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Regulation of mitochondrial quality control by membrane fission

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dc.contributor.advisor PUCADYIL, THOMAS
dc.contributor.author ROY, KRISHNENDU
dc.date.accessioned 2024-03-06T04:02:55Z
dc.date.available 2024-03-06T04:02:55Z
dc.date.issued 2024-03
dc.identifier.citation 115 en_US
dc.identifier.uri http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/8577
dc.description.abstract Mitochondria manage essential functions such as ATP production, Ca 2+ homeostasis and apoptotic signalling but are prone to damage. Surveillance mechanisms have evolved to selectively detect and rid the network of damaged mitochondria. Together, these constitute quality control (QC) pathways that either involve mitophagy or the budding and fission of mitochondria-derived vesicles (MDVs). A common theme among these QC pathways is to physically separate portions of the damaged organelle, which is achieved through membrane fission. Recent reports have linked the production of diacylglycerol (DAG) in mitophagy, but its functional relevance remains unclear. Local production of DAG on the outer mitochondrial membrane (OMM) causes the recruitment of the mitophagy-associated protein Endophilin B1 as well as the rapid fragmentation of the mitochondria in a dynamin-related protein 1 (Drp1)-dependent manner. We employed biochemical reconstitution to understand the mechanistic basis of both these phenomena. Our results indicate that DAG facilitates the binding and tubulation of bilayers by Endophilin B1. Furthermore, the presence of DAG stimulates Drp1functions. Together, these results provide a mechanistic basis for the how DAG facilitates mitophagy. On the other hand, MDVs are small vesicles that sort out mitochondrial proteins from the network and their formation is generally considered to be Drp1-independent, which led us to screen for fission catalysts that manage their release. Using cardiolipin (CL)-containing supported membrane tubes in a biochemical fission screen, we identified α-synuclein (α-syn) as a fission catalyst. Recombinant α-Syn preferential binds and severs CL-containing membrane tubes. α-Syn knockout (KO) cells show major respiratory defects, an over-dependence on glycolysis, an altered mitochondrial proteome and increased mitophagy. Importantly, Parkinson Disease (PD)-associated α-Syn mutants are incapable of causing fission, thus linking α-Syn functions to neurodegeneration acting via defects in mitochondrial QC pathways. Together, these results provide important new mechanistic insights into how membrane fission regulates QC pathways of the mitochondria. en_US
dc.language.iso en en_US
dc.subject Research Subject Categories::NATURAL SCIENCES en_US
dc.title Regulation of mitochondrial quality control by membrane fission en_US
dc.type Thesis en_US
dc.description.embargo 1 Year en_US
dc.type.degree Int.Ph.D en_US
dc.contributor.department Dept. of Biology en_US
dc.contributor.registration 20162005 en_US


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  • PhD THESES [592]
    Thesis submitted to IISER Pune in partial fulfilment of the requirements for the degree of Doctor of Philosophy

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