Coordinated Assembly of the Mitochondrial Electron Transport Chain

Mitochondrial oxidative phosphorylation is an efficient source of cellular energy. This pathway couples the oxidation of NADH and FADH2 to the establishment of an electrochemical gradient across the inner mitochondrial membrane to facilitate ATP generation. The respiratory chain is comprised of five complexes; however, these are not simple enzymes. Rather, they are highly intricate membrane-bound complexes. As such, the biogenesis of these complexes presents the cell with numerous problems. Thus, the cell expresses dozens of assembly factors that are required to support the biogenesis of individual complexes. In the end, this promotes cellular energy production and protects the cell from potentially damaging insults. Succinate dehydrogenase (SDH) or complex II is a member of the electron transport chain (ETC) and TCA cycle. It plays a central role in cellular energy generation and mutations in the genes encoding SDH subunits and assembly factors are associated with human disease, including cancer and neurodegeneration. This highly conserved family supports the maturation of SDHA/Sdh1, the catalytic subunit of SDH. As such, Sdh8 functions as an Sdh1-specific chaperone and prevents the spurious generation of reactive oxygen species during the assembly process. In Drosophila, Sdhaf4 is required to prevent neurodegeneration and maintain normal motility. In the end, this work has expanded our understanding of the SDH assembly pathway and provided novel insights into the development of SDH-deficient pathologies. In addition to the canonical cytosolic pathway, eukaryotic cells have maintained a mitochondrial fatty acid synthesis pathway (FASII). This pathway is homologous to prokaryotic fatty acid synthesis and utilizes a number of enzymes that interact transiently with the acyl carrier protein (ACP) to support elongation of nascent acyl chains. Herein, we describe a novel and unexpected role for ACP and FASII in the assembly and activation of the ETC. As such, FASII-dependent synthesis of ACP-bound acyl chains activates a network of complex-specific assembly factors to support the assembly of the ETC complexes and synthesis of their essential cofactors. In the end, FASII and ACP couple mitochondrial acetyl-CoA to ETC biogenesis.