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Mitochondrial Remodeling and the Targeting Strategies for Disease Treatment

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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: 1 May 2025 | Viewed by 14189

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Dr. Yong Teng

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Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
Interests: metastasis; molecular pathway; cancer models; metabolism; tumor microenvironment; drug screening and development
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Special Issue Information

Dear Colleagues,

Mitochondria are highly dynamic and responsive organelles, presenting multifaceted functions depending on environmental conditions and cellular requirements. It is well accepted that mitochondria alter their structure, proteome, metabolism, and even genome in response to cellular and environmental cues. As such, mitochondria are the hub for diverse signal processors that are fundamental to cellular homeostasis, energy production, metabolism, survival, and death. Mitochondrial remodeling, including rearranging, recycling, and reprogramming, is essential for mitochondrial quality control, structural integrity, and functional interaction with other cellular organelles. Although we are still far from fully understanding the complexity of mitochondrial remodeling, it has been implicated in the pathogenesis of many human disorders, including cancer and aging-related diseases. Because of the lack of defined mitochondrial targets, no proven effective treatments or cures for mitochondrial diseases are available in the clinic. With the advent of new information, technologies, and methodologies, it is time to delineate the significance and enigmatic mechanisms relevant to the remodeling of mitochondria in response to pathophysiological stresses more precisely and comprehensively. These provocative ideas and the scientific evidence are essential in effectively translating fundamental discoveries into therapeutics for disease treatment. Therefore, we kindly invite you to contribute to this Special Issue with original research articles or comprehensive reviews on all aspects related to the theme of “Mitochondrial Remodeling and the Targeting Strategies for Disease Treatment” at the molecular level. A short perspective or a pure clinical paper may not be considered, while a novel “Communication” with interesting molecular data would be acceptable. This Special Issue is being initiated to further our understanding of the role, regulations, and impact of mitochondrial remodeling in disease-specific pathology and to establish the foundation for novel and practical approaches to managing mitochondria-associated diseases.

Dr. Yong Teng
Guest Editor

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Keywords

structural and functional mitochondrial remodeling
mitochondrial turnover accomplished by mitophagy and biogenesis
proteomic alterations and posttranslational modifications mediated by mitochondrial remodeling
mitochondrial remodeling-mediated metabolic alterations
retrograde signaling whereby mitochondria modify the nuclear program
mitochondrial dynamism, fitness, biogenesis interactome
novel strategies for targeting mitochondrial remodeling
treatment of mitochondria-associated human diseases

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Published Papers (6 papers)

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Research

17 pages, 6248 KiB

Open AccessArticle

Inhibition of Drp1–Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria–Lipid Droplet Contact

by Kohei Ariyoshi, Kazuhiro Nishiyama, Yuri Kato, Xinya Mi, Tomoya Ito, Yasu-Taka Azuma, Akiyuki Nishimura and Motohiro Nishida

Int. J. Mol. Sci. 2024, 25(10), 5446; https://doi.org/10.3390/ijms25105446 - 17 May 2024

Cited by 2 | Viewed by 3966

Abstract

Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through β-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, can prevent pathological mitochondrial fission by inhibiting protein–protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca²⁺ channel-blocking action of cilnidipine, prevent the palmitic acid-induced Drp1–filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high-fat diet-fed mouse livers. These results propose that targeting the Drp1–filamin interaction become a new strategy for the prevention or treatment of fatty liver disease. Full article

(This article belongs to the Special Issue Mitochondrial Remodeling and the Targeting Strategies for Disease Treatment)

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25 pages, 7565 KiB

Open AccessArticle

Mitochondrial GpC and CpG DNA Hypermethylation Cause Metabolic Stress-Induced Mitophagy and Cholestophagy

by Claudia Theys, Joe Ibrahim, Ligia Mateiu, Archibold Mposhi, Laura García-Pupo, Tim De Pooter, Peter De Rijk, Mojca Strazisar, İkbal Agah İnce, Iuliana Vintea, Marianne G. Rots and Wim Vanden Berghe

Int. J. Mol. Sci. 2023, 24(22), 16412; https://doi.org/10.3390/ijms242216412 - 16 Nov 2023

Cited by 3 | Viewed by 1965

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by a constant accumulation of lipids in the liver. This hepatic lipotoxicity is associated with a dysregulation of the first step in lipid catabolism, known as beta oxidation, which occurs in the mitochondrial matrix. Eventually, this dysregulation will lead to mitochondrial dysfunction. To evaluate the possible involvement of mitochondrial DNA methylation in this lipid metabolic dysfunction, we investigated the functional metabolic effects of mitochondrial overexpression of CpG (MSssI) and GpC (MCviPI) DNA methyltransferases in relation to gene expression and (mito)epigenetic signatures. Overall, the results show that mitochondrial GpC and, to a lesser extent, CpG methylation increase bile acid metabolic gene expression, inducing the onset of cholestasis through mito-nuclear epigenetic reprogramming. Moreover, both increase the expression of metabolic nuclear receptors and thereby induce basal overactivation of mitochondrial respiration. The latter promotes mitochondrial swelling, favoring lipid accumulation and metabolic-stress-induced mitophagy and autophagy stress responses. In conclusion, both mitochondrial GpC and CpG methylation create a metabolically challenging environment that induces mitochondrial dysfunction, which may contribute to the progression of MASLD. Full article

(This article belongs to the Special Issue Mitochondrial Remodeling and the Targeting Strategies for Disease Treatment)

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16 pages, 5228 KiB

Open AccessArticle

Weakened Contractile Performance and Mitochondrial Respiratory Complex Activity in Skeletal Muscle Improve during Interbout Arousal in Hibernating Daurian Ground Squirrel, Spermophilus dauricus

by Huiping Wang, Yuxi Guo, Wenjing Yan, Liqi Cao, Xiaozhuo Bai, Jing Zhao, Kai Dang and Yunfang Gao

Int. J. Mol. Sci. 2023, 24(21), 15785; https://doi.org/10.3390/ijms242115785 - 30 Oct 2023

Cited by 1 | Viewed by 1167

Abstract

Mammalian hibernation is composed of multiple episodes of torpor bout, separated by phases of interbout arousal. During torpor, the skeletal muscles of mammals are undoubtedly inactive, but it has been proven to mitigate disuse atrophy. While interbout arousal has been implicated in the prevention of muscle atrophy, the underlying mechanisms sustaining muscle contraction remain to be explored. In the present study, Daurian ground squirrels (Spermophilus dauricus) were divided into four groups: pre-hibernation (PRE), torpor (TOR), interbout arousal (IBA), and post-hibernation (POST). The contractile performance of slow-twitch soleus muscle (SOL) and fast-twitch extensor digitorum longus muscle (EDL) was detected both in situ and in vitro. Concurrently, mitochondrial respiratory chain complex activity in these muscles was quantified. Our findings revealed that in situ contractile properties of both muscles, including force, power output, time duration, and force development/relaxation rates of twitch contraction, and force and power output of tetanic contraction declined in the TOR group compared to the PRE group, but improved in the IBA and POST groups. Fatigue resistance of muscles, determined by the power output of repetitive tetanic contractions in situ, decreased in the TOR group but recovered in the IBA and POST groups. In vitro studies demonstrated that tetanic contraction power output in isolated muscles increased with muscle temperature in both TOR and IBA groups. However, at the same temperature, power output was consistently lower in the TOR group compared to the IBA group. Moreover, the activity of the mitochondrial respiratory chain complex, especially Complexes I and II, decreased in the TOR group but showed recovery in the IBA and POST groups. These findings suggest that both the contractile performance and fatigue resistance of mammalian skeletal muscle are compromised during torpor but can be improved during interbout arousal and post-hibernation. The rebound in body temperature and rise in mitochondrial respiratory chain complex activity in skeletal muscle are involved in enhancing contractile performance and fatigue resistance. This study suggests that interbout arousal functions as a vital temporal interval during which skeletal muscles can transition from the inactivity induced by torpor to a state of restored contractile functionality. Thus, interbout arousal serves as a behavioral safeguard against disuse-induced damage to skeletal muscles during hibernation. Full article

(This article belongs to the Special Issue Mitochondrial Remodeling and the Targeting Strategies for Disease Treatment)

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19 pages, 4248 KiB

Open AccessArticle

Regulation of Smooth Muscle Cell Proliferation by Mitochondrial Ca2+ in Type 2 Diabetes

by Olha M. Koval, Emily K. Nguyen, Dylan J. Mittauer, Karima Ait-Aissa, William C. Chinchankar and Isabella M. Grumbach

Int. J. Mol. Sci. 2023, 24(16), 12897; https://doi.org/10.3390/ijms241612897 - 17 Aug 2023

Cited by 5 | Viewed by 1846

Abstract

Type 2 diabetes (T2D) is associated with increased risk of atherosclerotic vascular disease due to excessive vascular smooth muscle cell (VSMC) proliferation. Here, we investigated the role of mitochondrial dysfunction and Ca2+ levels in VSMC proliferation in T2D. VSMCs were isolated from normoglycemic and T2D-like mice induced by diet. The effects of mitochondrial Ca2+ uptake were studied using mice with selectively inhibited mitochondrial Ca2+/calmodulin-dependent kinase II (mtCaMKII) in VSMCs. Mitochondrial transition pore (mPTP) was blocked using ER-000444793. VSMCs from T2D compared to normoglycemic mice exhibited increased proliferation and baseline cytosolic Ca2+ levels ([Ca2+]cyto). T2D cells displayed lower endoplasmic reticulum Ca2+ levels, reduced mitochondrial Ca2+ entry, and increased Ca2+ leakage through the mPTP. Mitochondrial and cytosolic Ca2+ transients were diminished in T2D cells upon platelet-derived growth factor (PDGF) administration. Inhibiting mitochondrial Ca2+ uptake or the mPTP reduced VSMC proliferation in T2D, but had contrasting effects on [Ca2+]cyto. In T2D VSMCs, enhanced activation of Erk1/2 and its upstream regulators was observed, driven by elevated [Ca2+]cyto. Inhibiting mtCaMKII worsened the Ca2+ imbalance by blocking mitochondrial Ca2+ entry, leading to further increases in [Ca2+]cyto and Erk1/2 hyperactivation. Under these conditions, PDGF had no effect on VSMC proliferation. Inhibiting Ca2+-dependent signaling in the cytosol reduced excessive Erk1/2 activation and VSMC proliferation. Our findings suggest that altered Ca2+ handling drives enhanced VSMC proliferation in T2D, with mitochondrial dysfunction contributing to this process. Full article

(This article belongs to the Special Issue Mitochondrial Remodeling and the Targeting Strategies for Disease Treatment)

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13 pages, 3511 KiB

Open AccessArticle

Treprostinil Reconstitutes Mitochondrial Organisation and Structure in Idiopathic Pulmonary Fibrosis Cells

by Lei Fang, Wei-Chih Chen, Peter Jaksch, Antonio Molino, Alessandro Saglia, Michael Roth and Christopher Lambers

Int. J. Mol. Sci. 2023, 24(15), 12148; https://doi.org/10.3390/ijms241512148 - 29 Jul 2023

Cited by 1 | Viewed by 1650

Abstract

Idiopathic pulmonary fibrosis (IPF) presents as an incurable change in the lung tissue and mitochondrial dysfunction of unknown origin. Treprostinil, a prostacyclin analogue, has been suggested for IPF therapy. This study assessed the effect of treprostinil on the cAMP signalling and mitochondrial activity in healthy lung fibroblasts and fibroblast-like cells from IPF patients. Six control fibroblast strains and six fibroblast-like IPF cell strains were isolated and expanded from freshly resected lung tissue. The cells were grown to confluence before being treated with either transforming growth factor (TGF)-β1, treprostinil, their combination, or a vehicle for up to 2 days. Mitochondria-regulating proteins were analysed using Western blotting and immunofluorescence, and the mitochondria were analysed using cytochrome C, mitochondrial cytochrome C oxidase II (MTCO2), and MTCO4. The IPF cells showed an increased rate of damaged mitochondria, which were significantly reduced when the cells were treated with treprostinil over 24 h. In the control cells, treprostinil prevented TGF-β-induced mitochondrial damage. Treatment with treprostinil modified the expression of several mitochondria-regulating proteins. In both cell types, treprostinil upregulated the expression of PTEN, p21(Waf1/Cip1), beclin1, LC3 II, parkin, PINK1, MTCO2, and MTCO4. In contrast, treprostinil downregulated the phosphorylation of mTOR and the expression of p62, mitofusin1, and mtiofusin2 in IPF cells. This might explain the reduced mitochondrial damage observed in treprostinil-treated IPF cells and suggest an improvement in the mitochondrial function in IPF. In this study, treprostinil improved mitochondrial impairment in vitro, which might, in part, explain the beneficial clinical effects documented in patients. Full article

(This article belongs to the Special Issue Mitochondrial Remodeling and the Targeting Strategies for Disease Treatment)

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21 pages, 4273 KiB

Open AccessArticle

Polymer-Functionalized Mitochondrial Transplantation to Fibroblasts Counteracts a Pro-Fibrotic Phenotype

by Gherardo Baudo, Suhong Wu, Matteo Massaro, Haoran Liu, Hyunho Lee, Aijun Zhang, Dale J. Hamilton and Elvin Blanco

Int. J. Mol. Sci. 2023, 24(13), 10913; https://doi.org/10.3390/ijms241310913 - 30 Jun 2023

Cited by 6 | Viewed by 2760

Abstract

Fibroblast-to-myofibroblast transition (FMT) leads to excessive extracellular matrix (ECM) deposition—a well-known hallmark of fibrotic disease. Transforming growth factor-β (TGF-β) is the primary cytokine driving FMT, and this phenotypic conversion is associated with mitochondrial dysfunction, notably a metabolic reprogramming towards enhanced glycolysis. The objective of this study was to examine whether the establishment of favorable metabolic phenotypes in TGF-β-stimulated fibroblasts could attenuate FMT. The hypothesis was that mitochondrial replenishment of TGF-β-stimulated fibroblasts would counteract a shift towards glycolytic metabolism, consequently offsetting pro-fibrotic processes. Isolated mitochondria, functionalized with a dextran and triphenylphosphonium (TPP) (Dex-TPP) polymer conjugate, were administered to fibroblasts (MRC-5 cells) stimulated with TGF-β, and effects on bioenergetics and fibrotic programming were subsequently examined. Results demonstrate that TGF-β stimulation of fibroblasts led to FMT, which was associated with enhanced glycolysis. Dex-TPP-coated mitochondria (Dex-TPP/Mt) delivery to TGF-β-stimulated fibroblasts abrogated a metabolic shift towards glycolysis and led to a reduction in reactive oxygen species (ROS) generation. Importantly, TGF-β-stimulated fibroblasts treated with Dex-TPP/Mt had lessened expression of FMT markers and ECM proteins, as well as reduced migration and proliferation. Findings highlight the potential of mitochondrial transfer, as well as other strategies involving functional reinforcement of mitochondria, as viable therapeutic modalities in fibrosis. Full article

(This article belongs to the Special Issue Mitochondrial Remodeling and the Targeting Strategies for Disease Treatment)

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