Studying the role of coenzyme Q10 in mitochondrial calcium and redox signalingDoctoral thesis
Date of Examination:2022-03-01
Date of issue:2022-06-30
Advisor:Dr. Ivan Prof Bogeski
Referee:Dr. Ivan Prof Bogeski
Referee:Prof. Dr. Michael Meinecke
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Name:PhD Thesis_ Zuriñe Bonilla del Río.pdf
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EnglishMitochondria can take up large amounts of calcium (Ca2+) in order to control the activity of several enzymes and their bioenergetics output. As a consequence of this metabolic flux, reactive oxygen species (ROS) are generated that modulate cell signaling pathways, contributing to many cellular processes. Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial electron transport chain (mETC) and is also found in other cellular compartments such as the plasma membrane. Due to their role as effective antioxidants, CoQs act as radical scavengers in the mitochondria, and prevent lipid peroxidation (LPO) in the plasma membrane. Accordingly, CoQs are crucial regulators of the mitochondrial bioenergetics and of ferroptosis. Coenzyme Q10 insufficiency is related to severe pathologies in humans. This deficit can be caused by mutations in genes involved in CoQ10 biosynthesis or by defects in other biological functions that are indirectly related. Furthermore, statins, used as inhibitors of the mevalonate pathway in the treatment of hypercholesterolemia, also induce a CoQ10 deficiency causing serious side effects. In patients with CoQ10 deficiency, supplementation with CoQ10 is used as a first line of therapy. However, the effectiveness of this approach is rather limited. Here, we demonstrate that CoQ10 regulates mitochondrial Ca2+ and redox signaling as well as ferroptotic cell death in primary human skin fibroblasts (HSF) and iPSC-derived cardiomyocytes (iPSC-CM). In this regard, depletion of CoQ10 elevated mitochondrial Ca2+ (mCa2+) uptake while its upregulation caused a decrease in mCa2+. Treatment with mitochondrially targeted CoQ10 (mitoQ) reduced ROS levels but suppressed essential cellular parameters such as respiration, mitochondrial membrane potential (mΔΨ) and viability in HSF. Furthermore, addition of mitoQ to CoQ10 deficient patient-derived HSF caused similar negative effects and did not compensate for the intrinsic CoQ10 deficiency. Hydroxylated CoQ forms (OH-CoQs) act as potent antioxidants, transport Ca2+ across artificial bio-membranes and have been suggested to have superior properties when compared to the native CoQs. We generated mitochondrial targeted OH-CoQ10 (OH-mitoQ) and tested its role in the same cellular systems. Notably, the antioxidant effects of OH-mitoQ were comparable with those of mitoQ. However, OH-mitoQ had less side-effects when compared with mitoQ. We also found that both mitoQ and OH-mitoQ were effective inhibitors of ferroptosis. These findings suggested that mitochondrial redox and Ca2+ signalling play an important role in this form of cell death. To investigate the functional relevance and the role of mitochondria within the CoQ10-ferroptosis axis, we exposed CoQ10-deficient HSF and iPSC-CM to ferroptosis inducers (FINs). Surprisingly, we found that CoQ10 deficient cells display reduced ferroptotic sensitivity. These results thus suggested that CoQ10 protective properties are compensated by alternative regulatory pathway(s) or antioxidant system(s). In summary, our findings suggest that due to their redox properties, OH-CoQs are superior to the CoQs and are thus potential drugs for treating primary and secondary CoQ10 deficiencies. Moreover, our study indicates that mitochondrial redox signals are important regulators of ferroptosis.
Keywords: Coenzyme Q10; Hydroxylated-CoQs; Calcium signaling; Redox signaling; Reactive Oxygen Species; Lipid peroxidation; Ferroptosis; Fibroblasts; iPSC-cardiomyocytes