Dissecting the Roles of Mitochondrial Complex I Intermediate Assembly (MCIA) Complex Factors in the Biogenesis of Complex I

Abstract

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 centred on ACAD9. We also identify TMEM186 and COA1 as bona fide components of the MCIA complex with loss of either resulting in in MCIA complex defects and reduced complex I assembly. TMEM186 enriches with newly translated ND3, while COA1 enriches with ND2. Our findings provide new functional insights into the essential nature of the MCIA complex in complex I assembly.

The road to the structure of the mitochondrial respiratory chain supercomplex

“…High-resolution structures of the OXPHOS complexes have been critical to our understanding of their function in respiration, however, these structures also proved a valuable resource for researchers interested in the mechanisms of OXPHOS complex assembly and how defective OXPHOS might lead to disease. Our laboratory has benefitted immensely from the work of structural biologists, as we have found the mapping of massspectrometry derived data onto the 3D structures of OXPHOS complexes helpful for understanding the roles of specific subunits and assembly factors [17][18][19][20][21][22][23]. Complete high-resolution structures now exist for four of the five OXPHOS complexes, as well as multiple variations of the respiratory chain supercomplex.…”