Journal article
Two independent respiratory chains adapt OXPHOS performance to glycolytic switch
E Fernández-Vizarra, S López-Calcerrada, A Sierra-Magro, R Pérez-Pérez, LE Formosa, DH Hock, M Illescas, A Peñas, M Brischigliaro, S Ding, IM Fearnley, C Tzoulis, RDS Pitceathly, J Arenas, MA Martín, DA Stroud, M Zeviani, MT Ryan, C Ugalde
Cell Metabolism | CELL PRESS | Published : 2022
Abstract
The structural and functional organization of the mitochondrial respiratory chain (MRC) remains intensely debated. Here, we show the co-existence of two separate MRC organizations in human cells and postmitotic tissues, C-MRC and S-MRC, defined by the preferential expression of three COX7A subunit isoforms, COX7A1/2 and SCAFI (COX7A2L). COX7A isoforms promote the functional reorganization of distinct co-existing MRC structures to prevent metabolic exhaustion and MRC deficiency. Notably, prevalence of each MRC organization is reversibly regulated by the activation state of the pyruvate dehydrogenase complex (PDC). Under oxidative conditions, the C-MRC is bioenergetically more efficient, where..
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Grants
Awarded by Comunidad de Madrid
Funding Acknowledgements
We thank all lab members for constructive discussions and M.E. Harbour and P. Palenikova (University of Cambridge) for their help with the CP datasets. We thank E. Lamantea and the biobank "Cell line and DNA Bank of Genetic Movement Disorders and Mitochondrial Diseases,"member of the Telethon Network of Genetic Biobanks (project no. GTB12001), funded by Telethon Italy and the EuroBioBank network, for the PDH-deficient fibroblasts. We thank M.G. Hanna, co-lead for the London NHS England Highly Specialised Service for Rare Mitochondrial Disorders, for access to patient-derived tissue. We are grateful to A. Sanz and K. Tokatlidis (University of Glasgow) and C. Viscomi and T. Cali (University of Padova) for their support, as well as to C. Romualdi (University of Padova) and C. Doerrier (Oroboros Instruments) for insightful revision and discussions about the respirometry datasets. Research was funded by Instituto de Salud Carlos III-MINECO/European FEDER Funds grants PI17-00048, PI20-00057 (to C.U.), and PI18-01374 (to M.A.M.); by Comunidad Autonoma de Madrid/ERDF-ESF grant S2018/BAA-4403 (to C.U.); by Association Francaise contre les Myopathies (AFM) grant 16086 (to E.F.-V.); by Fondazione Telethon-Cariplo grant GJC21014 (to E.F.-V.); by Research Council of Norway (288164), Bergen Research Foundation (BFS2017REK05), and Western Norway Regional Health Authority (F-11470) (to C.T.); by a Clinician Scientist Fellowship (MR/S002065/1) and Strategic Award (MR/S005021/1) from Medical Research Council (MRC, UK) (to R.D.S.P.); by a Core Grant from MRC (MC_UU_00015/5), an Advanced Grant from the European Research Council (ERC) (MITCARE: FP7-322424), Mitofight Grant-Associazione Renato Comini Onlus, and NRJ Institut de France Grant (to M.Z.); and by the Australian National Health and Medical Research Council (NHMRC project grants #1165217 and #1164459 to M.T.R., #1125390 and #1140906 to D.A.S. and M.T.R., and NHMRC Fellowship 1140851 to D.A.S.). D.H.H. is supported by a Melbourne International Research Scholarship and Mito Foundation (incorporated as Australian Mitochondrial Disease Foundation) Top-up Scholarship. We acknowledge support from the Bio21 Mass Spectrometry and Proteomics Facility (MMSPF) for the provision of instrumentation, training, and technical support, and the Mito Foundation for the provision of instrumentation.