Pharmacological aspects of the inhibition of mammalian respiratory complex I

Mitochondrial complex I, a large respiratory enzyme located in the inner mitochondrial membrane, catalyses electron transfer from NADH to ubiquinone while concomitantly translocating protons across the membrane to sustain ATP synthesis. A crucial aspect of the pharmacology of complex I is drug-induced mitochondrial dysfunction, particularly its role in liver toxicity. Complex I inhibition causes an energy deficit and can lead to adverse changes in the status of the mitochondrial [NADH]/[NAD+] pool and increased reactive oxygen species production, causing widespread damage. A library of molecules that are known candidates for causing complex I-driven drug- induced mitochondrial dysfunction was compiled using database and literature searches and then tested with assays on isolated mammalian complex I, mitochondrial membranes and cultured mammalian cells. The results extend the knowledge of complex I-linked drug toxicity and define a proof-of-principle methodology for the investigation of further unknown candidate molecules. Using this methodology, the Screen-Well V2 library from Enzo Life Sciences, containing 786 FDA-approved drugs, was used to investigate the role of complex I-linked drug toxicity on a wider scale. The results show that complex I is targeted by many structurally unrelated pharmacological compounds, but whether catalysis is inhibited in vivo requires drug transport into the mitochondrion, limiting the adverse physiological consequences in most cases tested. Furthermore, three structure-activity relationship studies were carried out on specific classes of complex I inhibitors: rotenoid natural product compounds, a family of pyrazole-based compounds under investigation as anticancer drugs, and variants on the drug Mubritinib. These studies identified structural determinants of binding to complex I and improve our understanding of complex I inhibition.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2018

Author dc:creator

• Serreli, Riccardo

Advisor dc:contributor.advisor

• Hirst, Judy

• mitochondria
• drug-induced
• dysfunction
• pharmacology
• complex I
• OXPHOS

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f2f81153-ec0b-43ff-a5eb-405e8eb6e42e/download
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.20230

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/273222