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Mitochondria in Human Health and Disease

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

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 40167

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Guest Editor
Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece
Interests: steroid receptors; mitochondria; mitochondrial transcription; OXPHOS; apoptosis; ROS; SEGRAs; inflammation; energy metabolism; cancer
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Special Issue Information

Dear Colleagues,

Mitochondria are the powerhouses of the cell, generating over 90% of a cell’s energy requirements by way of oxidative phosphorylation in the respiratory chain. The mitochondria host several other important metabolic processes, such as Krebs cycle, β-oxidation of fatty acids, and heme biosynthesis, playing a central role in cellular events. Mitochondria are also involved in oxidative stress, redox regulation, in apoptosis, in immunomodulation, and in ageing. Mitochondria receive and integrate intracellular signals, contributing to the orchestration of cellular functions. Novel mitochondria-associated molecules have also been discovered, uncovering new roles of mitochondria in the regulation and fine-tuning control of cellular metabolism. Interestingly, mitochondrial dysfunction is associated with many pathological conditions such as cancer, myopathies, and metabolic, cardiovascular, and neurodegenerative diseases. Thus, mitochondria are considered to be important therapeutic targets for these highly prevalent diseases.

Authors are invited to submit articles highlighting recent novel findings on the characterization of the biochemical and molecular mechanism underlying mitochondrial functions, including mitochondrial biogenesis, bioenergetics, apoptosis, autophagy, reactive oxygen species generation, calcium homeostasis, interaction and communication of mitochondria with other cellular organelles, and the association of mitochondrial dysfunction with the pathophysiology of the cell. Computational studies and studies on in vitro, cellular, and animal models are welcome.

Dr. Anna-Maria Psarra
Guest Editor

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Keywords

  • OXPHOS
  • mitochondrial transcription
  • mitochondrial–nuclear interactions
  • mitochondrial–ER interactions
  • mitochondrial bioenergetics
  • mitochondrial fusion/fission
  • apoptosis
  • mitophagy
  • ROS–mitochondrial oxidative defense systems
  • neurodegenerative diseases
  • mitochondrial myopathies
  • mitochondrial diseases
  • mitochondrial disorders in cancer
  • mitochondria and inflammation
  • Ca2+ signaling

Published Papers (14 papers)

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Research

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21 pages, 5314 KiB  
Article
Acanthamoeba castellanii Uncoupling Protein: A Complete Sequence, Activity, and Role in Response to Oxidative Stress
by Nina Antos-Krzeminska, Anna Kicinska, Witold Nowak and Wieslawa Jarmuszkiewicz
Int. J. Mol. Sci. 2023, 24(15), 12501; https://doi.org/10.3390/ijms241512501 - 6 Aug 2023
Cited by 1 | Viewed by 1149
Abstract
Uncoupling proteins (UCPs) are mitochondrial inner membrane transporters that mediate free-fatty-acid-induced, purine-nucleotide-inhibited proton leak into the mitochondrial matrix, thereby uncoupling respiratory substrate oxidation from ATP synthesis. The aim of this study was to provide functional evidence that the putative Acucp gene of the [...] Read more.
Uncoupling proteins (UCPs) are mitochondrial inner membrane transporters that mediate free-fatty-acid-induced, purine-nucleotide-inhibited proton leak into the mitochondrial matrix, thereby uncoupling respiratory substrate oxidation from ATP synthesis. The aim of this study was to provide functional evidence that the putative Acucp gene of the free-living protozoan amoeba, A. castellanii, encodes the mitochondrial protein with uncoupling activity characteristic of UCPs and to investigate its role during oxidative stress. We report the sequencing and cloning of a complete Acucp coding sequence, its phylogenetic analysis, and the heterologous expression of AcUCP in the S. cerevisiae strain InvSc1. Measurements of mitochondrial respiratory activity and membrane potential indicate that the heterologous expression of AcUCP causes AcUCP-mediated uncoupling activity. In addition, in a model of oxidative stress with increased reactive oxygen species levels (superoxide dismutase 1 knockout yeasts), AcUCP expression strongly promotes cell survival and growth. The level of superoxide anion radicals is greatly reduced in the ΔSOD1 strain expressing AcUCP. These results suggest that AcUCP targeted to yeast mitochondria causes uncoupling and may act as an antioxidant system. Phylogenetic analysis shows that the A. castellanii UCP diverges very early from other UCPs, but clearly locates within the UCP subfamily rather than among other mitochondrial anion carrier proteins. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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17 pages, 5978 KiB  
Article
SAMHD1 Attenuates Acute Inflammation by Maintaining Mitochondrial Function in Macrophages via Interaction with VDAC1
by Bowen Xu, Qianyi Sui, Han Hu, Xiangjia Hu, Xuchang Zhou, Cheng Qian and Nan Li
Int. J. Mol. Sci. 2023, 24(9), 7888; https://doi.org/10.3390/ijms24097888 - 26 Apr 2023
Cited by 3 | Viewed by 1956
Abstract
Over-activation of Toll-like receptor 4 (TLR4) is the key mechanism in Gram-negative bacterial infection-induced sepsis. SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) inhibits multiple viruses, but whether it plays a role during bacterial invasion remains unelucidated. Monocyte-macrophage specific Samhd1 knockout ( [...] Read more.
Over-activation of Toll-like receptor 4 (TLR4) is the key mechanism in Gram-negative bacterial infection-induced sepsis. SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) inhibits multiple viruses, but whether it plays a role during bacterial invasion remains unelucidated. Monocyte-macrophage specific Samhd1 knockout (Samhd1−/−) mice and Samhd1−/− macrophage cell line RAW264.7 were constructed and used as research models to evaluate the role of SAMHD1 in TLR4-activated inflammation. In vivo, LPS-challenged Samhd1−/− mice showed higher serum inflammatory factors, accompanied with more severe inflammation infiltration and lower survival rate. In vitro, Samhd1−/− peritoneal macrophages had more activated TLR4 pathway upon LPS-stimulation, accompanied with mitochondrial depolarization and dysfunction and a higher tendency to be M1-polarized. These results could be rescued by overexpressing full-length wild-type SAMHD1 or its phospho-mimetic T634D mutant into Samhd1−/− RAW264.7 cells, whereas the mutants, dNTP hydrolase-function-deprived H238A and phospho-ablative T634A, did not exert the same effect. Lastly, co-IP and immunofluorescence assays confirmed that SAMHD1 interacted with an outer mitochondrial membrane-localized protein, voltage-dependent anion channel-1 (VDAC1). SAMHD1 inhibits TLR4-induced acute inflammation and M1 polarization of macrophages by interacting with VDAC1 and maintaining mitochondria function, which outlines a novel regulatory mechanism of TLR signaling upon LPS stimulation. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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23 pages, 5306 KiB  
Article
Developmental Stage-Dependent Changes in Mitochondrial Function in the Brain of Offspring Following Prenatal Maternal Immune Activation
by Magdalena Cieślik, Aleksandra Zawadzka, Grzegorz A. Czapski, Anna Wilkaniec and Agata Adamczyk
Int. J. Mol. Sci. 2023, 24(8), 7243; https://doi.org/10.3390/ijms24087243 - 14 Apr 2023
Cited by 1 | Viewed by 1652
Abstract
Maternal immune activation (MIA) is an important risk factor for neurodevelopmental disorders such as autism. The aim of the current study was to investigate the development-dependent changes in the mitochondrial function of MIA-exposed offspring, which may contribute to autism-like deficits. MIA was evoked [...] Read more.
Maternal immune activation (MIA) is an important risk factor for neurodevelopmental disorders such as autism. The aim of the current study was to investigate the development-dependent changes in the mitochondrial function of MIA-exposed offspring, which may contribute to autism-like deficits. MIA was evoked by the single intraperitoneal administration of lipopolysaccharide to pregnant rats at gestation day 9.5, and several aspects of mitochondrial function in fetuses and in the brains of seven-day-old pups and adolescent offspring were analyzed along with oxidative stress parameters measurement. It was found that MIA significantly increased the activity of NADPH oxidase (NOX), an enzyme generating reactive oxygen species (ROS) in the fetuses and in the brain of seven-day-old pups, but not in the adolescent offspring. Although a lower mitochondrial membrane potential accompanied by a decreased ATP level was already observed in the fetuses and in the brain of seven-day-old pups, persistent alterations of ROS, mitochondrial membrane depolarization, and lower ATP generation with concomitant electron transport chain complexes downregulation were observed only in the adolescent offspring. We suggest that ROS observed in infancy are most likely of a NOX activity origin, whereas in adolescence, ROS are produced by damaged mitochondria. The accumulation of dysfunctional mitochondria leads to the intense release of free radicals that trigger oxidative stress and neuroinflammation, resulting in an interlinked vicious cascade. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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19 pages, 7359 KiB  
Article
MitoSNARE Assembly and Disassembly Factors Regulate Basal Autophagy and Aging in C. elegans
by Ilias Gkikas, Ioanna Daskalaki, Konstantinos Kounakis, Nektarios Tavernarakis and Eirini Lionaki
Int. J. Mol. Sci. 2023, 24(4), 4230; https://doi.org/10.3390/ijms24044230 - 20 Feb 2023
Viewed by 2139
Abstract
SNARE proteins reside between opposing membranes and facilitate vesicle fusion, a physiological process ubiquitously required for secretion, endocytosis and autophagy. With age, neurosecretory SNARE activity drops and is pertinent to age-associated neurological disorders. Despite the importance of SNARE complex assembly and disassembly in [...] Read more.
SNARE proteins reside between opposing membranes and facilitate vesicle fusion, a physiological process ubiquitously required for secretion, endocytosis and autophagy. With age, neurosecretory SNARE activity drops and is pertinent to age-associated neurological disorders. Despite the importance of SNARE complex assembly and disassembly in membrane fusion, their diverse localization hinders the complete understanding of their function. Here, we revealed a subset of SNARE proteins, the syntaxin SYX-17, the synaptobrevins VAMP-7, SNB-6 and the tethering factor USO-1, to be either localized or in close proximity to mitochondria, in vivo. We term them mitoSNAREs and show that animals deficient in mitoSNAREs exhibit increased mitochondria mass and accumulation of autophagosomes. The SNARE disassembly factor NSF-1 seems to be required for the effects of mitoSNARE depletion. Moreover, we find mitoSNAREs to be indispensable for normal aging in both neuronal and non-neuronal tissues. Overall, we uncover a previously unrecognized subset of SNAREs that localize to mitochondria and propose a role of mitoSNARE assembly and disassembly factors in basal autophagy regulation and aging. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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21 pages, 5902 KiB  
Article
Increased Expression of the Mitochondrial Glucocorticoid Receptor Enhances Tumor Aggressiveness in a Mouse Xenograft Model
by Aikaterini G. Karra, Ioannis Tsialtas, Foteini D. Kalousi, Achilleas Georgantopoulos, Evangelia Sereti, Konstantinos Dimas and Anna-Maria G. Psarra
Int. J. Mol. Sci. 2023, 24(4), 3740; https://doi.org/10.3390/ijms24043740 - 13 Feb 2023
Cited by 2 | Viewed by 1983
Abstract
Mitochondria are important organelles for cellular physiology as they generate most of the energy requirements of the cell and orchestrate many biological functions. Dysregulation of mitochondrial function is associated with many pathological conditions, including cancer development. Mitochondrial glucocorticoid receptor (mtGR) is proposed as [...] Read more.
Mitochondria are important organelles for cellular physiology as they generate most of the energy requirements of the cell and orchestrate many biological functions. Dysregulation of mitochondrial function is associated with many pathological conditions, including cancer development. Mitochondrial glucocorticoid receptor (mtGR) is proposed as a crucial regulator of mitochondrial functions via its direct involvement in the regulation of mitochondrial transcription, oxidative phosphorylation (OXPHOS), enzymes biosynthesis, energy production, mitochondrial-dependent apoptosis, and regulation of oxidative stress. Moreover, recent observations revealed the interaction of mtGR with the pyruvate dehydrogenase (PDH), a key player in the metabolic switch observed in cancer, indicating direct involvement of mtGR in cancer development. In this study, by using a xenograft mouse model of mtGR-overexpressing hepatocarcinoma cells, we showed increased mtGR-associated tumor growth, which is accompanied by reduced OXPHOS biosynthesis, reduction in PDH activity, and alterations in the Krebs cycle and glucose metabolism, metabolic alterations similar to those observed in the Warburg effect. Moreover, autophagy activation is observed in mtGR-associated tumors, which further support tumor progression via increased precursors availability. Thus, we propose that increased mitochondrial localization of mtGR is associated with tumor progression possible via mtGR/PDH interaction, which could lead to suppression of PDH activity and modulation of mtGR-induced mitochondrial transcription that ends up in reduced OXPHOS biosynthesis and reduced oxidative phosphorylation versus glycolytic pathway energy production, in favor of cancer cells. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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18 pages, 3282 KiB  
Article
HIV Replication Increases the Mitochondrial DNA Content of Plasma Extracellular Vesicles
by Wilfried Wenceslas Bazié, Julien Boucher, Benjamin Goyer, Dramane Kania, Isidore Tiandiogo Traoré, Diane Yirgnur Somé, Michel Alary and Caroline Gilbert
Int. J. Mol. Sci. 2023, 24(3), 1924; https://doi.org/10.3390/ijms24031924 - 18 Jan 2023
Cited by 2 | Viewed by 1829
Abstract
Extracellular vesicles (EVs) and their cargo have been studied intensively as potential sources of biomarkers in HIV infection; however, their DNA content, particularly the mitochondrial portion (mtDNA), remains largely unexplored. It is well known that human immunodeficiency virus (HIV) infection and prolonged antiretroviral [...] Read more.
Extracellular vesicles (EVs) and their cargo have been studied intensively as potential sources of biomarkers in HIV infection; however, their DNA content, particularly the mitochondrial portion (mtDNA), remains largely unexplored. It is well known that human immunodeficiency virus (HIV) infection and prolonged antiretroviral therapy (ART) lead to mitochondrial dysfunction and reduced mtDNA copy in cells and tissues. Moreover, mtDNA is a well-known damage-associated molecular pattern molecule that could potentially contribute to increased immune activation, oxidative stress, and inflammatory response. We investigated the mtDNA content of large and small plasma EVs in persons living with HIV (PLWH) and its implications for viral replication, ART use, and immune status. Venous blood was collected from 196 PLWH, ART-treated or ART-naïve (66 with ongoing viral replication, ≥20 copies/mL), and from 53 HIV-negative persons, all recruited at five HIV testing or treatment centers in Burkina Faso. Large and small plasma EVs were purified and counted, and mtDNA level was measured by RT-qPCR. Regardless of HIV status, mtDNA was more abundant in large than small EVs. It was more abundant in EVs of viremic than aviremic and control participants and tended to be more abundant in participants treated with Tenofovir compared with Zidovudine. When ART treatment was longer than six months and viremia was undetectable, no variation in EV mtDNA content versus CD4 and CD8 count or CD4/CD8 ratio was observed. However, mtDNA in large and small EVs decreased with years of HIV infection and ART. Our results highlight the impact of viral replication and ART on large and small EVs’ mtDNA content. The mechanisms underlying the differential incorporation of mtDNA into EVs and their effects on the surrounding cells warrant further investigation. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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19 pages, 3616 KiB  
Article
A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity
by Pol Picón-Pagès, Mònica Bosch-Morató, Laia Subirana, Francisca Rubio-Moscardó, Biuse Guivernau, Hugo Fanlo-Ucar, Melisa Ece Zeylan, Simge Senyuz, Víctor Herrera-Fernández, Rubén Vicente, José M. Fernández-Fernández, Jordi García-Ojalvo, Attila Gursoy, Ozlem Keskin, Baldomero Oliva, Francesc Posas, Eulàlia de Nadal and Francisco J. Muñoz
Int. J. Mol. Sci. 2023, 24(2), 1278; https://doi.org/10.3390/ijms24021278 - 9 Jan 2023
Cited by 1 | Viewed by 5607
Abstract
Alzheimer’s disease (AD) is known to be caused by amyloid β-peptide (Aβ) misfolded into β-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in Aβ toxicity, we carried out a genome-wide screen in Saccharomyces [...] Read more.
Alzheimer’s disease (AD) is known to be caused by amyloid β-peptide (Aβ) misfolded into β-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in Aβ toxicity, we carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 5154 gene knock-out strains expressing Aβ1–42. We identified 81 mammalian orthologue genes that enhance Aβ1–42 toxicity, while 157 were protective. Next, we performed interactome and text-mining studies to increase the number of genes and to identify the main cellular functions affected by Aβ oligomers (oAβ). We found that the most affected cellular functions were calcium regulation, protein translation and mitochondrial activity. We focused on SURF4, a protein that regulates the store-operated calcium channel (SOCE). An in vitro analysis using human neuroblastoma cells showed that SURF4 silencing induced higher intracellular calcium levels, while its overexpression decreased calcium entry. Furthermore, SURF4 silencing produced a significant reduction in cell death when cells were challenged with oAβ1–42, whereas SURF4 overexpression induced Aβ1–42 cytotoxicity. In summary, we identified new enhancer and protective activities for Aβ toxicity and showed that SURF4 contributes to oAβ1–42 neurotoxicity by decreasing SOCE activity. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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14 pages, 3250 KiB  
Article
P. gingivalis-LPS Induces Mitochondrial Dysfunction Mediated by Neuroinflammation through Oxidative Stress
by Ambika Verma, Gohar Azhar, Xiaomin Zhang, Pankaj Patyal, Grishma Kc, Shakshi Sharma, Yingni Che and Jeanne Y. Wei
Int. J. Mol. Sci. 2023, 24(2), 950; https://doi.org/10.3390/ijms24020950 - 4 Jan 2023
Cited by 13 | Viewed by 3089
Abstract
Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, is associated with neuroinflammation. Periodontal disease increases with age; 70.1% of adults 65 years and older have periodontal problems. However, the P. gingivalis- lipopolysaccharide (LPS)induced mitochondrial dysfunction in neurodegenerative diseases remains elusive. In [...] Read more.
Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, is associated with neuroinflammation. Periodontal disease increases with age; 70.1% of adults 65 years and older have periodontal problems. However, the P. gingivalis- lipopolysaccharide (LPS)induced mitochondrial dysfunction in neurodegenerative diseases remains elusive. In this study, we investigated the possible role of P. gingivalis-LPS in mitochondrial dysfunction during neurodegeneration. We found that P. gingivalis-LPS treatment activated toll-like receptor (TLR) 4 signaling and upregulated the expression of Alzheimer’s disease-related dementia and neuroinflammatory markers. Furthermore, the LPS treatment significantly exacerbated the production of reactive oxygen species and reduced the mitochondrial membrane potential. Our study highlighted the pivotal role of P. gingivalis-LPS in the repression of serum response factor (SRF) and its co-factor p49/STRAP that regulate the actin cytoskeleton. The LPS treatment repressed the genes involved in mitochondrial function and biogenesis. P. gingivalis-LPS negatively altered oxidative phosphorylation and glycolysis and reduced total adenosine triphosphate (ATP) production. Additionally, it specifically altered the mitochondrial functions in complexes I, II, and IV of the mitochondrial electron transport chain. Thus, it is conceivable that P. gingivalis-LPS causes mitochondrial dysfunction through oxidative stress and inflammatory events in neurodegenerative diseases. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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12 pages, 4028 KiB  
Article
Preferred Migration of Mitochondria toward Cells and Tissues with Mitochondrial Damage
by Seo-Eun Lee, Young Cheol Kang, Yujin Kim, Soomin Kim, Shin-Hye Yu, Jong Hyeok Park, In-Hyeon Kim, Hyeon-Young Kim, Kyuboem Han, Hong Kyu Lee, Sung-Hwan Kim and Chun-Hyung Kim
Int. J. Mol. Sci. 2022, 23(24), 15734; https://doi.org/10.3390/ijms232415734 - 12 Dec 2022
Cited by 6 | Viewed by 2862
Abstract
Mitochondria are organelles that play a vital role in cellular survival by supplying ATP and metabolic substrates via oxidative phosphorylation and the Krebs cycle. Hence, mitochondrial dysfunction contributes to many human diseases, including metabolic syndromes, neurodegenerative diseases, cancer, and aging. Mitochondrial transfer between [...] Read more.
Mitochondria are organelles that play a vital role in cellular survival by supplying ATP and metabolic substrates via oxidative phosphorylation and the Krebs cycle. Hence, mitochondrial dysfunction contributes to many human diseases, including metabolic syndromes, neurodegenerative diseases, cancer, and aging. Mitochondrial transfer between cells has been shown to occur naturally, and mitochondrial transplantation is beneficial for treating mitochondrial dysfunction. In this study, the migration of mitochondria was tracked in vitro and in vivo using mitochondria conjugated with green fluorescent protein (MTGFP). When MTGFP were used in a coculture model, they were selectively internalized into lung fibroblasts, and this selectivity depended on the mitochondrial functional states of the receiving fibroblasts. Compared with MTGFP injected intravenously into normal mice, MTGFP injected into bleomycin-induced idiopathic pulmonary fibrosis model mice localized more abundantly in the lung tissue, indicating that mitochondrial homing to injured tissue occurred. This study shows for the first time that exogenous mitochondria are preferentially trafficked to cells and tissues in which mitochondria are damaged, which has implications for the delivery of therapeutic agents to injured or diseased sites. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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20 pages, 3398 KiB  
Article
The Critical Role of AMPKα1 in Regulating Autophagy and Mitochondrial Respiration in IL-15-Stimulated mTORC1Weak Signal-Induced T Cell Memory: An Interplay between Yin (AMPKα1) and Yang (mTORC1) Energy Sensors in T Cell Differentiation
by Anjuman Ara, Zhaojia Wu, Aizhang Xu, Khawaja Ashfaque Ahmed, Scot C. Leary, Md. Fahmid Islam, Rajni Chibbar, Yue Wu and Jim Xiang
Int. J. Mol. Sci. 2022, 23(17), 9534; https://doi.org/10.3390/ijms23179534 - 23 Aug 2022
Cited by 4 | Viewed by 2609
Abstract
Two common γ-chain family cytokines IL-2 and IL-15 stimulate the same mammalian target of rapamycin complex-1 (mTORC1) signaling yet induce effector T (TE) and memory T (TM) cell differentiation via a poorly understood mechanism(s). Here, we prepared in vitro [...] Read more.
Two common γ-chain family cytokines IL-2 and IL-15 stimulate the same mammalian target of rapamycin complex-1 (mTORC1) signaling yet induce effector T (TE) and memory T (TM) cell differentiation via a poorly understood mechanism(s). Here, we prepared in vitro IL-2-stimulated TE (IL-2/TE) and IL-15-stimulated TM (IL-15/TM) cells for characterization by flow cytometry, Western blotting, confocal microscopy and Seahorse-assay analyses. We demonstrate that IL-2 and IL-15 stimulate strong and weak mTORC1 signals, respectively, which lead to the formation of CD62 ligand (CD62L) killer cell lectin-like receptor subfamily G member-1 (KLRG)+ IL-2/TE and CD62L+KLRG IL-15/TM cells with short- and long-term survival following their adoptive transfer into mice. The IL-15/mTORC1Weak signal activates the forkhead box-O-1 (FOXO1), T cell factor-1 (TCF1) and Eomes transcriptional network and the metabolic adenosine monophosphate-activated protein kinase-α-1 (AMPKα1), Unc-51-like autophagy-activating kinase-1 (ULK1) and autophagy-related gene-7 (ATG7) axis, increasing the expression of mitochondrial regulators aquaporin-9 (AQP9), mitochondrial transcription factor-A (TFAM), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), carnitine palmitoyl transferase-1 (CPT1α), microtubule-associated protein light chain-3 II (LC3II), Complex I and ortic atrophy-1 (OPA1), leading to promoting mitochondrial biogenesis and fatty-acid oxidation (FAO). Interestingly, AMPKα1 deficiency abrogates these downstream responses to IL-15/mTORC1Weak signaling, leading to the upregulation of mTORC1 and hypoxia-inducible factor-1α (HIF-1α), a metabolic switch from FAO to glycolysis and reduced cell survival. Taken together, our data demonstrate that IL-15/mTORC1Weak signaling controls T-cell memory via activation of the transcriptional FOXO1-TCF1-Eomes and metabolic AMPKα1-ULK1-ATG7 pathways, a finding that may greatly impact the development of efficient vaccines and immunotherapies for the treatment of cancer and infectious diseases. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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23 pages, 5810 KiB  
Article
Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male Mice
by Pratsanee Hiengrach, Peerapat Visitchanakun, Pakteema Tongchairawewat, Ponphisudti Tangsirisatian, Thitiphat Jungteerapanich, Patcharee Ritprajak, Dhammika Leshan Wannigama, Pattarin Tangtanatakul and Asada Leelahavanichkul
Int. J. Mol. Sci. 2022, 23(10), 5445; https://doi.org/10.3390/ijms23105445 - 13 May 2022
Cited by 13 | Viewed by 2860
Abstract
BAM15 (a mitochondrial uncoupling agent) was tested on cecal ligation and puncture (CLP) sepsis mice with in vitro experiments. BAM15 attenuated sepsis as indicated by survival, organ histology (kidneys and livers), spleen apoptosis (activated caspase 3), brain injury (SHIRPA score, serum s100β, serum [...] Read more.
BAM15 (a mitochondrial uncoupling agent) was tested on cecal ligation and puncture (CLP) sepsis mice with in vitro experiments. BAM15 attenuated sepsis as indicated by survival, organ histology (kidneys and livers), spleen apoptosis (activated caspase 3), brain injury (SHIRPA score, serum s100β, serum miR370-3p, brain miR370-3p, brain TNF-α, and apoptosis), systemic inflammation (cytokines, cell-free DNA, endotoxemia, and bacteremia), and blood–brain barrier (BBB) damage (Evan’s blue dye and the presence of green fluorescent E. coli in brain after an oral administration). In parallel, brain miR arrays demonstrated miR370-3p at 24 h but not 120 h post-CLP, which was correlated with metabolic pathways. Either lipopolysaccharide (LPS) or TNF-α upregulated miR370-3p in PC12 (neuron cells). An activation by sepsis factors (LPS, TNF-α, or miR370-3p transfection) damaged mitochondria (fluorescent color staining) and reduced cell ATP, possibly through profound mitochondrial activity (extracellular flux analysis) that was attenuated by BAM15. In bone-marrow-derived macrophages, LPS caused mitochondrial injury, decreased cell ATP, enhanced glycolysis activity (extracellular flux analysis), and induced pro-inflammatory macrophages (iNOS and IL-1β) which were neutralized by BAM15. In conclusion, BAM15 attenuated sepsis through decreased mitochondrial damage, reduced neuronal miR370-3p upregulation, and induced anti-inflammatory macrophages. BAM15 is proposed to be used as an adjuvant therapy against sepsis hyperinflammation. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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Review

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21 pages, 776 KiB  
Review
Neurological Phenotypes in Mouse Models of Mitochondrial Disease and Relevance to Human Neuropathology
by Elizaveta A. Olkhova, Laura A. Smith, Carla Bradshaw, Gráinne S. Gorman, Daniel Erskine and Yi Shiau Ng
Int. J. Mol. Sci. 2023, 24(11), 9698; https://doi.org/10.3390/ijms24119698 - 2 Jun 2023
Viewed by 2384
Abstract
Mitochondrial diseases represent the most common inherited neurometabolic disorders, for which no effective therapy currently exists for most patients. The unmet clinical need requires a more comprehensive understanding of the disease mechanisms and the development of reliable and robust in vivo models that [...] Read more.
Mitochondrial diseases represent the most common inherited neurometabolic disorders, for which no effective therapy currently exists for most patients. The unmet clinical need requires a more comprehensive understanding of the disease mechanisms and the development of reliable and robust in vivo models that accurately recapitulate human disease. This review aims to summarise and discuss various mouse models harbouring transgenic impairments in genes that regulate mitochondrial function, specifically their neurological phenotype and neuropathological features. Ataxia secondary to cerebellar impairment is one of the most prevalent neurological features of mouse models of mitochondrial dysfunction, consistent with the observation that progressive cerebellar ataxia is a common neurological manifestation in patients with mitochondrial disease. The loss of Purkinje neurons is a shared neuropathological finding in human post-mortem tissues and numerous mouse models. However, none of the existing mouse models recapitulate other devastating neurological phenotypes, such as refractory focal seizures and stroke-like episodes seen in patients. Additionally, we discuss the roles of reactive astrogliosis and microglial reactivity, which may be driving the neuropathology in some of the mouse models of mitochondrial dysfunction, as well as mechanisms through which cellular death may occur, beyond apoptosis, in neurons undergoing mitochondrial bioenergy crisis. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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29 pages, 3291 KiB  
Review
The Drp1-Mediated Mitochondrial Fission Protein Interactome as an Emerging Core Player in Mitochondrial Dynamics and Cardiovascular Disease Therapy
by Mulate Zerihun, Surya Sukumaran and Nir Qvit
Int. J. Mol. Sci. 2023, 24(6), 5785; https://doi.org/10.3390/ijms24065785 - 17 Mar 2023
Cited by 24 | Viewed by 5972
Abstract
Mitochondria, the membrane-bound cell organelles that supply most of the energy needed for cell function, are highly regulated, dynamic organelles bearing the ability to alter both form and functionality rapidly to maintain normal physiological events and challenge stress to the cell. This amazingly [...] Read more.
Mitochondria, the membrane-bound cell organelles that supply most of the energy needed for cell function, are highly regulated, dynamic organelles bearing the ability to alter both form and functionality rapidly to maintain normal physiological events and challenge stress to the cell. This amazingly vibrant movement and distribution of mitochondria within cells is controlled by the highly coordinated interplay between mitochondrial dynamic processes and fission and fusion events, as well as mitochondrial quality-control processes, mainly mitochondrial autophagy (also known as mitophagy). Fusion connects and unites neighboring depolarized mitochondria to derive a healthy and distinct mitochondrion. In contrast, fission segregates damaged mitochondria from intact and healthy counterparts and is followed by selective clearance of the damaged mitochondria via mitochondrial specific autophagy, i.e., mitophagy. Hence, the mitochondrial processes encompass all coordinated events of fusion, fission, mitophagy, and biogenesis for sustaining mitochondrial homeostasis. Accumulated evidence strongly suggests that mitochondrial impairment has already emerged as a core player in the pathogenesis, progression, and development of various human diseases, including cardiovascular ailments, the leading causes of death globally, which take an estimated 17.9 million lives each year. The crucial factor governing the fission process is the recruitment of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, from the cytosol to the outer mitochondrial membrane in a guanosine triphosphate (GTP)-dependent manner, where it is oligomerized and self-assembles into spiral structures. In this review, we first aim to describe the structural elements, functionality, and regulatory mechanisms of the key mitochondrial fission protein, Drp1, and other mitochondrial fission adaptor proteins, including mitochondrial fission 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics 49 (Mid49), and mitochondrial dynamics 51 (Mid51). The core area of the review focuses on the recent advances in understanding the role of the Drp1-mediated mitochondrial fission adaptor protein interactome to unravel the missing links of mitochondrial fission events. Lastly, we discuss the promising mitochondria-targeted therapeutic approaches that involve fission, as well as current evidence on Drp1-mediated fission protein interactions and their critical roles in the pathogeneses of cardiovascular diseases (CVDs). Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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17 pages, 1824 KiB  
Review
Roles of LonP1 in Oral-Maxillofacial Developmental Defects and Tumors: A Novel Insight
by Haozhen Ma, Wanting Chen, Wenguo Fan, Hongwen He and Fang Huang
Int. J. Mol. Sci. 2022, 23(21), 13370; https://doi.org/10.3390/ijms232113370 - 2 Nov 2022
Cited by 1 | Viewed by 2129
Abstract
Recent studies have indicated a central role for LonP1 in mitochondrial function. Its physiological functions include proteolysis, acting as a molecular chaperone, binding mitochondrial DNA, and being involved in cellular respiration, cellular metabolism, and oxidative stress. Given its vital role in energy metabolism, [...] Read more.
Recent studies have indicated a central role for LonP1 in mitochondrial function. Its physiological functions include proteolysis, acting as a molecular chaperone, binding mitochondrial DNA, and being involved in cellular respiration, cellular metabolism, and oxidative stress. Given its vital role in energy metabolism, LonP1 has been suggested to be associated with multi-system neoplasms and developmental disorders. In this study, we investigated the roles, possible mechanisms of action, and therapeutic roles of LonP1 in oral and maxillofacial tumor development. LonP1 was highly expressed in oral-maxillofacial cancers and regulated their development through a sig-naling network. LonP1 may therefore be a promising anticancer therapy target. Mutations in LONP1 have been found to be involved in the etiology of cerebral, ocular, dental, auricular, and skeletal syndrome (CODAS). Only patients carrying specific LONP1 mutations have certain dental abnormalities (delayed eruption and abnormal morphology). LonP1 is therefore a novel factor in the development of oral and maxillofacial tumors. Greater research should therefore be conducted on the diagnosis and therapy of LonP1-related diseases to further define LonP1-associated oral phenotypes and their underlying molecular mechanisms. Full article
(This article belongs to the Special Issue Mitochondria in Human Health and Disease)
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