International Journal of Molecular Sciences

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13 pages, 945 KB

Open AccessArticle

Fusion Between Control Mesoangioblasts and mtDNA-Mutant Myotubes Preserves Myotube Morphology and Mitochondrial Network Organization

by Somaieh Ahmadian, Patrick J. Lindsey, Monique Ummelen, Anton Hopman, Marc A. M. J. van Zandvoort, Hubert J. M. Smeets and Florence H. J. van Tienen

Int. J. Mol. Sci. 2026, 27(3), 1357; https://doi.org/10.3390/ijms27031357 - 29 Jan 2026

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Abstract

Mitochondria are the energy factories of a cell and mitochondrial morphology, quantity, membrane potential, and DNA copy number can change depending on metabolic requirements and/or genetic defects. Different mutations in mitochondrial DNA might affect mitochondrial morphology and membrane potential differently. In this study [...] Read more.

Mitochondria are the energy factories of a cell and mitochondrial morphology, quantity, membrane potential, and DNA copy number can change depending on metabolic requirements and/or genetic defects. Different mutations in mitochondrial DNA might affect mitochondrial morphology and membrane potential differently. In this study we investigated mitochondrial morphology and membrane potential in vitro in mesoangioblast-derived human myotubes harboring a pathogenic mtDNA mutation and analyzed mitochondrial behavior following fusion with healthy mesoangioblasts. Myotubes were differentiated in vitro from mesoangioblasts obtained from two mitochondrial myopathy patients, M02 (96% m.3271T>C) and M11 (73% m.3291T>C), and from a functionally healthy male control, M06 (3% m.3243A>G). On day 5 of differentiation, healthy male mesoangioblasts (mM06) were added to mutant myotube cultures to allow cell fusion. On day 11, mitochondrial morphology and membrane potential were assessed by three-dimensional live-cell imaging using spinning disk confocal microscopy with tetramethylrhodamine methyl ester (TMRM). Following live imaging, cells were fixed and subjected to Y-chromosome fluorescence in situ hybridization (FISH), enabling identification and retrospective analysis of hybrid (i.e., fused with male control mesoangioblasts) and non-hybrid (i.e., not fused with these control mesoangioblasts) myotubes within the same imaging fields. Quantitative image analysis at the level of individual myotubes revealed that, when normalized to sarcoplasmic volume, mitochondrial volume, object number, and membrane potential did not differ between mutant and control myotubes despite heteroplasmy levels exceeding 70%. Fusion of healthy mM06 mesoangioblasts did not impair myotube formation and resulted in redistribution of mitochondrial content without an increase in mitochondrial object number, consistent with integration of donor mitochondria into the existing mitochondrial network. Across conditions, mitochondrial parameters were strongly influenced by myotube size, underscoring the importance of accounting for biological variation when quantifying mitochondrial features. Together, these findings demonstrate that high mtDNA mutation loads do not necessarily alter mitochondrial morphology or membrane potential under standard in vitro differentiation conditions and provide mechanistic insight into mitochondrial behavior following mesoangioblast fusion in human myotubes. Fusion of healthy mesoangioblasts supports integration of donor mitochondria into the existing network without compromising myogenesis, consistent with mitochondrial mixing rather than replacement. Full article

(This article belongs to the Special Issue Mitochondrial Function in Health and Diseases)

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28 pages, 2614 KB

Open AccessArticle

Combination of Low-Dose Sulforaphane and Docetaxel on Mitochondrial Function and Metabolic Reprogramming in Prostate Cancer Cell Lines

by Ana Peñata-Taborda, Pedro Espitia-Pérez, Lyda Espitia-Pérez, Andrés Coneo-Pretelt, Hugo Brango, Dina Ricardo-Caldera, Gean Arteaga-Arroyo, Luisa Jiménez-Vidal, Claudia Galeano-Páez, Karina Pastor-Sierra, Alicia Humanez-Alvarez, Osnamir Bru-Cordero, Nathalia Jones-Cifuentes, Bladimiro Rincón-Orozco, Stelia Mendez-Sanchez and Mario Negrette-Guzmán

Int. J. Mol. Sci. 2025, 26(3), 1013; https://doi.org/10.3390/ijms26031013 - 24 Jan 2025

Cited by 5 | Viewed by 4083

Abstract

Considering the limitations of monotherapies due to chemoresistance and side effects, this research aimed to determine whether low doses of sulforaphane (SFN) combined with docetaxel (DCT) could enhance therapeutic efficacy. Prostate cancer cell lines LNCaP and PC-3 were treated with individual IC50 doses [...] Read more.

Considering the limitations of monotherapies due to chemoresistance and side effects, this research aimed to determine whether low doses of sulforaphane (SFN) combined with docetaxel (DCT) could enhance therapeutic efficacy. Prostate cancer cell lines LNCaP and PC-3 were treated with individual IC50 doses of SFN and DCT and half-reduced IC50 values for the SFN:DCT combination. Metabolic markers, including glucose consumption, lactate production, reactive oxygen species (ROS), mitochondrial mass, and caspase activity, were assessed. In LNCaP cells, the SFN:DCT combination reduced cell viability to 50%, comparable to DCT monotherapy (48%). Caspase 3 activation was also higher with SFN:DCT (2.4 ± 0.75 RFU) than DCT alone (2.1 ± 0.47 RFU), while caspase 8 activation remained comparable, indicating equivalent effectiveness at lower concentrations. In PC-3 cells, the combination induced caspase 3 activation (1.16 ± 0.0484 RFU) at levels slightly lower than DCT (1.51 ± 0.2062 RFU) but achieved greater reductions in mitochondrial mass, reflecting its ability to target metabolic vulnerabilities in aggressive phenotypes. Our findings suggest that the SFN:DCT combination is a promising strategy for early-stage prostate cancer. By achieving comparable efficacy to DCT monotherapy at low doses, the SFN:DCT combination maintains the therapeutic impact, mitigating the adverse effects of conventional DCT treatment. Full article

(This article belongs to the Special Issue Mitochondrial Function in Health and Diseases)

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24 pages, 3729 KB

Open AccessArticle

Time Course of Mitochondrial Antioxidant Markers in a Preclinical Model of Severe Penetrating Traumatic Brain Injury

by Sudeep Musyaju, Hiren R. Modi, Deborah A. Shear, Anke H. Scultetus and Jignesh D. Pandya

Int. J. Mol. Sci. 2025, 26(3), 906; https://doi.org/10.3390/ijms26030906 - 22 Jan 2025

Cited by 9 | Viewed by 2719

Abstract

Traumatic brain injury (TBI) results from external mechanical forces exerted on the brain, triggering secondary injuries due to cellular excitotoxicity. A key indicator of damage is mitochondrial dysfunction, which is associated with elevated free radicals and disrupted redox balance following TBI. However, the [...] Read more.

Traumatic brain injury (TBI) results from external mechanical forces exerted on the brain, triggering secondary injuries due to cellular excitotoxicity. A key indicator of damage is mitochondrial dysfunction, which is associated with elevated free radicals and disrupted redox balance following TBI. However, the temporal changes in mitochondrial redox homeostasis after penetrating TBI (PTBI) have not been thoroughly examined. This study aimed to investigate redox alterations from 30 min to two-weeks post-injury in adult male Sprague Dawley rats that experienced either PTBI or a Sham craniectomy. Redox parameters were measured at several points: 30 min, 3 h, 6 h, 24 h, 3 d, 7 d, and 14 d post-injury. Mitochondrial samples from the injury core and perilesional areas exhibited significant elevations in protein modifications including 3-nitrotyrosine (3-NT) and protein carbonyl (PC) adducts (14–53%, vs. Sham). In parallel, antioxidants such as glutathione, NADPH, peroxiredoxin-3 (PRX-3), thioredoxin-2 (TRX-2), and superoxide dismutase 2 (SOD2) were significantly depleted (20–80%, vs. Sham). In contrast, catalase (CAT) expression showed a significant increase (45–75%, vs. Sham). These findings indicate a notable imbalance in redox parameters over the two-week post-PTBI period suggesting that the therapeutic window to employ antioxidant therapy extends well beyond 24 h post-TBI. Full article

(This article belongs to the Special Issue Mitochondrial Function in Health and Diseases)

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18 pages, 5240 KB

Open AccessArticle

Assessing the Efficacy of Mitochondria-Accumulating Self-Assembly Peptides in Pancreatic Cancer: An Animal Study

by Ho Joong Choi, Seongeon Jin, Junghyun Park, Dosang Lee, Hee Jeong Jeong, Ok-Hee Kim, Ja-Hyoung Ryu and Say-June Kim

Int. J. Mol. Sci. 2025, 26(2), 784; https://doi.org/10.3390/ijms26020784 - 17 Jan 2025

Cited by 1 | Viewed by 2814

Abstract

Although pancreatic cancer presents with one of the most unfavorable prognoses, its treatment options are very limited. Mitochondria-targeting moieties, considered a new and prominent treatment modality, are expected to demonstrate synergistic anticancer effects due to their distinct mechanism compared to conventional chemotherapeutic approaches. [...] Read more.

Although pancreatic cancer presents with one of the most unfavorable prognoses, its treatment options are very limited. Mitochondria-targeting moieties, considered a new and prominent treatment modality, are expected to demonstrate synergistic anticancer effects due to their distinct mechanism compared to conventional chemotherapeutic approaches. This study evaluated the therapeutic potential of mitochondria-accumulating self-assembly peptides, referred to as Mito-FFs, utilizing both in vitro and in vivo pancreatic cancer models. Cellular viability assays revealed a concentration-dependent decrease in the survival of MIA-PACA2 pancreatic cancer cells upon exposure to Mito-FF treatment (p < 0.05). Subsequent in vitro Mito-FF treatments prompted the use of several molecular analyses, including Real-time PCR, Western blot analysis, and MitoSOX staining, which collectively indicated an upsurge in apoptosis, a concurrent reduction in the antioxidant enzyme expression, and an elevation in mitochondrial ROS levels (p < 0.05). In a murine xenograft model of pancreatic cancer, the intravenous administration of Mito-FF yielded a notable reduction in the tumor volume. Moreover, it upregulated the expression of pro-apoptotic markers, such as cleaved PARP and c-caspase 3, while concurrently downregulating the expression of an anti-apoptotic marker, MCL-1, as evidenced by both Western blot analysis and immunohistochemical staining (p < 0.05). It also resulted in the reduced expression of antioxidant enzymes like HO-1, catalase, and SOD2 within excised tumor tissues, as confirmed using Western blot analysis (p < 0.05). Cumulatively, the findings underscore the significant anticancer efficacy of Mito-FF against pancreatic cancer cells, predominantly mediated through the induction of apoptosis, suppression of antioxidant enzyme expression, and enhancement of mitochondrial ROS levels within the tumor microenvironment. Full article

(This article belongs to the Special Issue Mitochondrial Function in Health and Diseases)

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Review

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26 pages, 1021 KB

Open AccessReview

Compartment-Specific Mitochondrial Proteomic Alterations in Rat Hippocampus Following Chronic Social Isolation Stress

by Dragana Filipović

Int. J. Mol. Sci. 2026, 27(8), 3386; https://doi.org/10.3390/ijms27083386 - 9 Apr 2026

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Abstract

Chronic social isolation (CSIS) is a form of psychosocial stressor strongly associated with the development of depression. Preclinical studies demonstrated that CSIS induces behavioral phenotypes resembling human depression, including anhedonia, behavioral despair and anxiety. This review summarizes proteomic-driven discoveries characterizing hippocampal non-synaptic mitochondria [...] Read more.

Chronic social isolation (CSIS) is a form of psychosocial stressor strongly associated with the development of depression. Preclinical studies demonstrated that CSIS induces behavioral phenotypes resembling human depression, including anhedonia, behavioral despair and anxiety. This review summarizes proteomic-driven discoveries characterizing hippocampal non-synaptic mitochondria (NSM) and synaptosomal fractions containing synaptic mitochondria from adult male rats exposed to six weeks of CSIS, an animal model of depression, compared to controls. The compartment-specific proteomic alterations reveal mechanisms underlying mitochondrial dysregulation, providing molecular insights into the depression-like phenotype. Hippocampal NSM exhibit changes in energy metabolism-related proteins, including components of the tricarboxylic acid cycle and oxidative phosphorylation, as well as mitochondrial transport proteins and alterations in chaperones, structural and translational proteins, and monoamine oxidase, further elucidating how these proteomic changes contribute to mitochondrial dysregulation. In contrast, synaptosomal proteomics reveal predominantly increased protein abundance associated with energy metabolism, signaling, cytoskeletal organization, protein quality control, and vesicle trafficking, suggesting compensatory adaptations. Together, these findings highlight compartment-specific mitochondrial proteomic changes that may underlie depression-like behaviors and represent potential targets for therapeutic intervention. Full article

(This article belongs to the Special Issue Mitochondrial Function in Health and Diseases)

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22 pages, 1571 KB

Open AccessReview

Therapeutic Potential of Mitochondrial Transplantation with Focus on DBD

by Chen Guo, Chenwei Gu, Anjie Chen, Sixin Li, Si Shen, Zhonghao Tang, Jiandong Gui, Lijie Zhu, Sheng Wu and Yuanyuan Mi

Int. J. Mol. Sci. 2026, 27(8), 3379; https://doi.org/10.3390/ijms27083379 - 9 Apr 2026

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Abstract

Diabetic Bladder Disease (DBD), a common urological complication of diabetes mellitus, severely compromises the quality of life of affected patients. Mitochondria, the primary energy-producing organelles in cells, are closely correlated with the pathogenesis and progression of DBD. As an emerging therapeutic modality, mitochondrial [...] Read more.

Diabetic Bladder Disease (DBD), a common urological complication of diabetes mellitus, severely compromises the quality of life of affected patients. Mitochondria, the primary energy-producing organelles in cells, are closely correlated with the pathogenesis and progression of DBD. As an emerging therapeutic modality, mitochondrial transplantation exhibits substantial potential for the management of DBD. This paper presents a comprehensive review of mitochondrial transplantation, with a focus on its fundamental theories, application conditions, safety profiles, and mitochondrial sources. Subsequently, we explore the association between mitochondrial dysfunction and the pathological mechanisms underlying DBD, analyze the disparities between mitochondrial transplantation and conventional therapeutic approaches, and discuss the prospects of combined and personalized treatment regimens. Finally, this review summarizes the ethical controversies surrounding this therapeutic strategy and outlines future research trends, aiming to lay a theoretical foundation for the development of novel therapeutic modalities against DBD. Full article

(This article belongs to the Special Issue Mitochondrial Function in Health and Diseases)

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19 pages, 1769 KB

Open AccessReview

Cofilin(s) and Mitochondria: Function Beyond Actin Dynamics

by Tatiana Kovaleva, Murat Gainullin, Irina Mukhina, Vladimir Pershin and Liudmila Matskova

Int. J. Mol. Sci. 2025, 26(9), 4094; https://doi.org/10.3390/ijms26094094 - 25 Apr 2025

Cited by 3 | Viewed by 2869

Abstract

ADF/cofilins form a family of small, widely expressed actin-binding proteins, regulating actin dynamics in various cellular and physiological processes in all eukaryotes, from yeasts to animals. Changes in the expression of the ADF/cofilin family proteins have been demonstrated under various pathological conditions. The [...] Read more.

ADF/cofilins form a family of small, widely expressed actin-binding proteins, regulating actin dynamics in various cellular and physiological processes in all eukaryotes, from yeasts to animals. Changes in the expression of the ADF/cofilin family proteins have been demonstrated under various pathological conditions. The well-established role of cofilin in migration, invasion, epithelial-mesenchymal transition, apoptosis, resistance to radiotherapy and chemotherapy, immune escape, and transcriptional dysregulation in malignant tumors is primarily attributed to its actin-modifying activity. Moreover, drugs targeting this function of cofilin have been developed for cancer treatment. However, its multilevel regulation, highly diverse effects across various pathological conditions, and conflicting data on the functional consequences of altered cofilin expression have prompted us to explore additional roles of cofilin—beyond actin modulation—particularly its involvement in lipid metabolism and mitochondrial homeostasis. Here, we review recent data on the expression of ADF/cofilin family proteins in various pathologies, account for the mutations and post-translational modifications of these proteins and their functional consequences, dwell on the role of K63-type ubiquitination of cofilin for its involvement in lipid metabolism and mitochondrial homeostasis, more specifically, a process of mitochondrial division or mitofission, point out conflicting data in cofilin research, and describe prospects for future studies of cofilin functions. Full article

(This article belongs to the Special Issue Mitochondrial Function in Health and Diseases)

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19 pages, 1528 KB

Open AccessReview

A Comprehensive Review of the Contribution of Mitochondrial DNA Mutations and Dysfunction in Polycystic Ovary Syndrome, Supported by Secondary Database Analysis

by Hiroshi Kobayashi, Sho Matsubara, Chiharu Yoshimoto, Hiroshi Shigetomi and Shogo Imanaka

Int. J. Mol. Sci. 2025, 26(3), 1172; https://doi.org/10.3390/ijms26031172 - 29 Jan 2025

Cited by 14 | Viewed by 5256

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age characterized by a spectrum of clinical, metabolic, reproductive, and psychological abnormalities. This syndrome is associated with significant long-term health risks, necessitating elucidation of its pathophysiology, early diagnosis, and comprehensive [...] Read more.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age characterized by a spectrum of clinical, metabolic, reproductive, and psychological abnormalities. This syndrome is associated with significant long-term health risks, necessitating elucidation of its pathophysiology, early diagnosis, and comprehensive management strategies. Several contributory factors in PCOS, including androgen excess and insulin resistance, collectively enhance oxidative stress, which subsequently leads to mitochondrial dysfunction. However, the precise mechanisms through which oxidative stress induces mitochondrial dysfunction remain incompletely understood. Comprehensive searches of electronic databases were conducted to identify relevant studies published up to 30 September 2024. Mitochondria, the primary sites of reactive oxygen species (ROS) generation, play critical roles in energy metabolism and cellular homeostasis. Oxidative stress can inflict damage on components, including lipids, proteins, and DNA. Damage to mitochondrial DNA (mtDNA), which lacks efficient repair mechanisms, may result in mutations that impair mitochondrial function. Dysfunctional mitochondrial activity further amplifies ROS production, thereby perpetuating oxidative stress. These disruptions are implicated in the complications associated with the syndrome. Advances in genetic analysis technologies, including next-generation sequencing, have identified point mutations and deletions in mtDNA, drawing significant attention to their association with oxidative stress. Emerging data from mtDNA mutation analyses challenge conventional paradigms and provide new insights into the role of oxidative stress in mitochondrial dysfunction. We are rethinking the pathogenesis of PCOS based on these database analyses. In conclusion, this review explores the intricate relationship between oxidative stress, mtDNA mutations, and mitochondrial dysfunction, offers an updated perspective on the pathophysiology of PCOS, and outlines directions for future research. Full article

(This article belongs to the Special Issue Mitochondrial Function in Health and Diseases)

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