NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate
Luigi D’Angelo,
Elisa Astro,
Monica De Luise,
Ivana Kurelac,
Nikkitha Umesh-Ganesh,
Shujing Ding,
Ian M. Fearnley,
Giuseppe Gasparre,
Massimo Zeviani,
Anna Maria Porcelli,
Erika Fernandez-Vizarra,
Luisa Iommarini
Affiliations
Luigi D’Angelo
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy
Elisa Astro
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy
Monica De Luise
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
Ivana Kurelac
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
Nikkitha Umesh-Ganesh
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
Shujing Ding
Medical Research Council-Mitochondrial Biology Unit, University of Cambridge, CB2 0XY Cambridge, UK
Ian M. Fearnley
Medical Research Council-Mitochondrial Biology Unit, University of Cambridge, CB2 0XY Cambridge, UK
Giuseppe Gasparre
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy; Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
Massimo Zeviani
Medical Research Council-Mitochondrial Biology Unit, University of Cambridge, CB2 0XY Cambridge, UK; Venetian Institute of Molecular Medicine, 35128 Padua, Italy; Department of Neurosciences, University of Padua, 35128 Padua, Italy
Anna Maria Porcelli
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy; Interdepartmental Center of Industrial Research (CIRI) Life Science and Health Technologies, University of Bologna, 40064 Ozzano dell’Emilia, Italy
Erika Fernandez-Vizarra
Medical Research Council-Mitochondrial Biology Unit, University of Cambridge, CB2 0XY Cambridge, UK; Institute of Molecular, Cell and Systems Biology, University of Glasgow, G12 8QQ Glasgow, UK; Corresponding author
Luisa Iommarini
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy; Corresponding author
Summary: 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 analyze the structural and functional consequences of the ablation of NDUFS3, a non-catalytic core subunit. We show 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 determine 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 in which the ND4 module remains stable and bound to TMEM126A. We, thus, uncover 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.
