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Mitochondria-Targeted Approaches in Health and Disease 2.0

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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 January 2022) | Viewed by 18219

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Special Issue Editor

Prof. Dr. Dmitry Zorov

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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 a prerequisite of a healthy cell. Inherited or acquired mitochondrial dysfunction 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 unfit mitochondria or their elements with their elimination from the cell, ultimately clearing the system of abnormal mitochondrial structures. However, because of intrinsic and extrinsic challenges, this machinery misses mitochondrial defects, yielding the co-existence of normal and abnormal mitochondria within a single cell, which is a main index of diseases and aging. To avoid the unnecessary appearance of an unhealthy mitochondrial population in the cell when intrinsic mechanisms of reparation have 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 mitochondrial structure and function.

Prof. Dr. Dmitry Zorov
Guest Editor

Manuscript Submission Information

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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 in International Journal of Molecular Sciences (10 articles)

Published Papers (7 papers)

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Research

22 pages, 2142 KiB

Open AccessArticle

Ketogenic Diet Consumption Inhibited Mitochondrial One-Carbon Metabolism

by Fan-Yu Hsu, Jia-Ying Liou, Feng-Yao Tang, Nga-Lai Sou, Jian-Hau Peng and En-Pei Isabel Chiang

Int. J. Mol. Sci. 2022, 23(7), 3650; https://doi.org/10.3390/ijms23073650 - 26 Mar 2022

Cited by 3 | Viewed by 3096

Abstract

Given the popularity of ketogenic diets, their potential long-term consequences deserve to be more carefully monitored. Mitochondrially derived formate has a critical role in mammalian one-carbon (1C) metabolism and development. The glycine cleavage system (GCS) accounts for another substantial source for mitochondrially derived 1C units. Objective: We investigated how the ketogenic state modulates mitochondrial formate generation and partitioning of 1C metabolic fluxes. Design: HepG2 cells treated with physiological doses (1 mM and 10 mM) of β-hydroxybutyrate (βHB) were utilized as the in vitro ketogenic model. Eight-week male C57BL/6JNarl mice received either a medium-chain fatty-acid-enriched ketogenic diet (MCT-KD) or a control diet AIN 93M for 8 weeks. Stable isotopic labeling experiments were conducted. Results and Conclusions: MCT-KD is effective in weight and fat loss. Deoxythymidine (dTMP) synthesis from the mitochondrial GCS-derived formate was significantly suppressed by βHB and consumption of MCT-KD. Consistently, plasma formate concentrations, as well as the metabolic fluxes from serine and glycine, were suppressed by MCT-KD. MCT-KD also decreased the fractional contribution of mitochondrially derived formate in methionine synthesis from serine. With the worldwide application, people and medical professionals should be more aware of the potential metabolic perturbations when practicing a long-term ketogenic diet. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease 2.0)

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10 pages, 2035 KiB

Open AccessArticle

Disease Outcome and Brain Metabolomics of Cyclophilin-D Knockout Mice in Sepsis

by Takayuki Kobayashi, Hiroyuki Uchino, Eskil Elmér, Yukihiko Ogihara, Hidetoshi Fujita, Shusuke Sekine, Yusuke Ishida, Iwao Saiki, Shoichiro Shibata and Aya Kawachi

Int. J. Mol. Sci. 2022, 23(2), 961; https://doi.org/10.3390/ijms23020961 - 16 Jan 2022

Cited by 10 | Viewed by 2228

Abstract

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction resulting from a systemic inflammatory response to infection, but the mechanism remains unclear. The mitochondrial permeability transition pore (MPTP) could play a central role in the neuronal dysfunction, induction of apoptosis, and cell death in SAE. The mitochondrial isomerase cyclophilin D (CypD) is known to control the sensitivity of MPTP induction. We, therefore, established a cecal ligation and puncture (CLP) model, which is the gold standard in sepsis research, using CypD knockout (CypD KO) mice, and analyzed the disease phenotype and the possible molecular mechanism of SAE through metabolomic analyses of brain tissue. A comparison of adult, male wild-type, and CypD KO mice demonstrated statistically significant differences in body temperature, mortality, and histological changes. In the metabolomic analysis, the main finding was the maintenance of reduced glutathione (GSH) levels and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio in the KO animals following CLP. In conclusion, we demonstrate that CypD is implicated in the pathogenesis of SAE, possibly related to the inhibition of MPTP induction and, as a consequence, the decreased production of ROS and other free radicals, thereby protecting mitochondrial and cellular function. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease 2.0)

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14 pages, 2136 KiB

Open AccessArticle

Etifoxine Restores Mitochondrial Oxidative Phosphorylation and Improves Cognitive Recovery Following Traumatic Brain Injury

by Eilam Palzur, Doron Edelman, Reem Sakas and Jean Francois Soustiel

Int. J. Mol. Sci. 2021, 22(23), 12881; https://doi.org/10.3390/ijms222312881 - 28 Nov 2021

Cited by 13 | Viewed by 2065

Abstract

The opening of the mitochondrial permeability transition pore (mPTP) has emerged as a pivotal event following traumatic brain injury (TBI). Evidence showing the impact of the translocator protein (TSPO) over mPTP activity has prompted several studies exploring the effect of TSPO ligands, including etifoxine, on the outcome of traumatic brain injury (TBI). Mitochondrial respiration was assessed by respirometry in isolated rat brain mitochondria (RBM) by measurements of oxidative phosphorylation capacity (OXPHOS). The addition of calcium to RBM was used to induce mitochondrial injury and resulted in significant OXPHOS reduction that could be reversed by preincubation of RBM with etifoxine. Sensorimotor and cognitive functions were assessed following controlled cortical impact and compared in vehicle and etifoxine-treated animals. There was no difference between the vehicle and etifoxine groups for sensorimotor functions as assessed by rotarod. In contrast, etifoxine resulted in a significant improvement of cognitive functions expressed by faster recovery in Morris water maze testing. The present findings show a significant neuroprotective effect of etifoxine in TBI through restoration of oxidative phosphorylation capacity associated with improved behavioral and cognitive outcomes. Since etifoxine is a registered drug used in common clinical practice, implementation in a phase II study may represent a reasonable step forward. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease 2.0)

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23 pages, 5419 KiB

Open AccessArticle

Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis

by Tom Kretzschmar, Mohamed M. Bekhite, Jasmine M. F. Wu, Daniela Haase, Martin Förster, Tina Müller, Sandor Nietzsche, Martin Westermann, Marcus Franz, Markus H. Gräler and P. Christian Schulze

Int. J. Mol. Sci. 2021, 22(21), 11852; https://doi.org/10.3390/ijms222111852 - 1 Nov 2021

Cited by 5 | Viewed by 2011

Abstract

Doxorubicin (Dox) is a chemotherapeutic agent with cardiotoxicity associated with profibrotic effects. Dox increases ceramide levels with pro-inflammatory effects, cell death, and fibrosis. The purpose of our study was to identify the underlying ceramide signaling pathways. We aimed to characterize the downstream effects on cell survival, metabolism, and fibrosis. Human fibroblasts (hFSF) were treated with 0.7 µM of Dox or transgenically overexpressed ceramide synthase 2 (FLAG-CerS2). Furthermore, cells were pre-treated with MitoTempo (MT) (2 h, 20 µM) or Fumonisin B1 (FuB) (4 h, 100 µM). Protein expression was measured by Western blot or immunofluorescence (IF). Ceramide levels were determined with mass spectroscopy (MS). Visualizations were conducted using laser scanning microscopy (LSM) or electron microscopy. Mitochondrial activity was measured using seahorse analysis. Dox and CerS2 overexpression increased CerS2 protein expression. Coherently, ceramides were elevated with the highest peak for C24:0. Ceramide- induced mitochondrial ROS production was reduced with MT or FuB preincubation. Mitochondrial homeostasis was reduced and accompanied by reduced ATP production. Our data show that the increase in pro-inflammatory ceramides is an essential contributor to Dox side-effects. The accumulation of ceramides resulted in a lipotoxic shift and subsequently mitochondrial structural and functional damage, which was partially reversible following inhibition of ceramide synthesis. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease 2.0)

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17 pages, 2995 KiB

Open AccessArticle

Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity

by Alina M. Bețiu, Imen Chamkha, Ellen Gustafsson, Elna Meijer, Vlad F. Avram, Eleonor Åsander Frostner, Johannes K. Ehinger, Lucian Petrescu, Danina M. Muntean and Eskil Elmér

Int. J. Mol. Sci. 2021, 22(21), 11786; https://doi.org/10.3390/ijms222111786 - 29 Oct 2021

Cited by 8 | Viewed by 2492

Abstract

Amiodarone is a potent antiarrhythmic drug and displays substantial liver toxicity in humans. It has previously been demonstrated that amiodarone and its metabolite (desethylamiodarone, DEA) can inhibit mitochondrial function, particularly complexes I (CI) and II (CII) of the electron transport system in various animal tissues and cell types. The present study, performed in human peripheral blood cells, and one liver-derived human cell line, is primarily aimed at assessing the concentration-dependent effects of these drugs on mitochondrial function (respiration and cellular ATP levels). Furthermore, we explore the efficacy of a novel cell-permeable succinate prodrug in alleviating the drug-induced acute mitochondrial dysfunction. Amiodarone and DEA elicit a concentration-dependent impairment of mitochondrial respiration in both intact and permeabilized platelets via the inhibition of both CI- and CII-supported respiration. The inhibitory effect seen in human platelets is also confirmed in mononuclear cells (PBMCs) and HepG2 cells. Additionally, amiodarone elicits a severe concentration-dependent ATP depletion in PBMCs, which cannot be explained solely by mitochondrial inhibition. The succinate prodrug NV118 alleviates the respiratory deficit in platelets and HepG2 cells acutely exposed to amiodarone. In conclusion, amiodarone severely inhibits metabolism in primary human mitochondria, which can be counteracted by increasing mitochondrial function using intracellular delivery of succinate. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease 2.0)

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13 pages, 11830 KiB

Open AccessArticle

Collecting Duct-Specific CR6-Interacting Factor-1-Deletion Aggravates Renal Inflammation and Fibrosis Induced by Unilateral Ureteral Obstruction

by Jin Young Jeong, Ki Ryang Na, Jin Ah Shin, Kwang-Sun Suh, Jwa-Jin Kim, Kang Wook Lee and Dae Eun Choi

Int. J. Mol. Sci. 2021, 22(21), 11699; https://doi.org/10.3390/ijms222111699 - 28 Oct 2021

Cited by 5 | Viewed by 2212

Abstract

Although inflammation and fibrosis, which are key mechanisms of chronic kidney disease, are associated with mitochondrial damage, little is known about the effects of mitochondrial damage on the collecting duct in renal inflammation and fibrosis. To generate collecting duct-specific mitochondrial injury mouse models, CR6-interacting factor-1 (CRIF1) ^flox/flox mice were bred with Hoxb7-Cre mice. We evaluated the phenotype of these mice. To evaluate the effects on unilateral ureteral obstruction (UUO)-induced renal injury, we divided the mice into the following four groups: a CRIF1^flox/flox (wild-type (WT)) group, a CRIF1^flox/flox-Hob7 Cre (CRIF1-KO) group, a WT-UUO group, and a CRIF1-KO UUO group. We evaluated the blood and urine chemistries, inflammatory and fibrosis markers, light microscopy, and electron microscopy of the kidneys. The inhibition of Crif1 mRNA in mIMCD cells reduced oxygen consumption and membrane potential. No significant differences in blood and urine chemistries were observed between WT and CRIF1-KO mice. In UUO mice, monocyte chemoattractant protein-1 and osteopontin expression, number of F4/80 positive cells, transforming growth factor-β and α-smooth muscle actin staining, and Masson’s trichrome staining were significantly higher in the kidneys of CRIF1-KO mice compared with the kidneys of WT mice. In sham mice, urinary 8-hydroxydeoxyguanosine (8-OHDG) was higher in CRIF1-KO mice than in WT mice. Moreover, CRIF1-KO sham mice had increased 8-OHDG-positive cell recruitment compared with WT-sham mice. CRIF1-KO-UUO kidneys had increased recruitment of 8-OHDG-positive cells compared with WT-UUO kidneys. In conclusion, collecting duct-specific mitochondrial injury increased oxidative stress. Oxidative stress associated with mitochondrial damage may aggravate UUO-induced renal injury. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease 2.0)

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14 pages, 16839 KiB

Open AccessArticle

Tamoxifen Sensitizes Acute Lymphoblastic Leukemia Cells to Cannabidiol by Targeting Cyclophilin-D and Altering Mitochondrial Ca²⁺ Homeostasis

by Miguel Olivas-Aguirre, Liliana Torres-López, Zeferino Gómez-Sandoval, Kathya Villatoro-Gómez, Igor Pottosin and Oxana Dobrovinskaya

Int. J. Mol. Sci. 2021, 22(16), 8688; https://doi.org/10.3390/ijms22168688 - 13 Aug 2021

Cited by 5 | Viewed by 2636

Abstract

Cytotoxic effects of cannabidiol (CBD) and tamoxifen (TAM) have been observed in several cancer types. We have recently shown that CBD primarily targets mitochondria, inducing a stable mitochondrial permeability transition pore (mPTP) and, consequently, the death of acute lymphoblastic leukemia (T-ALL) cells. Mitochondria have also been documented among cellular targets for the TAM action. In the present study we have demonstrated a synergistic cytotoxic effect of TAM and CBD against T-ALL cells. By measuring the mitochondrial membrane potential (ΔΨm), mitochondrial calcium ([Ca²⁺]_m) and protein-ligand docking analysis we determined that TAM targets cyclophilin D (CypD) to inhibit mPTP formation. This results in a sustained [Ca²⁺]_m overload upon the consequent CBD administration. Thus, TAM acting on CypD sensitizes T-ALL to mitocans such as CBD by altering the mitochondrial Ca²⁺ homeostasis. Full article

(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease 2.0)

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