New functional and biophysical insights into the mitochondrial Rieske iron-sulfur protein from genetic suppressor analysis inC. elegans

Abstract

Several intragenic mutations suppress the C. elegans isp-1(qm150) allele of the mitochondrial Rieske iron-sulfur protein (ISP), a catalytic subunit of Complex III of the respiratory chain. These mutations were located in a helical region of the "tether" span of ISP-1, distant from the primary mutation in the extrinsic head, and suppressed all pleiotropic phenotypes associated with the qm150 allele. Analysis of these suppressors revealed control of electron transfer into Complex III through a "spring-loaded" mechanism involving a binding force for formation of enzyme-substrate complex, counter balanced by forces (a chemical "spring") favoring helix formation in the tether. The primary P!S mutation results in inhibition of electron flow into the Q-cycle by decreasing the binding force, and the tether mutations relieve this inhibition by weakening the "spring." In this commentary we discuss additional control features, and relate the primary inhibition to outcomes at the organismal level. In particular, the sensitivity to hyperoxia and the elevated reactive oxygen species (ROS) seen in isp-1(qm150), likely reflect over-reduction of the quinone pool, which is upstream of the inhibited site; at high O 2 , this would lead to increased ROS production through complex I. We speculate that alternative NADH:ubiquinone oxidoreductase activity in C. elegans from the worm apoptosis inducing factor (AIF) homolog (WAH-1) might also be involved, and that WAH-1 might have a "canary" function in detection of this adverse state (high O 2 /reduced pool), and a role in protection of the organism by transformation to AIF-like products, and apoptotic recycling of defective cells.

WAH-1/AIF regulates mitochondrial oxidative phosphorylation in the nematode Caenorhabditis elegans

“…elegans . Alternatively, WAH-1 may modify the electron flow through the respiratory chain complexes, promoting proton pumping across the mitochondrial membrane in a similar manner to the yeast NADH-ubiquinone oxidoreductase Ndi1 as recently proposed 47 , 48 . Ultimately, WAH-1 may bind factors that directly regulate mitochondrial biogenesis.…”

Cell Biology of the Mitochondrion

“…In summary, the isp-1(qm150) mutation causes not only defective complex III activity but also indirect decreases in complex I and IV activity, probably due to supercomplex disruption. Interestingly, Jafari et al collected multiple suppressors of the qm150 allele and found them all to be intragenic in a six-amino-acid region of the ISP-1 protein (Jafari et al 2015(Jafari et al , 2016. Similar mutations in the yeast homolog of ISP-1had similar effects, clearly demonstrating the high level of conservation of ISP-1 across a wide phylogenetic range.…”

Apoptosis-Inducing Factor (AIF) in Physiology and Disease: The Tale of a Repented Natural Born Killer

“…As one possible explanation for this archaic metabolic function, it has been proposed that AIF might transfer equivalents to the electron transport chain and, as a consequence, would maintain the NAD + /NADH pool and/or the NADH-dependent proton pumping across the mitochondrial inner membrane (MIM) ( Elguindy and Nakamaru-Ogiso, 2015 ). This is supported by the fact that AIF shares homology with the yeast Ndi1, a NADH-oxidoreductase that sustains mitochondrial membrane potential and can bypass complex I lesions ( De Corby et al, 2007 ; Jafari et al, 2016 ). As an alternative mechanism, AIF may regulate mitochondrial function by participating in the assembly and/or stabilization of the respiratory complexes.…”