Dissecting the Roles of Mitochondrial Complex I Intermediate Assembly Complex Factors in the Biogenesis of Complex I
Luke E. Formosa,
Linden Muellner-Wong,
Boris Reljic,
Alice J. Sharpe,
Thomas D. Jackson,
Traude H. Beilharz,
Diana Stojanovski,
Michael Lazarou,
David A. Stroud,
Michael T. Ryan
Affiliations
Luke E. Formosa
Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; Corresponding author
Linden Muellner-Wong
Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Boris Reljic
Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, The Bio21 Institute, The University of Melbourne, Melbourne, VIC 3000, Australia
Alice J. Sharpe
Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Thomas D. Jackson
Department of Biochemistry and Molecular Biology, The Bio21 Institute, The University of Melbourne, Melbourne, VIC 3000, Australia
Traude H. Beilharz
Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
Diana Stojanovski
Department of Biochemistry and Molecular Biology, The Bio21 Institute, The University of Melbourne, Melbourne, VIC 3000, Australia
Michael Lazarou
Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
David A. Stroud
Department of Biochemistry and Molecular Biology, The Bio21 Institute, The University of Melbourne, Melbourne, VIC 3000, Australia
Michael T. Ryan
Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; Corresponding author
Summary: Mitochondrial complex I harbors 7 mitochondrial and 38 nuclear-encoded subunits. Its biogenesis requires the assembly and integration of distinct intermediate modules, mediated by numerous assembly factors. The mitochondrial complex I intermediate assembly (MCIA) complex, containing assembly factors NDUFAF1, ECSIT, ACAD9, and TMEM126B, is required for building the intermediate ND2-module. The role of the MCIA complex and the involvement of other proteins in the biogenesis of this module is unclear. Cell knockout studies reveal that while each MCIA component is critical for complex I assembly, a hierarchy of stability exists centered on ACAD9. We also identify TMEM186 and COA1 as bona fide components of the MCIA complex with loss of either resulting in MCIA complex defects and reduced complex I assembly. TMEM186 enriches with newly translated ND3, and COA1 enriches with ND2. Our findings provide new functional insights into the essential nature of the MCIA complex in complex I assembly. : Formosa et al. investigate the function of the MCIA complex in complex I assembly. They demonstrate the requirement of individual components for the formation of complex I intermediates and assembly of the final enzyme. Finally, they characterize the involvement of TMEM186 and COA1 in this process. Keywords: assembly factors, complex I, MCIA complex, mitochondria, NADH-ubiquinone dehydrogenase, oxidative phosphorylation
