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Biogenesis of NDUFS3-less complex I indicates TMEM126A/OPA7 as an assembly factor of the ND4-module

D'Angelo, L.; Astro, E.; De Luise, M.; Kurelac, I.; Umesh-Ganesh, N.; Ding, S.; Fearnley, I. M.; Zeviani, M.; Gasparre, G.; Porcelli, A. M.; Fernandez-Vizarra, E.; Iommarini, L.

2020-10-22 biochemistry
10.1101/2020.10.22.350587 bioRxiv
Show abstract

Complex I (CI) is the largest enzyme of the mitochondrial respiratory chain and its defects are the main cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we analyzed the structural and functional consequences of the ablation of NDUFS3, a non-catalytic core subunit. We prove that in diverse mammalian cell types a small amount of functional CI can still be detected in the complete absence of NDUFS3. In addition, we have determined the dynamics of CI disassembly when the amount of NDUFS3 is gradually decreased. The process of degradation of the complex occurs in a hierarchical and modular fashion where the ND4-module remains stable and bound to TMEM126A. We have thus, uncovered the function of TMEM126A, the product of a disease gene causing recessive optic atrophy, as a factor necessary for the correct assembly and function of CI.

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