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Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 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 "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 22073

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Dr. Andrey V. Kuznetsov

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Department of Heart Surgery, Medical University Innsbruck, 6020 Innsbruck, Austria
Interests: mitochondria; mitochondrial function; structure; intracellular organization; heterogeneity; bioenergetics; cardiac; muscles and liver energy metabolism in normal cells and diseases; cancer
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Dear Colleagues,

Mitochondria play a central role in maintaining cellular function by energy (ATP) production. They are also a source of reactive oxygen species and pro-apoptotic elements. In addition to oxidative phosphorylation (OXPHOS), mitochondria regulate a wide range of metabolic processes and cellular signaling mechanisms. The importance of mitochondria in many aspects of cell physiology, bioenergetics, normal cell function and ion control (particularly Ca²⁺) is well known. Changes in mitochondrial function and energy transfer play crucial roles in numerous diseases and in aging. Therefore, the multifaceted and comprehensive analysis of mitochondria is central to studies of energy metabolism and the pathophysiology of human diseases, including ischemia–reperfusion injury, myopathies, neurodegenerative diseases and cancer. The study of mitochondrial oxygen consumption (OXPHOS) can be performed using isolated mitochondria or in situ, in permeabilized cells or muscle fibers. Moreover, changes in mitochondrial structure, dynamics, organization and function can be analyzed by fluorescent imaging.

Dr. Andrey V. Kuznetsov
Guest Editor

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Keywords

confocal fluorescent imaging
mitochondria
energy metabolism
mitochondrial function
mitochondrial dynamics
mitochondrial intracellular organization
heterogeneity
metabolic diseases
reactive oxygen species
signaling

Related Special Issue

Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization in International Journal of Molecular Sciences (11 articles)

Published Papers (14 papers)

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Editorial

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4 pages, 186 KiB

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Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization

by Andrey V. Kuznetsov and Michael J. Ausserlechner

Int. J. Mol. Sci. 2023, 24(1), 886; https://doi.org/10.3390/ijms24010886 - 03 Jan 2023

Cited by 1 | Viewed by 1668

Abstract

Mitochondria have been recognized as the energy (in the form of ATP)-producing cell organelles, required for cell viability, survival and normal cell function [...] Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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16 pages, 2700 KiB

Open AccessArticle

Potassium Ions Decrease Mitochondrial Matrix pH: Implications for ATP Production and Reactive Oxygen Species Generation

by Jannatul Naima and Yoshihiro Ohta

Int. J. Mol. Sci. 2024, 25(2), 1233; https://doi.org/10.3390/ijms25021233 - 19 Jan 2024

Viewed by 739

Abstract

Potassium (K⁺) is the most abundant cation in the cytosol and is maintained at high concentrations within the mitochondrial matrix through potassium channels. However, many effects of K⁺ at such high concentrations on mitochondria and the underlying mechanisms remain unclear. This study aims to elucidate these effects and mechanisms by employing fluorescence imaging techniques to distinguish and precisely measure signals inside and outside the mitochondria. We stained the mitochondrial matrix with fluorescent dyes sensitive to K⁺, pH, reactive oxygen species (ROS), and membrane potential in plasma membrane-permeabilized C6 cells and isolated mitochondria from C6 cells. Fluorescence microscopy facilitated the accurate measurement of fluorescence intensity inside and outside the matrix. Increasing extramitochondrial K⁺ concentration from 2 mM to 127 mM led to a reduction in matrix pH and a decrease in the generation of highly reactive ROS. In addition, elevated K⁺ levels electrically polarized the inner membrane of the mitochondria and promoted efficient ATP synthesis via FoF₁-ATPase. Introducing protons (H⁺) into the matrix through phosphate addition led to further mitochondrial polarization, and this effect was more pronounced in the presence of K⁺. K⁺ at high concentrations, reaching sub-hundred millimolar levels, increased H⁺ concentration within the matrix, suppressing ROS generation and boosting ATP synthesis. Although this study does not elucidate the role of specific types of potassium channels in mitochondria, it does suggest that mitochondrial K⁺ plays a beneficial role in maintaining cellular health. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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13 pages, 1476 KiB

Open AccessArticle

Vanadium Pentoxide Exposure Causes Strain-Dependent Changes in Mitochondrial DNA Heteroplasmy, Copy Number, and Lesions, but Not Nuclear DNA Lesions

by Nick L. Dobson, Steven R. Kleeberger, Adam B. Burkholder, Dianne M. Walters, Wesley Gladwell, Kevin Gerrish and Heather L. Vellers

Int. J. Mol. Sci. 2023, 24(19), 14507; https://doi.org/10.3390/ijms241914507 - 25 Sep 2023

Viewed by 812

Abstract

Interstitial lung diseases (ILDs) are lethal lung diseases characterized by pulmonary inflammation and progressive lung interstitial scarring. We previously developed a mouse model of ILD using vanadium pentoxide (V₂O₅) and identified several gene candidates on chromosome 4 associated with pulmonary fibrosis. While these data indicated a significant genetic contribution to ILD susceptibility, they did not include any potential associations and interactions with the mitochondrial genome that might influence disease risk. To conduct this pilot work, we selected the two divergent strains we previously categorized as V₂O₅-resistant C57BL6J (B6) and -responsive DBA/2J (D2) and compared their mitochondrial genome characteristics, including DNA variants, heteroplasmy, lesions, and copy numbers at 14- and 112-days post-exposure. While we did not find changes in the mitochondrial genome at 14 days post-exposure, at 112 days, we found that the responsive D2 strain exhibited significantly fewer mtDNA copies and more lesions than control animals. Alongside these findings, mtDNA heteroplasmy frequency decreased. These data suggest that mice previously shown to exhibit increased susceptibility to pulmonary fibrosis and inflammation sustain damage to the mitochondrial genome that is evident at 112 days post-V₂O₅ exposure. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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19 pages, 7419 KiB

Open AccessArticle

Puerarin Inhibits NLRP3-Caspase-1-GSDMD-Mediated Pyroptosis via P2X7 Receptor in Cardiomyocytes and Macrophages

by Shuchan Sun, Difei Gong, Ruiqi Liu, Ranran Wang, Di Chen, Tianyi Yuan, Shoubao Wang, Cheng Xing, Yang Lv, Guanhua Du and Lianhua Fang

Int. J. Mol. Sci. 2023, 24(17), 13169; https://doi.org/10.3390/ijms241713169 - 24 Aug 2023

Cited by 3 | Viewed by 1413

Abstract

Diabetic cardiomyopathy (DCM) is a critical complication of long-term chronic diabetes mellitus, and it is characterized by myocardial fibrosis and myocardial hypertrophy. Previous studies have shown that the pyroptosis pathway was significantly activated in DCM and may be related to the P2X7 receptor. However, the role of the P2X7 receptor in the development of DCM with pyroptosis is still unclear. In this study, we aimed to explore the mechanism of puerarin and whether the P2X7 receptor can be used as a new target for puerarin in the treatment of DCM. We adopted systematic pharmacology and bioinformatic approaches to identify the potential targets of puerarin for treating DCM. Additionally, we employed D-glucose-induced H9C2 rat cardiomyocytes and lipopolysaccharide-treated RAW264.7 mouse mononuclear macrophages as the in vitro model on DCM research, which is close to the pathological conditions. The mRNA expression of cytokines in H9C2 cells and RAW264.7 macrophages was detected. The protein expressions of NLRP3, N-GSDMD, cleaved-caspase-1, and the P2X7 receptor were investigated with Western blot analysis. Furthermore, molecular docking of puerarin and the P2X7 receptor was conducted based on CDOCKER. A total of 348 puerarin targets and 4556 diabetic cardiomyopathy targets were detected, of which 218 were cross targets. We demonstrated that puerarin is effective in enhancing cardiomyocyte viability and improving mitochondrial function. In addition, puerarin is efficacious in blocking NLRP3-Caspase-1-GSDMD-mediated pyroptosis in H9C2 cells and RAW264.7 cells, alleviating cellular inflammation. On the other hand, similar experimental results were obtained by intervention with the P2X7 receptor antagonist A740003, suggesting that the protective effects of puerarin are related to the P2X7 receptor. The molecular docking results indicated key binding activity between the P2X7 receptor and puerarin. These findings indicate that puerarin effectively regulated the pyroptosis signaling pathway during DCM, and this regulation was associated with the P2X7 receptor. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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14 pages, 1767 KiB

Open AccessArticle

Mitochondrial Genome Variation in Polish Elite Athletes

by Agnieszka Piotrowska-Nowak, Krzysztof Safranow, Jakub G. Adamczyk, Ireneusz Sołtyszewski, Paweł Cięszczyk, Katarzyna Tońska, Cezary Żekanowski and Beata Borzemska

Int. J. Mol. Sci. 2023, 24(16), 12992; https://doi.org/10.3390/ijms241612992 - 20 Aug 2023

Viewed by 946

Abstract

Energy efficiency is one of the fundamental athletic performance-affecting features of the cell and the organism as a whole. Mitochondrial DNA (mtDNA) variants and haplogroups have been linked to the successful practice of various sports, but despite numerous studies, understanding of the correlation is far from being comprehensive. In this study, the mtDNA sequence and copy number were determined for 99 outstanding Polish male athletes performing in power (n = 52) or endurance sports (n = 47) and 100 controls. The distribution of haplogroups, single nucleotide variant association, heteroplasmy, and mtDNA copy number were analyzed in the blood and saliva. We found no correlation between any haplogroup, single nucleotide variant, especially rare or non-synonymous ones, and athletic performance. Interestingly, heteroplasmy was less frequent in the study group, especially in endurance athletes. We observed a lower mtDNA copy number in both power and endurance athletes compared to controls. This could result from an inactivity of compensatory mechanisms activated by disadvantageous variants present in the general population and indicates a favorable genetic makeup of the athletes. The results emphasize a need for a more comprehensive analysis of the involvement of the mitochondrial genome in physical performance, combining nucleotide and copy number analysis in the context of nuclear gene variants. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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17 pages, 3806 KiB

Open AccessArticle

PNPLA3-I148M Variant Promotes the Progression of Liver Fibrosis by Inducing Mitochondrial Dysfunction

by Yusong Gou, Lifei Wang, Jinhan Zhao, Xiaoyi Xu, Hangfei Xu, Fang Xie, Yanjun Wang, Yingmei Feng, Jing Zhang and Yang Zhang

Int. J. Mol. Sci. 2023, 24(11), 9681; https://doi.org/10.3390/ijms24119681 - 02 Jun 2023

Cited by 3 | Viewed by 1674

Abstract

Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism (I148M) is strongly associated with non-alcoholic steatohepatitis and advanced fibrosis; however, the underlying mechanisms remain largely unknown. In this study, we investigated the effect of PNPLA3-I148M on the activation of hepatic stellate cell line LX-2 and the progression of liver fibrosis. Immunofluorescence staining and enzyme-linked immunosorbent assay were used to detect lipid accumulation. The expression levels of fibrosis, cholesterol metabolism, and mitochondria-related markers were measured via real-time PCR or western blotting. Electron microscopy was applied to analyze the ultrastructure of the mitochondria. Mitochondrial respiration was measured by a Seahorse XFe96 analyzer. PNPLA3-I148M significantly promoted intracellular free cholesterol aggregation in LX-2 cells by decreasing cholesterol efflux protein (ABCG1) expression; it subsequently induced mitochondrial dysfunction characterized by attenuated ATP production and mitochondrial membrane potential, elevated ROS levels, caused mitochondrial structural damage, altered the oxygen consumption rate, and decreased the expression of mitochondrial-function-related proteins. Our results demonstrated for the first time that PNPLA3-I148M causes mitochondrial dysfunction of LX-2 cells through the accumulation of free cholesterol, thereby promoting the activation of LX-2 cells and the development of liver fibrosis. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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13 pages, 2663 KiB

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Impact of Acute High Glucose on Mitochondrial Function in a Model of Endothelial Cells: Role of PDGF-C

by Adriana Grismaldo Rodríguez, Jairo Zamudio Rodríguez, Alfonso Barreto, Sandra Sanabria-Barrera, José Iglesias and Ludis Morales

Int. J. Mol. Sci. 2023, 24(5), 4394; https://doi.org/10.3390/ijms24054394 - 23 Feb 2023

Cited by 2 | Viewed by 1762

Abstract

An increase in plasma high glucose promotes endothelial dysfunction mainly through increasing mitochondrial ROS production. High glucose ROS—induced has been implicated in the fragmentation of the mitochondrial network, mainly by an unbalance expression of mitochondrial fusion and fission proteins. Mitochondrial dynamics alterations affect cellular bioenergetics. Here, we assessed the effect of PDGF-C on mitochondrial dynamics and glycolytic and mitochondrial metabolism in a model of endothelial dysfunction induced by high glucose. High glucose induced a fragmented mitochondrial phenotype associated with the reduced expression of OPA1 protein, high DRP1^pSer616 levels and reduced basal respiration, maximal respiration, spare respiratory capacity, non-mitochondrial oxygen consumption and ATP production, regarding normal glucose. In these conditions, PDGF-C significantly increased the expression of OPA1 fusion protein, diminished DRP1^pSer616 levels and restored the mitochondrial network. On mitochondrial function, PDGF-C increased the non-mitochondrial oxygen consumption diminished by high glucose conditions. These results suggest that PDGF-C modulates the damage induced by HG on the mitochondrial network and morphology of human aortic endothelial cells; additionally, it compensates for the alteration in the energetic phenotype induced by HG. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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25 pages, 7117 KiB

Open AccessArticle

AICAR Ameliorates Non-Alcoholic Fatty Liver Disease via Modulation of the HGF/NF-κB/SNARK Signaling Pathway and Restores Mitochondrial and Endoplasmic Reticular Impairments in High-Fat Diet-Fed Rats

by Doaa Hussein Zineldeen, Nahid Mohamed Tahoon and Naglaa Ibrahim Sarhan

Int. J. Mol. Sci. 2023, 24(4), 3367; https://doi.org/10.3390/ijms24043367 - 08 Feb 2023

Cited by 4 | Viewed by 1911

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a global health problem characterized by altered lipid and redox homeostasis, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. The AMP-dependent kinase (AMPK) agonist 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) has been shown to improve the outcome of NAFLD in the context of AMPK activation, yet the underlying molecular mechanism remains obscure. This study investigated the potential mechanism(s) of AICAR to attenuate NAFLD by exploring AICAR’s effects on the HGF/NF-κB/SNARK axis and downstream effectors as well as mitochondrial and ER derangements. High-fat diet (HFD)-fed male Wistar rats were given intraperitoneal AICAR at 0.7 mg/g body weight or left untreated for 8 weeks. In vitro steatosis was also examined. ELISA, Western blotting, immunohistochemistry and RT-PCR were used to explore AICAR’s effects. NAFLD was confirmed by steatosis score, dyslipidemia, altered glycemic, and redox status. HGF/NF-κB/SNARK was downregulated in HFD-fed rats receiving AICAR with improved hepatic steatosis and reduced inflammatory cytokines and oxidative stress. Aside from AMPK dominance, AICAR improved hepatic fatty acid oxidation and alleviated the ER stress response. In addition, it restored mitochondrial homeostasis by modulating Sirtuin 2 and mitochondrial quality gene expression. Our results provide a new mechanistic insight into the prophylactic role of AICAR in the prevention of NAFLD and its complications. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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17 pages, 2481 KiB

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Loss of Myostatin Alters Mitochondrial Oxidative Phosphorylation, TCA Cycle Activity, and ATP Production in Skeletal Muscle

by Xueqiao Wang, Zhuying Wei, Mingjuan Gu, Lin Zhu, Chao Hai, Anqi Di, Di Wu, Chunling Bai, Guanghua Su, Xuefei Liu, Lei Yang and Guangpeng Li

Int. J. Mol. Sci. 2022, 23(24), 15707; https://doi.org/10.3390/ijms232415707 - 11 Dec 2022

Cited by 5 | Viewed by 2156

Abstract

Myostatin (MSTN) is an important negative regulator of skeletal muscle growth in animals. A lack of MSTN promotes lipolysis and glucose metabolism but inhibits oxidative phosphorylation (OXPHOS). Here, we aimed to investigate the possible mechanism of MSTN regulating the mitochondrial energy homeostasis of skeletal muscle. To this end, MSTN knockout mice were generated by the CRISPR/Cas9 technique. Expectedly, the MSTN null (Mstn^−/−) mouse has a hypermuscular phenotype. The muscle metabolism of the Mstn^−/− mice was detected by an enzyme-linked immunosorbent assay, indirect calorimetry, ChIP-qPCR, and RT-qPCR. The resting metabolic rate and body temperature of the Mstn^−/− mice were significantly reduced. The loss of MSTN not only significantly inhibited the production of ATP by OXPHOS and decreased the activity of respiratory chain complexes, but also inhibited key rate-limiting enzymes related to the TCA cycle and significantly reduced the ratio of NADH/NAD+ in the Mstn^−/− mice, which then greatly reduced the total amount of ATP. Further ChIP-qPCR results confirmed that the lack of MSTN inhibited both the TCA cycle and OXPHOS, resulting in decreased ATP production. The reason may be that Smad2/3 is not sufficiently bound to the promoter region of the rate-limiting enzymes Idh2 and Idh3a of the TCA cycle, thus affecting their transcription. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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14 pages, 3379 KiB

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Structural and Dynamic Features of Liver Mitochondria and Mitophagy in Rats with Hyperthyroidism

by Natalya Venediktova, Ilya Solomadin, Vlada Starinets and Galina Mironova

Int. J. Mol. Sci. 2022, 23(22), 14327; https://doi.org/10.3390/ijms232214327 - 18 Nov 2022

Cited by 3 | Viewed by 1344

Abstract

This work investigated the effect of thyroxine on the biogenesis and quality control system of rat liver mitochondria. Chronic administration of thyroxine to experimental animals induced hyperthyroidism, which was confirmed by a severalfold increase in serum-free triiodothyronine and thyroxine concentrations. The uptake of oxygen was found to increase with a decrease in ADP phosphorylation efficiency and respiratory state ratio. Electron microscopy showed 36% of liver mitochondria to be swollen and approximately 18% to have a lysed matrix with a reduced number of cristae. Frequently encountered multilamellar bodies associated with defective mitochondria were located either at the edge of or inside the organelle. The number, area and perimeter of hyperthyroid rat mitochondria increased. Administration of thyroxine increased mitochondrial biogenesis and the quantity of mitochondrial DNA in liver tissue. Mitochondrial dynamics and mitophagy changed significantly. The data obtained indicate that excess thyroid hormones cause a disturbance of the mitochondrial quality control system and ultimately to the incorporation of potentially toxic material in the mitochondrial pool. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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25 pages, 17842 KiB

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Puerarin-V Improve Mitochondrial Respiration and Cardiac Function in a Rat Model of Diabetic Cardiomyopathy via Inhibiting Pyroptosis Pathway through P2X7 Receptors

by Shuchan Sun, Awaguli Dawuti, Difei Gong, Ranran Wang, Tianyi Yuan, Shoubao Wang, Cheng Xing, Yang Lu, Guanhua Du and Lianghua Fang

Int. J. Mol. Sci. 2022, 23(21), 13015; https://doi.org/10.3390/ijms232113015 - 27 Oct 2022

Cited by 9 | Viewed by 1674

Abstract

There is a new form of puerarin, puerarin-V, that has recently been developed, and it is unclear whether puerarin-V has a cardioprotective effect on diabetic cardiomyopathy (DCM). Here, we determined whether puerarin-V had any beneficial influence on the pathophysiology of DCM and explored its possible mechanisms. By injecting 30 mg/kg of STZ intraperitoneally, diabetes was induced in rats. After a week of stability, the rats were injected subcutaneously with ISO (5 mg/kg). We randomly assigned the rats to eight groups: (1) control; (2) model; (3) metformin; (4–6) puerarin-V at different doses; (7) puerarin (API); (8) puerarin injection. DCM rats were found to have severe cardiac insufficiency (arrythmia, decreased LVdP/dt, and increased E/A ratio). In addition, cardiac injury biomarkers (cTn-T, NT-proBNP, AST, LDH, and CK-MB), inflammatory cytokines (IL-1β, IL-18, IL-6, and TNF-α), and oxidative damage markers (MDA, SOD and GSH) were markedly increased. Treatment with puerarin-V positively adjusts these parameters mentioned above by improving cardiac function and mitochondrial respiration, suppressing myocardial inflammation, and maintaining the structural integrity of the cardiac muscle. Moreover, treatment with puerarin-V inhibits the P2X7 receptor-mediated pyroptosis pathway that was upregulated in diabetic hearts. Given these results, the current study lends credence to the idea that puerarin-V can reduce myocardial damage in DCM rats. Furthermore, it was found that the effect of puerarin-V in diabetic cardiomyopathy is better than the API, the puerarin injection, and metformin. Collectively, our research provides a new therapeutic option for the treatment of DCM in clinic. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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20 pages, 13155 KiB

Open AccessArticle

Lead Disrupts Mitochondrial Morphology and Function through Induction of ER Stress in Model of Neurotoxicity

by Jianbin Zhang, Peng Su, Chong Xue, Diya Wang, Fang Zhao, Xuefeng Shen and Wenjing Luo

Int. J. Mol. Sci. 2022, 23(19), 11435; https://doi.org/10.3390/ijms231911435 - 28 Sep 2022

Cited by 3 | Viewed by 1615

Abstract

Lead exposure may weaken the ability of learning and memory in the nervous system through mitochondrial paramorphia and dysfunction. However, the underlying mechanism has not been fully elucidated. In our works, with SD rats, primary culture of hippocampal neuron and PC12 cell line model were built up and behavioral tests were performed to determine the learning and memory insults; Western blot, immunological staining, and electron microscope were then conducted to determine endoplasmic reticulum stress and mitochondrial paramorphia and dysfunction. Co-immunoprecipitation were performed to investigate potential protein–protein interaction. The results show that lead exposure may cripple rats’ learning and memory capability by inducing endoplasmic reticulum stress and mitochondrial paramorphia and dysfunction. Furthermore, we clarify that enhanced MFN2 ubiquitination degradation mediated by PINK1 may account for mitochondrial paramorphia and endoplasmic reticulum stress. Our work may provide important clues for research on the mechanism of how Pb exposure leads to nervous system damage. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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16 pages, 2671 KiB

Open AccessArticle

Dual Mode of Mitochondrial ROS Action during Reprogramming to Pluripotency

by Elena V. Skvortsova, Igor B. Nazarov, Alexey N. Tomilin and Sergey A. Sinenko

Int. J. Mol. Sci. 2022, 23(18), 10924; https://doi.org/10.3390/ijms231810924 - 18 Sep 2022

Cited by 7 | Viewed by 2034

Abstract

Essential changes in cell metabolism and redox signaling occur during the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). In this paper, using genetic and pharmacological approaches, we have investigated the role of electron transport chain (ETC) complex-I (CI) of mitochondria in the process of cell reprogramming to pluripotency. Knockdown of NADH-ubiquinone oxidoreductase core subunits S1 (Ndufs1) or subunit B10 (Ndufb10) of the CI or inhibition of this complex with rotenone during mouse embryonic fibroblast (MEF) reprogramming resulted in a significantly decreased number of induced pluripotent stem cells (iPSCs). We have found that mitochondria and ROS levels due course of the reprogramming tightly correlate with each other, both reaching peak by day 3 and significantly declining by day 10 of the process. The transient augmentation of mitochondrial reactive oxygen species (ROS) could be attenuated by antioxidant treatment, which ameliorated overall reprogramming. However, ROS scavenging after day 3 or during the entire course of reprogramming was suppressive for iPSC formation. The ROS scavenging within the CI-deficient iPSC-precursors did not improve, but further suppressed the reprogramming. Our data therefore point to distinct modes of mitochondrial ROS action during the early versus mid and late stages of reprogramming. The data further substantiate the paradigm that balanced levels of oxidative phosphorylation have to be maintained on the route to pluripotency. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration

by Hariprasath Ragupathy, Manasvi Vukku and Sandeep Kumar Barodia

Int. J. Mol. Sci. 2023, 24(19), 14421; https://doi.org/10.3390/ijms241914421 - 22 Sep 2023

Cited by 4 | Viewed by 1337

Abstract

Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging is the main risk factor for neurodegenerative diseases. During aging, activated microglia undergo phenotypic alterations that can lead to neuroinflammation, which is a well-accepted event in the pathogenesis of neurodegenerative diseases. Several common mechanisms are shared by genetically or pathologically distinct neurodegenerative diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding and translational dysfunction, autophagy and microglia activation. Progressive loss of the neuronal population due to increased oxidative stress leads to neurodegenerative diseases, mostly due to the accumulation of dysfunctional mitochondria. Mitochondrial dysfunction and excessive neuroinflammatory responses are both sufficient to induce pathology in age-dependent neurodegeneration. Therefore, mitochondrial quality control is a key determinant for the health and survival of neuronal cells in the brain. Research has been primarily focused to demonstrate the significance of neuronal mitochondrial health, despite the important contributions of non-neuronal cells that constitute a significant portion of the brain volume. Moreover, mitochondrial morphology and function are distinctly diverse in different tissues; however, little is known about their molecular diversity among cell types. Mitochondrial dynamics and quality in different cell types markedly decide the fate of overall brain health; therefore, it is not justifiable to overlook non-neuronal cells and their significant and active contribution in facilitating overall neuronal health. In this review article, we aim to discuss the mitochondrial quality control of different cell types in the brain and how important and remarkable the diversity and highly synchronized connecting property of non-neuronal cells are in keeping the neurons healthy to control neurodegeneration. Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

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