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Mitochondrial Medicine: Pharmacological Targeting of Mitochondria in Disease

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

Deadline for manuscript submissions: closed (20 November 2023) | Viewed by 14801

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Prof. Dr. Roberto Scatena

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Dipartimento di Medicina di Laboratorio, Madre Giuseppina Vannini Hospital, Via di Acqua Bullicante 4, 00177 Rome, Italy
Interests: cancer; biomarkers; mitochondria; target drugs; clinical chemistry; laboratory medicine
Special Issues, Collections and Topics in MDPI journals

Dr. Patrizia Bottoni

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Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
Interests: cell differentiation; cancer; cancer cell metabolism; mitochondria; mitochondrial metabolism; oxidative phosphorylation; tumor markers; Warburg effect
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Dear Colleagues,

Mitochondria are fundamental organelles in cell biology. They can no longer be considered simply the powerhouse of the cell because this fundamental function is strictly related to different activities of the cell (apoptosis, signal transduction, thermogenesis, proliferation, differentiation, and so on). Experimental research gives some light to molecular mechanisms at the basis of these complex and interconnected functions with significant advances in knowledge of the etiopathogenesis, pathophysiology, and therapeutic approaches of different diseases. Importantly, these different pathologies are not limited to typical mitochondrial disorders but affect a wide range of acute and chronic diseases (i.e., ischemic disorders, infectious diseases, neurodegenerative diseases, infertility, psychotic disorder, dermopathies, sepsis, and above all, cancer). The growing pathophysiological role of mitochondria is further demonstrated by the number of clinical studies, recorded by ClinicalTrials.gov, showing mitochondria in their keywords panel (at present, more than 1500 clinical studies).

To date, the pharmacology of mitochondria includes molecules which can enrich the NAD+ pool and/or “stimulate” oxidative metabolism (i.e., carnitine), molecules that protect these organelles by the end products of their oxidative metabolism (i.e., Q10, mitoQ, dicumarols and son on); however, some interesting new drugs are now under evaluation.

Last but not least, some intriguing parmacotoxicological aspects, too often neglected, on mitochondria, as innocent bystanders, are well-known (fibrates, statins, reverse-transcriptase inhibitors). All these data further push to deepen our understanding of and promote such a fascinating, innovative, and promising therapeutic approach.

This Special Issue focuses on the research field of the pharmacology of mitochondria; Original research articles, short communications, and reviews, both narrative and systematic, are all welcome for submission to this Special Issue.

Dr. Roberto Scatena
Dr. Patrizia Bottoni
Guest Editors

Manuscript Submission Information

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

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

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

Keywords

cancer
complex I (NADH: ubiquinone oxidoreductase)
drug toxicity
mitochondria
reactive oxygen species (ROS)
therapeutic drug monitoring
cancer stem cells
cancer cell differentiation
cancer cell metabolism
cancer diagnosis
cancer therapy
complex I
oxidative phoshorylation
tumor markers
Warburg effect

Related Special Issue

Mitochondrial Medicine: Pharmacological Targeting of Mitochondria in Disease 2.0 in International Journal of Molecular Sciences

Published Papers (8 papers)

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Research

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11 pages, 1179 KiB

Open AccessCommunication

Evaluation of Mitochondrial Dysfunction and Idebenone Responsiveness in Fibroblasts from Leber’s Hereditary Optic Neuropathy (LHON) Subjects

by Mirko Baglivo, Alessia Nasca, Eleonora Lamantea, Stefano Vinci, Manuela Spagnolo, Silvia Marchet, Holger Prokisch, Alessia Catania, Costanza Lamperti and Daniele Ghezzi

Int. J. Mol. Sci. 2023, 24(16), 12580; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241612580 - 08 Aug 2023

Cited by 1 | Viewed by 914

Abstract

Leber’s hereditary optic neuropathy (LHON) is a disease that affects the optical nerve, causing visual loss. The diagnosis of LHON is mostly defined by the identification of three pathogenic variants in the mitochondrial DNA. Idebenone is widely used to treat LHON patients, but only some of them are responders to treatment. In our study, we assessed the maximal respiration rate (MRR) and other respiratory parameters in eight fibroblast lines from subjects carrying LHON pathogenic variants. We measured also the effects of idebenone treatment on cell growth and mtDNA amounts. Results showed that LHON fibroblasts had significantly reduced respiratory parameters in untreated conditions, but no significant gain in MRR after idebenone supplementation. No major toxicity toward mitochondrial function and no relevant compensatory effect in terms of mtDNA quantity were found for the treatment at the tested conditions. Our findings confirmed that fibroblasts from subjects harboring LHON pathogenic variants displayed impaired respiration, regardless of the disease penetrance and severity. Testing responsiveness to idebenone treatment in cultured cells did not fully recapitulate in vivo data. The in-depth evaluation of cellular respiration in fibroblasts is a good approach to evaluating novel mtDNA variants associated with LHON but needs further evaluation as a potential biomarker for disease prognosis and treatment responsiveness. Full article

(This article belongs to the Special Issue Mitochondrial Medicine: Pharmacological Targeting of Mitochondria in Disease)

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23 pages, 5144 KiB

Open AccessArticle

Contemporary Antiretroviral Therapy Dysregulates Iron Transport and Augments Mitochondrial Dysfunction in HIV-Infected Human Microglia and Neural-Lineage Cells

by Harpreet Kaur, Paige Minchella, David Alvarez-Carbonell, Neeraja Purandare, Vijay K. Nagampalli, Daniel Blankenberg, Todd Hulgan, Mariana Gerschenson, Jonathan Karn, Siddhesh Aras and Asha R. Kallianpur

Int. J. Mol. Sci. 2023, 24(15), 12242; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241512242 - 31 Jul 2023

Cited by 2 | Viewed by 1367

Abstract

HIV-associated cognitive dysfunction during combination antiretroviral therapy (cART) involves mitochondrial dysfunction, but the impact of contemporary cART on chronic metabolic changes in the brain and in latent HIV infection is unclear. We interrogated mitochondrial function in a human microglia (hμglia) cell line harboring inducible HIV provirus and in SH-SY5Y cells after exposure to individual antiretroviral drugs or cART, using the MitoStress assay. cART-induced changes in protein expression, reactive oxygen species (ROS) production, mitochondrial DNA copy number, and cellular iron were also explored. Finally, we evaluated the ability of ROS scavengers or plasmid-mediated overexpression of the antioxidant iron-binding protein, Fth1, to reverse mitochondrial defects. Contemporary antiretroviral drugs, particularly bictegravir, depressed multiple facets of mitochondrial function by 20–30%, with the most pronounced effects in latently infected HIV+ hμglia and SH-SY5Y cells. Latently HIV-infected hμglia exhibited upregulated glycolysis. Increases in total and/or mitochondrial ROS, mitochondrial DNA copy number, and cellular iron accompanied mitochondrial defects in hμglia and SH-SY5Y cells. In SH-SY5Y cells, cART reduced mitochondrial iron–sulfur-cluster-containing supercomplex and subunit expression and increased Nox2 expression. Fth1 overexpression or pre-treatment with N-acetylcysteine prevented cART-induced mitochondrial dysfunction. Contemporary cART impairs mitochondrial bioenergetics in hμglia and SH-SY5Y cells, partly through cellular iron accumulation; some effects differ by HIV latency. Full article

(This article belongs to the Special Issue Mitochondrial Medicine: Pharmacological Targeting of Mitochondria in Disease)

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29 pages, 11545 KiB

Open AccessArticle

Experimental Treatment with Edaravone in a Mouse Model of Spinocerebellar Ataxia 1

by Martina Sucha, Simona Benediktova, Filip Tichanek, Jan Jedlicka, Stepan Kapl, Dana Jelinkova, Zdenka Purkartova, Jan Tuma, Jitka Kuncova and Jan Cendelin

Int. J. Mol. Sci. 2023, 24(13), 10689; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310689 - 26 Jun 2023

Viewed by 1420

Abstract

Edaravone is a mitochondrially targeted drug with a suggested capability to modify the course of diverse neurological diseases. Nevertheless, edaravone has not been tested yet in the context of spinocerebellar ataxia 1 (SCA1), an incurable neurodegenerative disease characterized mainly by cerebellar disorder, with a strong contribution of inflammation and mitochondrial dysfunction. This study aimed to address this gap, exploring the potential of edaravone to slow down SCA1 progression in a mouse knock-in SCA1 model. SCA1^154Q/2Q and healthy SCA1^2Q/2Q mice were administered either edaravone or saline daily for more than 13 weeks. The functional impairments were assessed via a wide spectrum of behavioral assays reflecting motor and cognitive deficits and behavioral abnormalities. Moreover, we used high-resolution respirometry to explore mitochondrial function, and immunohistochemical and biochemical tools to assess the magnitude of neurodegeneration, inflammation, and neuroplasticity. Data were analyzed using (hierarchical) Bayesian regression models, combined with the methods of multivariate statistics. Our analysis pointed out various previously documented neurological and behavioral deficits of SCA1 mice. However, we did not detect any plausible therapeutic effect of edaravone on either behavioral dysfunctions or other disease hallmarks in SCA1 mice. Thus, our results did not provide support for the therapeutic potential of edaravone in SCA1. Full article

(This article belongs to the Special Issue Mitochondrial Medicine: Pharmacological Targeting of Mitochondria in Disease)

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23 pages, 2512 KiB

Open AccessArticle

Redox-Cycling “Mitocans” as Effective New Developments in Anticancer Therapy

by Rumiana Bakalova, Dessislava Lazarova, Akira Sumiyoshi, Sayaka Shibata, Zhivko Zhelev, Biliana Nikolova, Severina Semkova, Tatyana Vlaykova, Ichio Aoki and Tatsuya Higashi

Int. J. Mol. Sci. 2023, 24(9), 8435; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24098435 - 08 May 2023

Cited by 1 | Viewed by 1912

Abstract

Our study proposes a pharmacological strategy to target cancerous mitochondria via redox-cycling “mitocans” such as quinone/ascorbate (Q/A) redox-pairs, which makes cancer cells fragile and sensitive without adverse effects on normal cells and tissues. Eleven Q/A redox-pairs were tested on cultured cells and cancer-bearing mice. The following parameters were analyzed: cell proliferation/viability, mitochondrial superoxide, steady-state ATP, tissue redox-state, tumor-associated NADH oxidase (tNOX) expression, tumor growth, and survival. Q/A redox-pairs containing unprenylated quinones exhibited strong dose-dependent antiproliferative and cytotoxic effects on cancer cells, accompanied by overproduction of mitochondrial superoxide and accelerated ATP depletion. In normal cells, the same redox-pairs did not significantly affect the viability and energy homeostasis, but induced mild mitochondrial oxidative stress, which is well tolerated. Benzoquinone/ascorbate redox-pairs were more effective than naphthoquinone/ascorbate, with coenzyme Q0/ascorbate exhibiting the most pronounced anticancer effects in vitro and in vivo. Targeted anticancer effects of Q/A redox-pairs and their tolerance to normal cells and tissues are attributed to: (i) downregulation of quinone prenylation in cancer, leading to increased mitochondrial production of semiquinone and, consequently, superoxide; (ii) specific and accelerated redox-cycling of unprenylated quinones and ascorbate mainly in the impaired cancerous mitochondria due to their redox imbalance; and (iii) downregulation of tNOX. Full article

(This article belongs to the Special Issue Mitochondrial Medicine: Pharmacological Targeting of Mitochondria in Disease)

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18 pages, 2985 KiB

Open AccessArticle

Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma

by Tadataka Takagi, Rina Fujiwara-Tani, Shiori Mori, Shingo Kishi, Yukiko Nishiguchi, Takamitsu Sasaki, Ruiko Ogata, Ayaka Ikemoto, Rika Sasaki, Hitoshi Ohmori, Yi Luo, Ujjal Kumar Bhawal, Masayuki Sho and Hiroki Kuniyasu

Int. J. Mol. Sci. 2023, 24(8), 7506; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087506 - 19 Apr 2023

Cited by 4 | Viewed by 1299

Abstract

Although gemcitabine (GEM) is widely used in chemotherapy for pancreatic ductal adenocarcinoma (PDA), drug resistance restricts its clinical effectiveness. To examine the mechanism of GEM resistance, we established two GEM-resistant cell lines from human PDA cells by continuous treatment with GEM and CoCl₂-induced chemical hypoxia. One resistant cell line possessed reduced energy production and decreased mitochondrial reactive oxygen species levels, while the other resistant cell line possessed increased stemness. In both cell lines, ethidium bromide-stained mitochondrial DNA levels decreased, suggesting mitochondrial DNA damage. Inhibition of hypoxia-inducible factor-1α in both cell lines did not restore the GEM sensitivity. In contrast, treatment of both cell types with lauric acid (LAA), a medium-chain fatty acid, restored GEM sensitivity. These results suggest that decreased energy production, decreased mitochondrial reactive oxygen species levels, and increased stemness associated with mitochondrial damage caused by GEM lead to GEM resistance, and that hypoxia may promote this process. Furthermore, forced activation of oxidative phosphorylation by LAA could be a tool to overcome GEM resistance. Clinical verification of the effectiveness of LAA in GEM resistance is necessary in the future. Full article

(This article belongs to the Special Issue Mitochondrial Medicine: Pharmacological Targeting of Mitochondria in Disease)

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Review

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34 pages, 1216 KiB

Open AccessReview

Drug Drop Test: How to Quickly Identify Potential Therapeutic Compounds for Mitochondrial Diseases Using Yeast Saccharomyces cerevisiae

by Martina Magistrati, Alexandru Ionut Gilea, Maria Carla Gerra, Enrico Baruffini and Cristina Dallabona

Int. J. Mol. Sci. 2023, 24(13), 10696; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310696 - 27 Jun 2023

Cited by 1 | Viewed by 1431

Abstract

Mitochondrial diseases (MDs) refer to a group of clinically and genetically heterogeneous pathologies characterized by defective mitochondrial function and energy production. Unfortunately, there is no effective treatment for most MDs, and current therapeutic management is limited to relieving symptoms. The yeast Saccharomyces cerevisiae has been efficiently used as a model organism to study mitochondria-related disorders thanks to its easy manipulation and well-known mitochondrial biogenesis and metabolism. It has been successfully exploited both to validate alleged pathogenic variants identified in patients and to discover potential beneficial molecules for their treatment. The so-called “drug drop test”, a phenotype-based high-throughput screening, especially if coupled with a drug repurposing approach, allows the identification of molecules with high translational potential in a cost-effective and time-saving manner. In addition to drug identification, S. cerevisiae can be used to point out the drug’s target or pathway. To date, drug drop tests have been successfully carried out for a variety of disease models, leading to very promising results. The most relevant aspect is that studies on more complex model organisms confirmed the effectiveness of the drugs, strengthening the results obtained in yeast and demonstrating the usefulness of this screening as a novel approach to revealing new therapeutic molecules for MDs. Full article

(This article belongs to the Special Issue Mitochondrial Medicine: Pharmacological Targeting of Mitochondria in Disease)

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22 pages, 1759 KiB

Open AccessReview

Mitochondria Deregulations in Cancer Offer Several Potential Targets of Therapeutic Interventions

by Clara Musicco, Anna Signorile, Vito Pesce, Paola Loguercio Polosa and Antonella Cormio

Int. J. Mol. Sci. 2023, 24(13), 10420; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310420 - 21 Jun 2023

Cited by 9 | Viewed by 2425

Abstract

Mitochondria play a key role in cancer and their involvement is not limited to the production of ATP only. Mitochondria also produce reactive oxygen species and building blocks to sustain rapid cell proliferation; thus, the deregulation of mitochondrial function is associated with cancer disease development and progression. In cancer cells, a metabolic reprogramming takes place through a different modulation of the mitochondrial metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, the Krebs cycle, glutamine and heme metabolism. Alterations of mitochondrial homeostasis, in particular, of mitochondrial biogenesis, mitophagy, dynamics, redox balance, and protein homeostasis, were also observed in cancer cells. The use of drugs acting on mitochondrial destabilization may represent a promising therapeutic approach in tumors in which mitochondrial respiration is the predominant energy source. In this review, we summarize the main mitochondrial features and metabolic pathways altered in cancer cells, moreover, we present the best known drugs that, by acting on mitochondrial homeostasis and metabolic pathways, may induce mitochondrial alterations and cancer cell death. In addition, new strategies that induce mitochondrial damage, such as photodynamic, photothermal and chemodynamic therapies, and the development of nanoformulations that specifically target drugs in mitochondria are also described. Thus, mitochondria-targeted drugs may open new frontiers to a tailored and personalized cancer therapy. Full article

(This article belongs to the Special Issue Mitochondrial Medicine: Pharmacological Targeting of Mitochondria in Disease)

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Other

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9 pages, 815 KiB

Open AccessOpinion

Mitochondria in Human Fertility and Infertility

by Jan Tesarik and Raquel Mendoza-Tesarik

Int. J. Mol. Sci. 2023, 24(10), 8950; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108950 - 18 May 2023

Cited by 4 | Viewed by 2603

Abstract

In human spermatozoa and oocytes (and their surrounding granulosa cells), mitochondria carry out important functions relating to human fertility and infertility. Sperm mitochondria are not transmitted to the future embryo, but are closely related to the generation of energy needed for sperm movement, capacitation, and acrosome reactions, as well as for sperm–oocyte fusion. On the other hand, oocyte mitochondria produce energy required for oocyte meiotic division and their abnormalities can thus cause oocyte and embryo aneuploidy. In addition, they play a role in oocyte calcium metabolism and in essential epigenetic events during the oocyte-to-embryo transition. They are transmitted to the future embryos and may thus cause hereditary diseases in the offspring. Due to the long life span of the female germ cells, the accumulation of mitochondrial DNA abnormalities often causes ovarian aging. Mitochondrial substitution therapy is the only way of dealing with these issues nowadays. New therapies based on mitochondrial DNA editing are under investigation. Full article

(This article belongs to the Special Issue Mitochondrial Medicine: Pharmacological Targeting of Mitochondria in Disease)

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