARP inhibitors’ therapeutic potential in the non-oncological indications. To this end, we endeavoured to summarise the basic features regarding mitochondrial structure and function, review the major PARP activation-induced cellular processes leading to mitochondrial damage, and discuss the role of PARP inhibition-mediated mitochondrial protection in several oxidative stress-associated diseases. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Mitochondria-Targeted Approaches in Health and Disease

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Related Special Issue

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI