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Title: The role of complex II of the mitochondrial respiratory chain in cell death induction
Author: Hwang, Ming
ISNI:       0000 0004 5349 0795
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Complex II of the respiratory chain (RC) recently emerged as a prominent regulator of cell death. In both cancer as well as neurodegenerative diseases, mutations in its subunits have been found along with other genetic alterations indirectly affecting this complex. Moreover, anticancer compounds were developed that target complex II and cause cell death in a tumour-specific way. I found evidence that this protein assembly is specifically activated for cell death via the dissociation of its SDHA and SDHB subunits from the membrane-anchoring proteins through mitochondrial Ca2+ influx. The relationship between Ca2+ and cell death activation has been under intense investigation, but not much has been identified on the associated mechanisms. Ca2+ influx into mitochondria plays a significant role in cell death induction, but it was unknown how the observed massive Ca2 accumulation activates the organelle for cell destruction. The disintegration of complex II subunits is prevented in vitro when cardiolipin is substituted with a lipid devoid of Ca2+ binding. Cardiolipin is known to associate with complex II, but coalesces into tight homotypic clusters upon Ca2+ binding. When complex II is deprived of this lipid, it disintegrates for ROS formation and cell death induction. My results reveal Ca2+ binding to cardiolipin and subsequent complex II disintegration as a crucial step for oxidative stress and cell death induction. Ultimately, it emphasizes the important role that Ca2+ plays in ROS-induced cell death via the respiratory chain, which can be used for many translational investigations. For instance, future studies on Ca2+ and its binding to cardiolipin for cell death induction will further elucidate complex II as a target for cancer treatment as well as neurodegenerative diseases and reveal its role as a nexus for many diverse stimuli in cell death signalling.
Supervisor: Grimm, Stefan Sponsor: AstraZeneca
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available