Understanding and targeting mitochondria to counteract cellular senescene: elucidation of novel senotherapies
The pathologic role of senescent cells is well established in a variety of diseases. Despite the ample evidence that mitochondria play a central role in cellular senescence, the understanding of the adaptations in the mitochondria of senescent cells is rather superficial. In this work, we have chara...
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| Format: | doctoral thesis |
| Status: | Published version |
| Publication Date: | 2024 |
| Country: | España |
| Institution: | CBUC, CESCA |
| Repository: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/690466 |
| Online Access: | http://hdl.handle.net/10803/690466 |
| Access Level: | Embargoed access |
| Keyword: | Senescence SASP Senolytics Senomorphics Mitochondria Antiviral mtdsRNA Aging Senescencia Senolíticos Senomórficos Mitocondria RNAbc Envejecimiento 576 |
| Summary: | The pathologic role of senescent cells is well established in a variety of diseases. Despite the ample evidence that mitochondria play a central role in cellular senescence, the understanding of the adaptations in the mitochondria of senescent cells is rather superficial. In this work, we have characterized that senescent cells display a substantial increase in mitochondrial mass and mtDNA copies, coupled to reduced mitochondrial membrane potential, increased ROS levels and hyperfusion. Comparative proteomic analyses showed significant changes in the composition and quantity of mitochondrial proteins, in particular, increased levels of proteins related to fatty acid β-oxidation and ATP synthesis. Our results demonstrate the involvement of the mtdsRNA/MAVS/MFN1 axis as an important source of the inflammatory phenotype of senescent cells. Inhibition of mitochondrial RNA polymerase, dsRNA sensors, MAVS or MFN1 result in SASP reduction. Our study further identified PPIF/CypD as a promising senolytic target through CRISPR/Cas9-based screening, whose inhibition has shown efficiency in eliminating senescent cells. Altogether, these findings identify potential senescence mitochondrial vulnerabilities and open new avenues for treating senescence-associated disorders. |
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