Haem's relevance genuine? Re-visiting the roles of TANGO2 homologues including HRG-9 and HRG-10 in C. elegans.

ABSTRACT

Mutations in the TANGO2 gene cause severe illness in humans, including life-threatening metabolic crises; however, the function of TANGO2 protein remains unknown. In a recent publication in Nature, Sun et al. proposed that TANGO2 helps transport haem within and between cells, from areas with high haem concentrations to those with lower concentrations. Caenorhabditis elegans has two versions of TANGO2 that Sun et al. called HRG-9 and HRG-10. They demonstrated that worms deficient in these proteins show increased survival upon exposure to a toxic haem analog, which Sun et al. interpreted as evidence of decreased haem uptake from intestinal cells into the rest of the organism. We repeated several experiments using the same C. elegans strain as Sun et al. and believe that their findings are better explained by reduced feeding behavior in these worms. We demonstrate that hrg-9 in particular is highly responsive to oxidative stress, independent of haem status. Our group also performed several experiments in yeast and zebrafish models of TANGO2 deficiency and was unable to replicate key findings from these models reported in Sun et al.'s original study. Overall, we believe there is insufficient evidence to support haem transport as the primary function for TANGO2.