Horizontal mitochondrial transfer as a novel bioenergetic tool for mesenchymal stromal/stem cells: molecular mechanisms and therapeutic potential in a variety of diseases

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Май 24, 2024

Abstract Intercellular mitochondrial transfer (MT) is a newly discovered form of cell-to-cell signalling involving the active incorporation healthy mitochondria into stressed/injured recipient cells, contributing to restoration bioenergetic profile and cell viability, reduction inflammatory processes normalisation calcium dynamics. Recent evidence has shown that MT can occur through multiple cellular structures mechanisms: tunneling nanotubes (TNTs), via gap junctions (GJs), mediated by extracellular vesicles (EVs) other mechanisms (cell fusion, extrusion migrasome-mediated mitocytosis) in different contexts, such as under physiological (tissue homeostasis stemness maintenance) pathological conditions (hypoxia, inflammation cancer). As Mesenchimal Stromal/ Stem Cells (MSC)-mediated emerged critical regulatory restorative mechanism for tissue regeneration damage repair recent years, its potential stem therapy received increasing attention. In particular, therapeutic role MSCs been reported several articles, suggesting enhance after injury membrane vesicle release. For these reasons, this review, we will discuss MSCs-mediated effects on diseases neuronal, ischaemic, vascular pulmonary diseases. Therefore, understanding molecular demonstrating efficacy could be an important milestone lays foundation future clinical trials.

Язык: Английский

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Enhanced SIRT3 expression restores mitochondrial quality control mechanism to reverse osteogenic impairment in type 2 diabetes mellitus

Bone Research, Год журнала: 2025, Номер 13(1)

Опубликована: Март 3, 2025

Abstract Osteoporosis represents a prevalent and debilitating comorbidity in patients diagnosed with type 2 diabetes mellitus (T2DM), which is characterized by suppressed osteoblast function disrupted bone microarchitecture. In this study, we utilized male C57BL/6 J mice to investigate the role of SIRT3 T2DM. Decreased expression impaired mitochondrial quality control mechanism are observed both vitro vivo models Mechanistically, suppression results hyperacetylation FOXO3, hindering activation PINK1/PRKN mediated mitophagy pathway resulting accumulation dysfunctional mitochondria. Genetical overexpression or pharmacological restores deacetylation status thus facilitating ameliorating osteogenic impairment Collectively, our findings highlight fundamental regulatory control, crucial for maintaining homeostasis These insights not only enhance understanding molecular mechanisms underlying diabetic osteoporosis but also identify as promising therapeutic target osteoporosis.

Язык: Английский

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Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(21), С. 15788 - 15788

Опубликована: Окт. 31, 2023

Due to their beneficial effects in an array of diseases, Mesenchymal Stromal Cells (MSCs) have been the focus intense preclinical research and clinical implementation for decades. MSCs multilineage differentiation capacity, support hematopoiesis, secrete pro-regenerative factors exert immunoregulatory functions promoting homeostasis resolution injury/inflammation. The main include modulation immune cells (macrophages, neutrophils, lymphocytes), secretion antimicrobial peptides, transfer mitochondria (Mt) injured cells. These actions can be enhanced by priming (i.e., licensing) prior exposure deleterious microenvironments. Preclinical evidence suggests that therapeutic a variety pathological states, including cardiac, respiratory, hepatic, renal, neurological diseases. One key emerging is improvement mitochondrial tissues enhancing quality control (MQC). Recent advances understanding cellular MQC, biogenesis, mitophagy, fission, fusion, helped uncover how enhance these processes. Specifically, suggested regulate peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)-dependent Parkin-dependent Mitofusins (Mfn1/2) or Dynamin Related Protein-1 (Drp1)-mediated fission/fusion. In addition, previous studies also verified from through tunneling nanotubes via microvesicular transport. Combined, improve functions, thereby contributing injury inflammation. Thus, uncovering affect MQC opens new avenues organ injury, transplantation MSC-derived might represent attractive approach.

Язык: Английский

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Implication of Rac1 GTPase in molecular and cellular mitochondrial functions

Life Sciences, Год журнала: 2024, Номер 342, С. 122510 - 122510

Опубликована: Фев. 20, 2024

Rac1 is a member of the Rho GTPase family which plays major roles in cell mobility, polarity and migration, as fundamental regulator actin cytoskeleton. Signal transduction by occurs through interaction with multiple effector proteins, its activity regulated guanine nucleotide exchange factors (GEFs) GTPase-activating proteins (GAPs). The small protein mainly anchored to inner side plasma membrane but it can be found endocellular compartments, notably endosomes nuclei. localizes also into mitochondria where contributes regulation mitochondrial dynamics, including both mitobiogenesis mitophagy, addition signaling processes via different partners, such proapoptotic Bcl-2 chaperone sigma-1 receptor (σ-1R). form (mtRac1) has been understudied thus far, essential nuclear or forms, implication oxidative stress DNA damages. subject diverse post-translational modifications, geranylgeranylation importantly import anchorage membranes. In addition, translocation other p53. localization functions are discussed here, context human diseases cancers. Inhibitors have identified (NSC-23766, EHT-1864) some being developed for treatment cancer (MBQ-167) central nervous system (JK-50561). Their effects on mtRac1 warrant further investigations. An overview provided here.

Язык: Английский

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A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan

Nature Aging, Год журнала: 2023, Номер 3(12), С. 1529 - 1543

Опубликована: Ноя. 13, 2023

Язык: Английский

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Corosolic acid attenuates cardiac ischemia/reperfusion injury through the PHB2/PINK1/parkin/mitophagy pathway

iScience, Год журнала: 2024, Номер 27(8), С. 110448 - 110448

Опубликована: Июль 8, 2024

Despite advances in treatment, myocardial infarction remains the leading cause of heart failure and death worldwide, restoration coronary blood flow can also damage. In this study, we found that corosolic acid (CA), known as plant insulin, significantly protects from ischemia-reperfusion (I/R) injury. addition, CA inhibit oxidative stress improve mitochondrial structure function cardiomyocytes. Subsequently, our study demonstrated improved expression mitophagy-related proteins Prohibitin 2 (PHB2), PTEN-induced putative kinase protein-1 (PINK1), Parkin. Meanwhile, through molecular docking, an excellent binding between PHB2 protein. Finally, knockdown eliminated protective effect on hypoxia-reoxygenation Taken together, reveals increases mitophagy cardiomyocytes via PHB2/PINK1/Parkin signaling pathway, inhibits response, maintains function, thereby improving cardiac after I/R.

Язык: Английский

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Novel Prospects in Targeting Neurodegenerative Disorders via Autophagy

European Journal of Pharmacology, Год журнала: 2024, Номер 984, С. 177060 - 177060

Опубликована: Окт. 18, 2024

Язык: Английский

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Sepsis-induced cardiac dysfunction: mitochondria and energy metabolism

Intensive Care Medicine Experimental, Год журнала: 2025, Номер 13(1)

Опубликована: Фев. 18, 2025

Abstract Sepsis is a life-threatening multi-organ dysfunction syndrome caused by dysregulated host response to infection, posing significant global healthcare challenge. Sepsis-induced myocardial (SIMD) common complication of sepsis, significantly increasing mortality due its high energy demands and low compensatory reserves. The substantial mitochondrial damage rather than cell apoptosis in SIMD suggests disrupted cardiac metabolism as crucial pathophysiological mechanism. Therefore, we systematically reviewed the mechanisms underlying SIMD, including alterations substrates, excitation–contraction coupling processes, dysfunction, autophagy biogenesis, summarizing potential therapeutic targets within them.

Язык: Английский

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Therapeutic Efficacy of Small Extracellular Vesicles Loaded with ROCK Inhibitor in Parkinson’s Disease

Pharmaceutics, Год журнала: 2025, Номер 17(3), С. 365 - 365

Опубликована: Март 13, 2025

Background/Objectives: Parkinson’s disease (PD) is a rapidly growing neurological disorder in the developed world, affecting millions over age of 60. The decline motor functions occurs due to progressive loss midbrain dopaminergic neurons, resulting lowered dopamine levels and impaired muscle function. Studies show defective mitochondrial autophagy (or “mitophagy”) links PD. Rho-associated coiled-coil containing protein kinases (ROCK) 1 ROCK2 are serine/threonine kinases, their inhibition can enhance neuroprotection PD by promoting mitophagy. Methods: We examine effects ROCK inhibitor SR3677, delivered via macrophage-derived small extracellular vesicles (sEVs) Parkin Q311X(A) mouse models. sEVs with administered intranasally, increased mitophagy gene expression, reduced inflammatory factors, elevated brain tissues. Results: expression decreased, showing drug’s inhibitory effect. sEV-SR3677 treatment was more effective than drug alone, although sham EVs showed lower effects. This suggests that EV-SR3677 not only activates processes but also promotes degradation damaged mitochondria through autophagy. Mitochondrial functional assays oxygen consumption ex vivo glial cultures revealed significantly improved respiration compared untreated or SR3677-only treated cells. Conclusion: demonstrated efficacy on function model, necessitating further studies explore design challenges mechanisms as mitochondria-targeted therapy for

Язык: Английский

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Neuroprotective Potential of the Flavonoids Quercetin and Epicatechin in a C. elegans Tauopathy Model

Molecular Nutrition & Food Research, Год журнала: 2025, Номер unknown

Опубликована: Май 12, 2025

ABSTRACT The prevalence of cognitive disorders such as Alzheimer's disease (AD) is increasing due to the global rise in longevity. accumulation amyloid β (Aβ) deposits and hyperphosphorylated Tau protein (p‐Tau) are considered main hallmarks AD. A growing body evidence suggests that regular intake flavonoid‐rich foods could reduce risk developing AD or mitigate its progression. This study explores potential quercetin (Q) epicatechin (EC) effective molecules against AD‐like pathology, using Caenorhabditis elegans BR5270 strain, which expresses pro‐aggregant F3DK280 fragment human protein. results showed after exposure 150 µM EC Q, worms exhibited increased lifespan, improved chemotaxis, delayed age‐related decline locomotion. To explore molecular mechanisms involved, expression genes associated with inhibition p‐Tau proteotoxicity were measured by RT‐qPCR. It was found Q significantly levels autophagy‐related a key gene for de novo synthesis α‐ tubulin. delay neurodegeneration C. tauopathy model, suggesting their

Язык: Английский

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