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Biomolecules
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Mitochondrial Diseases
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Mitochondrial Diseases

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (15 June 2019) | Viewed by 29682

Special Issue Editor

Prof. Dr. Josephine S. Modica-Napolitano

E-Mail Website
Guest Editor
Merrimack College, 315 Turnpike Street, North Andover, MA 01845, USA
Interests: mitochondrial bioenergetics; mitochondrial dysfunction and disease; mitochondria and cancer; mitochondria-targeted anti-cancer compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria have long been recognized as the subcellular sites for oxidative phosphorylation and, thus, the majority of cellular ATP production. More recently, however, a number of new roles for mitochondria in the regulation of the cell life and death have also been revealed. It is now known, for example, that mitochondria play important roles in cell signaling, proliferation, metabolism, aging, and apoptosis, and that mitochondrial dysfunction is implicated as a causal or contributing factor in the development and/or progression of multiple diseases. For some of these diseases, such as myoclonic epilepsy with ragged red fibers (MERRF) and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndromes, the link between specific genetic or metabolic alterations in mitochondria and the resulting pathology is well characterized. For other diseases, such as diabetes, Parkinson’s, and cancer, the putative link between mitochondrial dysfunction and the pathology has proven significantly much more difficult to ascertain.

The purpose of this Special Issue is to provide a current overview of a variety of known and suspected mitochondria-linked diseases, to highlight recent advances in understanding the role of mitochondria in disease etiology and progression, and to explore promising new compounds and therapeutic strategies for the treatment of mitochondrial disease. Submission of reviews and basic or translational research papers are encouraged.

Prof. Dr. Josephine S. Modica-Napolitano
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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mitochondrial disease
  • mitochondrial dysfunction
  • mtDNA mutations
  • nDNA mutations in genes encoding mitochondrial proteins
  • mitochondria-targeted therapy

Published Papers (6 papers)

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Research

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16 pages, 3891 KiB  
Article
The Anticancer Agent Elesclomol Has Direct Effects on Mitochondrial Bioenergetic Function in Isolated Mammalian Mitochondria
by Josephine S. Modica-Napolitano, Leena P. Bharath, Alison J. Hanlon and Liam D. Hurley
Biomolecules 2019, 9(8), 298; https://doi.org/10.3390/biom9080298 - 24 Jul 2019
Cited by 20 | Viewed by 3504
Abstract
Elesclomol ((N-malonyl-bis(N′-methyl-N′-thiobenzoylhydrazide)); formerly STA-4783) is a mitochondria-targeted chemotherapeutic agent that has demonstrated efficacy in selective cancer cell killing in pre-clinical and clinical testing. The biologically active form of elesclomol is a deprotonated copper chelate (elesclomol:copper; E:C), which [...] Read more.
Elesclomol ((N-malonyl-bis(N′-methyl-N′-thiobenzoylhydrazide)); formerly STA-4783) is a mitochondria-targeted chemotherapeutic agent that has demonstrated efficacy in selective cancer cell killing in pre-clinical and clinical testing. The biologically active form of elesclomol is a deprotonated copper chelate (elesclomol:copper; E:C), which has been shown to enhance reactive oxygen species (ROS) production and induce a transcriptional gene profile characteristic of an oxidative stress response in vitro. Previous studies suggest that E:C interacts with the electron transport chain (ETC) to generate high levels of ROS within the organelle and ultimately induce cell death. The purpose of this study was to further explore the mechanism of cellular and mitochondrial toxicity of E:C by examining its direct effect on mitochondrial bioenergetic function. The results obtained indicate that E:C treatment in whole cells of non-tumorigenic origin at high concentrations (40 μM and higher) induces a rapid and substantial increase in mitochondrial superoxide levels and dissipation of mitochondrial membrane potential. Furthermore, similar higher concentrations of E:C act as a direct uncoupler of oxidative phosphorylation and generalized inhibitor of electron transport activity in isolated, intact mitochondria, and induce a dose-dependent inhibition of mitochondrial NADH-ubiquinone oxidoreductase activity in freeze-thawed mitochondrial preparations. The results of this study are important in that they are the first to demonstrate a direct effect of the E:C chelate on bioenergetic function in isolated mammalian mitochondria, and suggest the possibility that the increase in ROS production and cytotoxicity induced by E:C may in part be due to uncoupling of mitochondrial oxidative phosphorylation and/or inhibition of electron transport activity. These results also provide important information about the mechanisms of mitochondrial and cellular toxicity induced by E:C and will ultimately contribute to a better understanding of the therapeutic potential of elesclomol as an anticancer compound. Full article
(This article belongs to the Special Issue Mitochondrial Diseases)
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24 pages, 3011 KiB  
Article
Differential Effects of Yeast NADH Dehydrogenase (Ndi1) Expression on Mitochondrial Function and Inclusion Formation in a Cell Culture Model of Sporadic Parkinson’s Disease
by Emily N. Cronin-Furman, Jennifer Barber-Singh, Kristen E. Bergquist, Takao Yagi and Patricia A. Trimmer
Biomolecules 2019, 9(4), 119; https://doi.org/10.3390/biom9040119 - 27 Mar 2019
Cited by 6 | Viewed by 3670
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder that exhibits aberrant protein aggregation and mitochondrial dysfunction. Ndi1, the yeast mitochondrial NADH dehydrogenase (complex I) enzyme, is a single subunit, internal matrix-facing protein. Previous studies have shown that Ndi1 expression leads to improved mitochondrial function [...] Read more.
Parkinson’s disease (PD) is a neurodegenerative disorder that exhibits aberrant protein aggregation and mitochondrial dysfunction. Ndi1, the yeast mitochondrial NADH dehydrogenase (complex I) enzyme, is a single subunit, internal matrix-facing protein. Previous studies have shown that Ndi1 expression leads to improved mitochondrial function in models of complex I-mediated mitochondrial dysfunction. The trans-mitochondrial cybrid cell model of PD was created by fusing mitochondrial DNA-depleted SH-SY5Y cells with platelets from a sporadic PD patient. PD cybrid cells reproduce the mitochondrial dysfunction observed in a patient’s brain and periphery and form intracellular, cybrid Lewy bodies comparable to Lewy bodies in PD brain. To improve mitochondrial function and alter the formation of protein aggregates, Ndi1 was expressed in PD cybrid cells and parent SH-SY5Y cells. We observed a dramatic increase in mitochondrial respiration, increased mitochondrial gene expression, and increased PGC-1α gene expression in PD cybrid cells expressing Ndi1. Total cellular aggregated protein content was decreased but Ndi1 expression was insufficient to prevent cybrid Lewy body formation. Ndi1 expression leads to improved mitochondrial function and biogenesis signaling, both processes that could improve neuron survival during disease. However, other aspects of PD pathology such as cybrid Lewy body formation were not reduced. Consequently, resolution of mitochondrial dysfunction alone may not be sufficient to overcome other aspects of PD-related cellular pathology. Full article
(This article belongs to the Special Issue Mitochondrial Diseases)
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14 pages, 2623 KiB  
Article
Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism
by Grace McCambridge, Madhur Agrawal, Alanna Keady, Philip A. Kern, Hatice Hasturk, Barbara S. Nikolajczyk and Leena P. Bharath
Biomolecules 2019, 9(2), 79; https://doi.org/10.3390/biom9020079 - 25 Feb 2019
Cited by 17 | Viewed by 5545
Abstract
Circulating fatty acids (FAs) increase with obesity and can drive mitochondrial damage and inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial protein that positively regulates nicotinamide adenine dinucleotide phosphate (NADPH), a key mediator of energy transduction and redox homeostasis. The role that NNT-regulated [...] Read more.
Circulating fatty acids (FAs) increase with obesity and can drive mitochondrial damage and inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial protein that positively regulates nicotinamide adenine dinucleotide phosphate (NADPH), a key mediator of energy transduction and redox homeostasis. The role that NNT-regulated bioenergetics play in the inflammatory response of immune cells in obesity is untested. Our objective was to determine how free fatty acids (FFAs) regulate inflammation through impacts on mitochondria and redox homeostasis of peripheral blood mononuclear cells (PBMCs). PBMCs from lean subjects were activated with a T cell-specific stimulus in the presence or absence of generally pro-inflammatory palmitate and/or non-inflammatory oleate. Palmitate decreased immune cell expression of NNT, NADPH, and anti-oxidant glutathione, but increased reactive oxygen and proinflammatory Th17 cytokines. Oleate had no effect on these outcomes. Genetic inhibition of NNT recapitulated the effects of palmitate. PBMCs from obese (BMI >30) compared to lean subjects had lower NNT and glutathione expression, and higher Th17 cytokine expression, none of which were changed by exogenous palmitate. Our data identify NNT as a palmitate-regulated rheostat of redox balance that regulates immune cell function in obesity and suggest that dietary or therapeutic strategies aimed at increasing NNT expression may restore redox balance to ameliorate obesity-associated inflammation. Full article
(This article belongs to the Special Issue Mitochondrial Diseases)
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16 pages, 3733 KiB  
Article
Administration of Enalapril Started Late in Life Attenuates Hypertrophy and Oxidative Stress Burden, Increases Mitochondrial Mass, and Modulates Mitochondrial Quality Control Signaling in the Rat Heart
by Anna Picca, Giuseppe Sirago, Vito Pesce, Angela Maria Serena Lezza, Riccardo Calvani, Maurizio Bossola, Emanuele Rocco Villani, Francesco Landi, Christiaan Leeuwenburgh, Roberto Bernabei, Christy S. Carter and Emanuele Marzetti
Biomolecules 2018, 8(4), 177; https://doi.org/10.3390/biom8040177 - 17 Dec 2018
Cited by 17 | Viewed by 4005
Abstract
Mitochondrial dysfunction is a relevant mechanism in cardiac aging. Here, we investigated the effects of late-life enalapril administration at a non-antihypertensive dose on mitochondrial genomic stability, oxidative damage, and mitochondrial quality control (MQC) signaling in the hearts of aged rats. The protein expression [...] Read more.
Mitochondrial dysfunction is a relevant mechanism in cardiac aging. Here, we investigated the effects of late-life enalapril administration at a non-antihypertensive dose on mitochondrial genomic stability, oxidative damage, and mitochondrial quality control (MQC) signaling in the hearts of aged rats. The protein expression of selected mediators (i.e., mitochondrial antioxidant enzymes, energy metabolism, mitochondrial biogenesis, dynamics, and autophagy) was measured in old rats randomly assigned to receive enalapril (n = 8) or placebo (n = 8) from 24 to 27 months of age. We also assessed mitochondrial DNA (mtDNA) content, citrate synthase activity, oxidative lesions to protein and mtDNA (i.e., carbonyls and the abundance of mtDNA4834 deletion), and the mitochondrial transcription factor A (TFAM) binding to specific mtDNA regions. Enalapril attenuated cardiac hypertrophy and oxidative stress-derived damage (mtDNA oxidation, mtDNA4834 deletion, and protein carbonylation), while increasing mitochondrial antioxidant defenses. The binding of mitochondrial transcription factor A to mtDNA regions involved in replication and deletion generation was enhanced following enalapril administration. Increased mitochondrial mass as well as mitochondriogenesis and autophagy signaling were found in enalapril-treated rats. Late-life enalapril administration mitigates age-dependent cardiac hypertrophy and oxidative damage, while increasing mitochondrial mass and modulating MQC signaling. Further analyses are needed to conclusively establish whether enalapril may offer cardioprotection during aging. Full article
(This article belongs to the Special Issue Mitochondrial Diseases)
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Review

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10 pages, 2577 KiB  
Review
Sporadic Inclusion Body Myositis: An Acquired Mitochondrial Disease with Extras
by Boel De Paepe
Biomolecules 2019, 9(1), 15; https://doi.org/10.3390/biom9010015 - 07 Jan 2019
Cited by 21 | Viewed by 7115
Abstract
The sporadic form of inclusion body myositis (IBM) is the most common late-onset myopathy. Its complex pathogenesis includes degenerative, inflammatory and mitochondrial aspects. However, which of those mechanisms are cause and which effect, as well as their interrelations, remain partly obscured to this [...] Read more.
The sporadic form of inclusion body myositis (IBM) is the most common late-onset myopathy. Its complex pathogenesis includes degenerative, inflammatory and mitochondrial aspects. However, which of those mechanisms are cause and which effect, as well as their interrelations, remain partly obscured to this day. In this review the nature of the mitochondrial dysregulation in IBM muscle is explored and comparison is made with other muscle disorders. Mitochondrial alterations in IBM are evidenced by histological and serum biomarkers. Muscular mitochondrial dynamics is disturbed, with deregulated organelle fusion leading to subsequent morphological alterations and muscle displays abnormal mitophagy. The tissue increases mitochondrial content in an attempt to compensate dysfunction, yet mitochondrial DNA (mtDNA) alterations and mild mtDNA depletion are also present. Oxidative phosphorylation defects have repeatedly been shown, most notably a reduction in complex IV activities and levels of mitokines and regulatory RNAs are perturbed. Based on the cumulating evidence of mitochondrial abnormality as a disease contributor, it is therefore warranted to regard IBM as a mitochondrial disease, offering a feasible therapeutic target to be developed for this yet untreatable condition. Full article
(This article belongs to the Special Issue Mitochondrial Diseases)
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Other

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13 pages, 720 KiB  
Perspective
The Michael J. Fox Foundation for Parkinson’s Research Strategy to Advance Therapeutic Development of PINK1 and Parkin
by Shalini Padmanabhan, Nicole K. Polinski, Liliana B. Menalled, Marco A.S. Baptista and Brian K. Fiske
Biomolecules 2019, 9(8), 296; https://doi.org/10.3390/biom9080296 - 24 Jul 2019
Cited by 15 | Viewed by 5174
Abstract
The role of mitochondria in Parkinson’s disease (PD) has been investigated since the 1980s and is gaining attention with recent advances in PD genetics research. Mutations in PRKN and PTEN-Induced Putative Kinase 1 (PINK1) are well-established causes of autosomal recessive early-onset [...] Read more.
The role of mitochondria in Parkinson’s disease (PD) has been investigated since the 1980s and is gaining attention with recent advances in PD genetics research. Mutations in PRKN and PTEN-Induced Putative Kinase 1 (PINK1) are well-established causes of autosomal recessive early-onset PD. Genetic and biochemical studies have revealed that PINK1 and Parkin proteins function together in the same biological pathway to govern mitochondrial quality control. These proteins have also been implicated in the regulation of innate and adaptive immunity and other mitochondrial functions. Additionally, structural studies on Parkin have delineated an activation mechanism and have identified druggable regions that are currently being explored by academic and industry groups. To de-risk therapeutic development for these genetic targets, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has deployed a strategic funding and enabling framework that brings together the research community to discuss important breakthroughs and challenges in research on PINK1-Parkin biology, supports collaborative initiatives to further our understanding within this field and develops high-quality research tools and assays that are widely available to all researchers. The Foundation’s efforts are leading to significant advances in understanding of the underlying biology of these genes, proteins and pathways and in the development of Parkinson’s therapies. Full article
(This article belongs to the Special Issue Mitochondrial Diseases)
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