Mitochondrial Bol1 and Bol3 function as assembly factors for specific iron-sulfur proteins.

Proteins perform almost all the tasks necessary for cells to survive. However, some proteins, especially enzymes involved in metabolism and energy production, need to contain extra molecules called co-factors to work properly. In human, yeast and other eukaryotic cells, co-factors called iron-sulfur clusters are made in compartments called mitochondria before being packaged into target proteins. Defects that affect the assembly of proteins with iron-sulfur clusters are associated with severe diseases that affect metabolism, the nervous system and the blood. Mitochondria contain at least 17 proteins involved in making iron-sulfur proteins, but there may be others that have not yet been identified. For example, a study on patients with a rare human genetic disease suggested that a protein called BOLA3 might also play a role in this process. BOLA3 is closely related to the BOLA1 proteins. Here, Uzarska, Nasta, Weiler et al. used yeast to test how these proteins contribute to the assembly of iron-sulfur proteins. Biochemical techniques showed that the yeast equivalents of BOLA1 and BOLA3 (known as Bol1 and Bol3) play specific roles in the assembly pathway. When both of these proteins were missing from yeast, some iron-sulfur proteins – including an important enzyme called lipoic acid synthase – did not assemble properly. The experiments suggest that yeast Bol1 and Bol3 play overlapping and critical roles during the last step of iron-sulfur protein assembly when the iron-sulfur cluster is inserted into the target protein. Lastly, Uzarska, Nasta, Weiler et al. used biophysical techniques to show how Bol1 and Bol3 interact with another mitochondrial protein that performs a more general role in iron-sulfur protein assembly. Defects in assembling iron-sulfur proteins are generally more harmful to human cells than yeast cells. Therefore, the next step is to investigate what exact roles BOLA1 and BOLA3 play in human cells and how similar this pathway is in different eukaryotes.