Mitochondrial complex III Rieske Fe-S protein processing and assembly

Abstract

Regulation of the mitochondrial respiratory chain biogenesis is a matter of great interest because of its implications for mitochondrial disease. One of the mitochondrial disease genes recently discovered associated to encephalopathy and mitochondrial complex III (cIII) deficiency is TTC19. Our study of TTC19-deficient human and mouse models, has led us to propose a post-assembly quality control role or 'husbandry' function for this factor that is linked to Rieske Fe-S protein (UQCRFS1). UQCRFS1 is the last incorporated cIII subunit, and its presence is essential for enzymatic activity. During UQCRFS1 assembly, the precursor is cleaved and its N-terminal part remains bound to the complex, between the two core subunits (UQCRC1 and UQCRC2). In the absence of TTC19 there is a prominent accumulation of these UQCRFS1-derived N-terminal fragments that proved to be detrimental for cIII function. In this article we will discuss some ideas around the UQCRFS1 processing and assembly and its importance for the regulation of cIII activity and biogenesis.

Keywords: Mitochondrial respiratory chain; OXPHOS; Rieske Fe-S protein; TTC19; UQCRFS1; mitochondria; mitochondrial complex III; mitochondrial disease.

Figure 1.

UQCRFS1 pathway from synthesis of the precursor in the cytoplasm, transport into the mitochondrial matrix through the TOM/TIM23 import system, incorporation of the [2Fe-2S] clusters in the matrix and translocation to pre-cIII₂ in the inner membrane (IM). According to our model, the N-terminal MTS is cleaved off in situ by the UQCRC1+UQCRC2 MPP activity. See main text for more details.

Figure 2.

Graphic alignment of the Rieske protein precursors from yeast (S. cerevisiae), fruit fly (D. melanogaster), chicken (G. gallus) and mammals (bovine, mouse and human). Numbers indicate relevant residue positions. The two yeast cleavage sites, at positions 22 and 30 are indicated with arrows. The main cleavage site, conserved in all organisms is indicated with the big arrow. Different color MTS indicates the lack of homology of these sequences, while the homology in the mature protein sequences in very high.

Figure 3.

Structures of full complex III dimer (cIII₂) and of isolated UQCRFS1 (of only one of the monomers), from bovine (PDB ID: 1BGY) and chicken (PDB ID: 3H1J). The arrows indicate the presence of the UQCRFS1 fragments in the cavity between UQCRC1 and UQCRC2. Images were generated with MacPyMol.