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16 pages, 12039 KiB

Open AccessArticle

Low-Energy Shock Wave Suppresses Prostatic Pain and Inflammation by Modulating Mitochondrial Dynamics Regulators on a Carrageenan-Induced Prostatitis Model in Rats

by Zong-Sheng Wu, Hung-Jen Wang, Wei-Chia Lee, Hou Lun Luo, Tsu-Kung Lin and Yao-Chi Chuang

Int. J. Mol. Sci. 2023, 24(4), 3898; https://doi.org/10.3390/ijms24043898 - 15 Feb 2023

Cited by 2 | Viewed by 1361

Abstract

A low-energy shock wave (LESW) has therapeutic effects on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); however, its mechanism of action remains unclear. We explored the effects of LESW on the prostate and mitochondrial dynamics regulators in a rat model of carrageenan-induced prostatitis. The [...] Read more.

A low-energy shock wave (LESW) has therapeutic effects on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); however, its mechanism of action remains unclear. We explored the effects of LESW on the prostate and mitochondrial dynamics regulators in a rat model of carrageenan-induced prostatitis. The imbalance of mitochondrial dynamics regulators may affect the inflammatory process and molecules and contribute to CP/CPPS. Male Sprague–Dawley rats received intraprostatic 3% or 5% carrageenan injections. The 5% carrageenan group also received LESW treatment at 24 h, 7 days, and 8 days. Pain behavior was evaluated at baseline, 1 week, and 2 weeks after a saline or carrageenan injection. The bladder and the prostate were harvested for immunohistochemistry and quantitative reverse-transcription polymerase chain reaction analysis. Intraprostatic carrageenan injection induced inflammatory reaction in the prostate and the bladder, decreased the pain threshold, and resulted in the upregulation of Drp-1, MFN-2, NLRP3 (mitochondrial integrity markers), substance P, and CGRP-RCP, whose effects were maintained for 1–2 weeks. LESW treatment suppressed carrageenan-induced prostatic pain, inflammatory reaction, mitochondrial integrity markers, and expression of sensory molecules. These findings support a link between the anti-neuroinflammatory effects of LESW in CP/CPPS and the reversal of cellular perturbations caused by imbalances in mitochondrial dynamics in the prostate. Full article

(This article belongs to the Special Issue Mitochondria in Human Diseases)

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13 pages, 1206 KiB

Open AccessArticle

Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency

by Liza Douiev, Chaya Miller, Guy Keller, Hadar Benyamini, Bassam Abu-Libdeh and Ann Saada

Int. J. Mol. Sci. 2022, 23(8), 4149; https://doi.org/10.3390/ijms23084149 - 8 Apr 2022

Cited by 3 | Viewed by 1945

Abstract

Cytochrome c oxidase (COX), a multimeric protein complex, is the final electron acceptor in the mitochondrial electron transfer chain. Primary COX deficiency, caused by mutations in either mitochondrial DNA or nuclear-encoded genes, is a heterogenous group of mitochondrial diseases with a wide range [...] Read more.

Cytochrome c oxidase (COX), a multimeric protein complex, is the final electron acceptor in the mitochondrial electron transfer chain. Primary COX deficiency, caused by mutations in either mitochondrial DNA or nuclear-encoded genes, is a heterogenous group of mitochondrial diseases with a wide range of presentations, ranging from fatal infantile to subtler. We previously reported a patient with primary COX deficiency due to a pathogenic variant in COX4I1 (encoding the common isoform of COX subunit 4, COX4-1), who presented with bone marrow failure, genomic instability, and short stature, mimicking Fanconi anemia (FA). In the present study, we demonstrated that accumulative DNA damage coincided primarily with proliferative cells in the patient’s fibroblasts and in COX4i1 knockdown cells. Expression analysis implicated a reduction in DNA damage response pathways, which was verified by demonstrating impaired recovery from genotoxic insult and decreased DNA repair. The premature senescence of the COX4-1-deficient cells prevented us from undertaking additional studies; nevertheless, taken together, our results indicate replicative stress and impaired nuclear DNA damage response in COX4-1 deficiency. Interestingly, our in vitro findings recapitulated the patient’s presentation and present status. Full article

(This article belongs to the Special Issue Mitochondria in Human Diseases)

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27 pages, 5981 KiB

Open AccessArticle

Relationships between Mitochondrial Function, AMPK, and TORC1 Signaling in Lymphoblasts with Premutation Alleles of the FMR1 Gene

by Paul R. Fisher, Claire Y. Allan, Oana Sanislav, Anna Atkinson, Kevin R. W. Ngoei, Bruce E. Kemp, Elsdon Storey, Danuta Z. Loesch and Sarah J. Annesley

Int. J. Mol. Sci. 2021, 22(19), 10393; https://doi.org/10.3390/ijms221910393 - 27 Sep 2021

Cited by 3 | Viewed by 2354

Abstract

The X-linked FMR1 gene contains a non-coding trinucleotide repeat in its 5’ region that, in normal, healthy individuals contains 20–44 copies. Large expansions of this region (>200 copies) cause fragile X syndrome (FXS), but expansions of 55–199 copies (referred to as premutation alleles) [...] Read more.

The X-linked FMR1 gene contains a non-coding trinucleotide repeat in its 5’ region that, in normal, healthy individuals contains 20–44 copies. Large expansions of this region (>200 copies) cause fragile X syndrome (FXS), but expansions of 55–199 copies (referred to as premutation alleles) predispose carriers to a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS). The cytopathological mechanisms underlying FXTAS are poorly understood, but abnormalities in mitochondrial function are believed to play a role. We previously reported that lymphoblastoid cell lines (LCLs, or lymphoblasts) of premutation carriers have elevated mitochondrial respiratory activities. In the carriers, especially those not clinically affected with FXTAS, AMP-activated protein kinase (AMPK) activity was shown to be elevated. In the FXTAS patients, however, it was negatively correlated with brain white matter lesions, suggesting a protective role in the molecular mechanisms. Here, we report an enlarged and extended study of mitochondrial function and associated cellular stress-signaling pathways in lymphoblasts isolated from male and female premutation carriers, regardless of their clinical status, and healthy controls. The results confirmed the elevation of AMPK and mitochondrial respiratory activities and reduction in reactive O₂ species (ROS) levels in premutation cells and revealed for the first time that target of rapamycin complex I (TORC1) activities are reduced. Extensive correlation, multiple regression, and principal components analysis revealed the best fitting statistical explanations of these changes in terms of the other variables measured. These suggested which variables might be the most “proximal” regulators of the others in the extensive network of known causal interactions amongst the measured parameters of mitochondrial function and cellular stress signaling. In the resulting model, the premutation alleles activate AMPK and inhibit both TORC1 and ROS production, the reduced TORC1 activity contributes to activation of AMPK and of nonmitochondrial metabolism, and the higher AMPK activity results in elevated catabolic metabolism, mitochondrial respiration, and ATP steady state levels. In addition, the results suggest a separate CGG repeat number-dependent elevation of TORC1 activity that is insufficient to overcome the inhibition of TORC1 in premutation cells but may presage the previously reported activation of TORC1 in FXS cells. Full article

(This article belongs to the Special Issue Mitochondria in Human Diseases)

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12 pages, 2079 KiB

Open AccessArticle

Uridine Treatment of the First Known Case of SLC25A36 Deficiency

by Luisa Jasper, Pasquale Scarcia, Stephan Rust, Janine Reunert, Ferdinando Palmieri and Thorsten Marquardt

Int. J. Mol. Sci. 2021, 22(18), 9929; https://doi.org/10.3390/ijms22189929 - 14 Sep 2021

Cited by 4 | Viewed by 2183

Abstract

SLC25A36 is a pyrimidine nucleotide carrier playing an important role in maintaining mitochondrial biogenesis. Deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction. In human beings, diseases triggered by SLC25A36 mutations have not [...] Read more.

SLC25A36 is a pyrimidine nucleotide carrier playing an important role in maintaining mitochondrial biogenesis. Deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction. In human beings, diseases triggered by SLC25A36 mutations have not been described yet. We report the first known case of SLC25A36 deficiency in a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. Whole exome analysis identified the homozygous mutation c.803dupT, p.Ser269llefs*35 in the SLC25A36 gene. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with oral uridine led to an improvement of thyroid function and obstipation, increase of growth and developmental progress. Our findings suggest an important role of SLC25A36 in hormonal regulations and oral uridine as a safe and effective treatment. Full article

(This article belongs to the Special Issue Mitochondria in Human Diseases)

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18 pages, 1614 KiB

Open AccessArticle

Daytime Dependence of the Activity of the Rat Brain Pyruvate Dehydrogenase Corresponds to the Mitochondrial Sirtuin 3 Level and Acetylation of Brain Proteins, All Regulated by Thiamine Administration Decreasing Phosphorylation of PDHA Ser293

by Vasily A. Aleshin, Artem V. Artiukhov, Thilo Kaehne, Anastasia V. Graf and Victoria I. Bunik

Int. J. Mol. Sci. 2021, 22(15), 8006; https://doi.org/10.3390/ijms22158006 - 27 Jul 2021

Cited by 11 | Viewed by 2784

Abstract

Coupling glycolysis and mitochondrial tricarboxylic acid cycle, pyruvate dehydrogenase (PDH) complex (PDHC) is highly responsive to cellular demands through multiple mechanisms, including PDH phosphorylation. PDHC also produces acetyl-CoA for protein acetylation involved in circadian regulation of metabolism. Thiamine (vitamin B1) diphosphate (ThDP) is [...] Read more.

Coupling glycolysis and mitochondrial tricarboxylic acid cycle, pyruvate dehydrogenase (PDH) complex (PDHC) is highly responsive to cellular demands through multiple mechanisms, including PDH phosphorylation. PDHC also produces acetyl-CoA for protein acetylation involved in circadian regulation of metabolism. Thiamine (vitamin B1) diphosphate (ThDP) is known to activate PDH as both coenzyme and inhibitor of the PDH inactivating kinases. Molecular mechanisms integrating the function of thiamine-dependent PDHC into general redox metabolism, underlie physiological fitness of a cell or an organism. Here, we characterize the daytime- and thiamine-dependent changes in the rat brain PDHC function, expression and phosphorylation, assessing their impact on protein acetylation and metabolic regulation. Morning administration of thiamine significantly downregulates both the PDH phosphorylation at Ser293 and SIRT3 protein level, the effects not observed upon the evening administration. This action of thiamine nullifies the daytime-dependent changes in the brain PDHC activity and mitochondrial acetylation, inducing diurnal difference in the cytosolic acetylation and acetylation of total brain proteins. Screening the daytime dependence of central metabolic enzymes and proteins of thiol/disulfide metabolism reveals that thiamine also cancels daily changes in the malate dehydrogenase activity, opposite to those of the PDHC activity. Correlation analysis indicates that thiamine abrogates the strong positive correlation between the total acetylation of the brain proteins and PDHC function. Simultaneously, thiamine heightens interplay between the expression of PDHC components and total acetylation or SIRT2 protein level. These thiamine effects on the brain acetylation system change metabolic impact of acetylation. The changes are exemplified by the thiamine enhancement of the SIRT2 correlations with metabolic enzymes and proteins of thiol-disulfide metabolism. Thus, we show the daytime- and thiamine-dependent changes in the function and phosphorylation of brain PDHC, contributing to regulation of the brain acetylation system and redox metabolism. The daytime-dependent action of thiamine on PDHC and SIRT3 may be of therapeutic significance in correcting perturbed diurnal regulation. Full article

(This article belongs to the Special Issue Mitochondria in Human Diseases)

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17 pages, 18980 KiB

Open AccessArticle

Anti-Apoptotic and Antioxidant Activities of the Mitochondrial Estrogen Receptor Beta in N2A Neuroblastoma Cells

by Ioannis Tsialtas, Achilleas Georgantopoulos, Maria E. Karipidou, Foteini D. Kalousi, Aikaterini G. Karra, Demetrios D. Leonidas and Anna-Maria G. Psarra

Int. J. Mol. Sci. 2021, 22(14), 7620; https://doi.org/10.3390/ijms22147620 - 16 Jul 2021

Cited by 15 | Viewed by 2605

Abstract

Estrogens are steroid hormones that play a crucial role in the regulation of the reproductive and non-reproductive system physiology. Among non-reproductive systems, the nervous system is mainly affected by estrogens due to their antioxidant, anti-apoptotic, and anti-inflammatory activities, which are mediated by membranous [...] Read more.

Estrogens are steroid hormones that play a crucial role in the regulation of the reproductive and non-reproductive system physiology. Among non-reproductive systems, the nervous system is mainly affected by estrogens due to their antioxidant, anti-apoptotic, and anti-inflammatory activities, which are mediated by membranous and nuclear estrogen receptors, and also by non-estrogen receptor-associated estrogen actions. Neuronal viability and functionality are also associated with the maintenance of mitochondrial functions. Recently, the localization of estrogen receptors, especially estrogen receptor beta, in the mitochondria of many types of neuronal cells is documented, indicating the direct involvement of the mitochondrial estrogen receptor beta (mtERβ) in the maintenance of neuronal physiology. In this study, cell lines of N2A cells stably overexpressing a mitochondrial-targeted estrogen receptor beta were generated and further analyzed to study the direct involvement of mtERβ in estrogen neuroprotective antioxidant and anti-apoptotic actions. Results from this study revealed that the presence of estrogen receptor beta in mitochondria render N2A cells more resistant to staurosporine- and H₂O₂-induced apoptotic stimuli, as indicated by the reduced activation of caspase-9 and -3, the increased cell viability, the increased ATP production, and the increased resistance to mitochondrial impairment in the presence or absence of 17-β estradiol (E2). Thus, the direct involvement of mtERβ in antioxidant and anti-apoptotic activities is documented, rendering mtERβ a promising therapeutic target for mitochondrial dysfunction-associated degenerative diseases. Full article

(This article belongs to the Special Issue Mitochondria in Human Diseases)

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Review

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23 pages, 2157 KiB

Open AccessReview

The Journey of Mitochondrial Protein Import and the Roadmap to Follow

by Mary Oluwadamilola Haastrup, Kunwar Somesh Vikramdeo, Seema Singh, Ajay Pratap Singh and Santanu Dasgupta

Int. J. Mol. Sci. 2023, 24(3), 2479; https://doi.org/10.3390/ijms24032479 - 27 Jan 2023

Cited by 6 | Viewed by 3439

Abstract

Mitochondria are double membrane-bound organelles that play critical functions in cells including metabolism, energy production, regulation of intrinsic apoptosis, and maintenance of calcium homeostasis. Mitochondria are fascinatingly equipped with their own genome and machinery for transcribing and translating 13 essential proteins of the [...] Read more.

Mitochondria are double membrane-bound organelles that play critical functions in cells including metabolism, energy production, regulation of intrinsic apoptosis, and maintenance of calcium homeostasis. Mitochondria are fascinatingly equipped with their own genome and machinery for transcribing and translating 13 essential proteins of the oxidative phosphorylation system (OXPHOS). The rest of the proteins (99%) that function in mitochondria in the various pathways described above are nuclear-transcribed and synthesized as precursors in the cytosol. These proteins are imported into the mitochondria by the unique mitochondrial protein import system that consists of seven machineries. Proper functioning of the mitochondrial protein import system is crucial for optimal mitochondrial deliverables, as well as mitochondrial and cellular homeostasis. Impaired mitochondrial protein import leads to proteotoxic stress in both mitochondria and cytosol, inducing mitochondrial unfolded protein response (UPR^mt). Altered UPR^mt is associated with the development of various disease conditions including neurodegenerative and cardiovascular diseases, as well as cancer. This review sheds light on the molecular mechanisms underlying the import of nuclear-encoded mitochondrial proteins, the consequences of defective mitochondrial protein import, and the pathological conditions that arise due to altered UPR^mt. Full article

(This article belongs to the Special Issue Mitochondria in Human Diseases)

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21 pages, 1729 KiB

Open AccessReview

Role of eIF5A in Mitochondrial Function

by Marina Barba-Aliaga and Paula Alepuz

Int. J. Mol. Sci. 2022, 23(3), 1284; https://doi.org/10.3390/ijms23031284 - 24 Jan 2022

Cited by 15 | Viewed by 4705

Abstract

The eukaryotic translation initiation factor 5A (eIF5A) is an evolutionarily conserved protein that binds ribosomes to facilitate the translation of peptide motifs with consecutive prolines or combinations of prolines with glycine and charged amino acids. It has also been linked to other molecular [...] Read more.

The eukaryotic translation initiation factor 5A (eIF5A) is an evolutionarily conserved protein that binds ribosomes to facilitate the translation of peptide motifs with consecutive prolines or combinations of prolines with glycine and charged amino acids. It has also been linked to other molecular functions and cellular processes, such as nuclear mRNA export and mRNA decay, proliferation, differentiation, autophagy, and apoptosis. The growing interest in eIF5A relates to its association with the pathogenesis of several diseases, including cancer, viral infection, and diabetes. It has also been proposed as an anti-aging factor: its levels decay in aged cells, whereas increasing levels of active eIF5A result in the rejuvenation of the immune and vascular systems and improved brain cognition. Recent data have linked the role of eIF5A in some pathologies with its function in maintaining healthy mitochondria. The eukaryotic translation initiation factor 5A is upregulated under respiratory metabolism and its deficiency reduces oxygen consumption, ATP production, and the levels of several mitochondrial metabolic enzymes, as well as altering mitochondria dynamics. However, although all the accumulated data strongly link eIF5A to mitochondrial function, the precise molecular role and mechanisms involved are still unknown. In this review, we discuss the findings linking eIF5A and mitochondria, speculate about its role in regulating mitochondrial homeostasis, and highlight its potential as a target in diseases related to energy metabolism. Full article

(This article belongs to the Special Issue Mitochondria in Human Diseases)

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18 pages, 1973 KiB

Open AccessReview

The Roles of Coenzyme Q in Disease: Direct and Indirect Involvement in Cellular Functions

by Francesco Pallotti, Christian Bergamini, Costanza Lamperti and Romana Fato

Int. J. Mol. Sci. 2022, 23(1), 128; https://doi.org/10.3390/ijms23010128 - 23 Dec 2021

Cited by 35 | Viewed by 4695

Abstract

Coenzyme Q (CoQ) is a key component of the respiratory chain of all eukaryotic cells. Its function is closely related to mitochondrial respiration, where it acts as an electron transporter. However, the cellular functions of coenzyme Q are multiple: it is present in [...] Read more.

Coenzyme Q (CoQ) is a key component of the respiratory chain of all eukaryotic cells. Its function is closely related to mitochondrial respiration, where it acts as an electron transporter. However, the cellular functions of coenzyme Q are multiple: it is present in all cell membranes, limiting the toxic effect of free radicals, it is a component of LDL, it is involved in the aging process, and its deficiency is linked to several diseases. Recently, it has been proposed that coenzyme Q contributes to suppressing ferroptosis, a type of iron-dependent programmed cell death characterized by lipid peroxidation. In this review, we report the latest hypotheses and theories analyzing the multiple functions of coenzyme Q. The complete knowledge of the various cellular CoQ functions is essential to provide a rational basis for its possible therapeutic use, not only in diseases characterized by primary CoQ deficiency, but also in large number of diseases in which its secondary deficiency has been found. Full article

(This article belongs to the Special Issue Mitochondria in Human Diseases)

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21 pages, 3284 KiB

Open AccessReview

Therapeutic Approach of Flavonoid in Ameliorating Diabetic Cardiomyopathy by Targeting Mitochondrial-Induced Oxidative Stress

by Syaifuzah Sapian, Izatus Shima Taib, Jalifah Latip, Haliza Katas, Kok-Yong Chin, Nor Anizah Mohd Nor, Fatin Farhana Jubaidi and Siti Balkis Budin

Int. J. Mol. Sci. 2021, 22(21), 11616; https://doi.org/10.3390/ijms222111616 - 27 Oct 2021

Cited by 12 | Viewed by 3288

Abstract

Diabetes cardiomyopathy is one of the key factors of mortality among diabetic patients around the globe. One of the prior contributors to the progression of diabetic cardiomyopathy is cardiac mitochondrial dysfunction. The cardiac mitochondrial dysfunction can induce oxidative stress in cardiomyocytes and was [...] Read more.

Diabetes cardiomyopathy is one of the key factors of mortality among diabetic patients around the globe. One of the prior contributors to the progression of diabetic cardiomyopathy is cardiac mitochondrial dysfunction. The cardiac mitochondrial dysfunction can induce oxidative stress in cardiomyocytes and was found to be the cause of majority of the heart morphological and dynamical changes in diabetic cardiomyopathy. To slow down the occurrence of diabetic cardiomyopathy, it is crucial to discover therapeutic agents that target mitochondrial-induced oxidative stress. Flavonoid is a plentiful phytochemical in plants that shows a wide range of biological actions against human diseases. Flavonoids have been extensively documented for their ability to protect the heart from diabetic cardiomyopathy. Flavonoids’ ability to alleviate diabetic cardiomyopathy is primarily attributed to their antioxidant properties. In this review, we present the mechanisms involved in flavonoid therapies in ameliorating mitochondrial-induced oxidative stress in diabetic cardiomyopathy. Full article

(This article belongs to the Special Issue Mitochondria in Human Diseases)

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23 pages, 8788 KiB

Open AccessReview

Metabolic Remodeling and Implicated Calcium and Signal Transduction Pathways in the Pathogenesis of Heart Failure

by Antoine H. Chaanine

Int. J. Mol. Sci. 2021, 22(19), 10579; https://doi.org/10.3390/ijms221910579 - 30 Sep 2021

Cited by 8 | Viewed by 2681

Abstract

The heart is an organ with high-energy demands in which the mitochondria are most abundant. They are considered the powerhouse of the cell and occupy a central role in cellular metabolism. The intermyofibrillar mitochondria constitute the majority of the three-mitochondrial subpopulations in the [...] Read more.

The heart is an organ with high-energy demands in which the mitochondria are most abundant. They are considered the powerhouse of the cell and occupy a central role in cellular metabolism. The intermyofibrillar mitochondria constitute the majority of the three-mitochondrial subpopulations in the heart. They are also considered to be the most important in terms of their ability to participate in calcium and cellular signaling, which are critical for the regulation of mitochondrial function and adenosine triphosphate (ATP) production. This is because they are located in very close proximity with the endoplasmic reticulum (ER), and for the presence of tethering complexes enabling interorganelle crosstalk via calcium signaling. Calcium is an important second messenger that regulates mitochondrial function. It promotes ATP production and cellular survival under physiological changes in cardiac energetic demand. This is accomplished in concert with signaling pathways that regulate both calcium cycling and mitochondrial function. Perturbations in mitochondrial homeostasis and metabolic remodeling occupy a central role in the pathogenesis of heart failure. In this review we will discuss perturbations in ER-mitochondrial crosstalk and touch on important signaling pathways and molecular mechanisms involved in the dysregulation of calcium homeostasis and mitochondrial function in heart failure. Full article

(This article belongs to the Special Issue Mitochondria in Human Diseases)

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