Mitochondrial Transfer Regulates Cell Fate Through Metabolic Remodeling in Osteoporosis
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ABSTRACT:
PROVIDER: PRJNA816909 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR18339000_1.fastq.gz | Fastqsanger.gz | |||
| SRR18339000_2.fastq.gz | Fastqsanger.gz | |||
| SRR18339001_1.fastq.gz | Fastqsanger.gz | |||
| SRR18339001_2.fastq.gz | Fastqsanger.gz | |||
| SRR18339002_1.fastq.gz | Fastqsanger.gz |
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Project description:To reveal an unappreciated mechanism of mitochondrial regulation of skeletal metabolic homeostasis via mitochondria transfer and provide new insights of the mechanism of glucocorticoid-induced osteoporosis progression.
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Project description:To reveal an unappreciated mechanism of mitochondrial regulation of skeletal metabolic homeostasis via mitochondria transfer and provide new insights of the mechanism of glucocorticoid-induced osteoporosis progression.
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Project description:Intercellular mitochondrial transfer has recently been discovered as a strategy for local microenvironment regulation and repair. However, improving the efficiency of mitochondrial transfer and reducing immune rejection caused by implants is challenging for its application in bone regeneration tissue engineering. We found that bone marrow mesenchymal stem cells (BMSC)s can obtain mitochondria from macrophages through tunnel nanotubes (TNT)s. Mitochondria are crucial for the metabolism and function of BMSC. We further designed a composite hydrogel based on aldehyde sodium hyaluronate and chitosan as the network matrix, containing anti-inflammatory dimethyl itaconate (DMI) and macrophage-targeted zwitterionic nanoparticles (MDVNPs). The acidic bone injury microenvironment triggers a reversible Schiff base reaction in response to pH; further, the released DMI upregulates the M2 phenotype of macrophages by reducing the ROS level. Subsequently, MDVNPs with targeting, high transfection, and low immunogenicity accelerated the efficiency of mitochondrial transfer between macrophages and BMSC by increasing the expression of the mitochondrial transfer regulatory protein Rho GTPase 1 (Miro1). In vitro studies have confirmed that promoting mitochondrial transfer can effectively increase adenosine triphosphate (ATP) and oxidative phosphorylation (OXPHOS) levels in BMSC, promoting osteoblastic differentiation. In the mouse model of critical defect, the composite hydrogel (Gel@MDI) can reduce inflammatory reactions, improve energy metabolism, and enhance bone repair by promoting the balance between the immune system and bone metabolism. This study establishes a potential method for the immune microenvironment to enhance cellular mitochondrial bioenergy and achieve tissue regeneration by regulating mitochondrial transfer between cells.
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Project description:Metabolic abnormalities and mild inflammation are hallmarks of aging and major driving factors for aging-related damage and bone metabolic diseases. Mitochondria are crucial links in energy metabolism and immune homeostasis regulation. Mitochondrial dysfunction is considered one of the pathogenic factors of aging-related osteoporosis, but its mechanism of action needs further research. Here, we demonstrated that the interaction between stimulator of interferon genes (STING)-mediated regulation of hexokinase 2 (Hk2)-voltage-dependent anion channel-1 (Vdac1) is a critical factor contributing to mitochondrial dysfunction and osteogenic abnormalities during aging. As the aging process progresses, factors related to aging cause an increase in STING expression, which disrupts the interaction between Hk2 and Vdac1. Dissociation of Hk2 from Vadc1 triggered the opening of the mitochondrial inner mitochondrial permeability transition pore (mPTP), leading to mitochondrial dysfunction and abnormal osteogenic differentiation, thereby disrupting bone homeostasis. In brief, this study demonstrates that STING acts as an intracellular metabolic Checkpoint, influencing mitochondrial function to promote the development of osteoporosis. These findings significantly enhance the development of STING-targeted treatments for aging-related osteoporosis.
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