Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.22.350587v1?rss=1 Authors: 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. Abstract: Complex I (CI) is the largest enzyme of the mitochondrial respiratory chain and its defects constitute the principal cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we dissected the structural and functional consequences of the depletion of NDUFS3, a non-catalytic core subunit. We prove that in diverse cell contexts a small, but still detectable, proportion of functional CI can still be found in the absence of NDUFS3. In addition, we have determined the dynamics of disassembly of CI when the amounts of NDUFS3 are 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 optic atrophy, as a factor necessary for the correct assembly and function of CI. Copy rights belong to original authors. Visit the link for more info