PUBLICATION
Cross-species evaluation of TANGO2 homologs, including HRG-9 and HRG-10 in Caenorhabditis elegans, challenges a proposed role in heme trafficking
- Authors
- Sandkuhler, S.E., Youngs, K.S., Gottipalli, O., Owlett, L.D., Bandora, M.B., Naaz, A., Kim, E., Wang, L., Wojtovich, A., Gupta, V., Sacher, M., Mackenzie, S.J.
- ID
- ZDB-PUB-260109-3
- Date
- 2026
- Source
- eLIFE 14: (Journal)
- Registered Authors
- Gupta, Vandana A
- Keywords
- C. elegans, S. cerevisiae, TANGO2 deficiency, cell biology, genetics, genomics, heme metabolism, metabolic dysfunction, mitochondria, oxidative stress, rare disease, zebrafish
- MeSH Terms
-
- Animals
- Biological Transport
- Caenorhabditis elegans*/genetics
- Caenorhabditis elegans*/metabolism
- Caenorhabditis elegans Proteins*/genetics
- Caenorhabditis elegans Proteins*/metabolism
- Heme*/metabolism
- Humans
- Oxidative Stress
- Saccharomyces cerevisiae/genetics
- Zebrafish
- PubMed
- 41504601 Full text @ Elife
Citation
Sandkuhler, S.E., Youngs, K.S., Gottipalli, O., Owlett, L.D., Bandora, M.B., Naaz, A., Kim, E., Wang, L., Wojtovich, A., Gupta, V., Sacher, M., Mackenzie, S.J. (2026) Cross-species evaluation of TANGO2 homologs, including HRG-9 and HRG-10 in Caenorhabditis elegans, challenges a proposed role in heme trafficking. eLIFE. 14:.
Abstract
Mutations in the TANGO2 gene are associated with a severe neurometabolic disorder in humans, often presenting with life-threatening metabolic crisis. However, the function of TANGO2 protein remains unknown. It has recently been proposed that TANGO2 transports heme within and between cells, from areas with high heme concentrations to those with lower concentrations. Here, we demonstrate that prior heme-related observations in Caenorhabditis elegans lacking TANGO2 homologs HRG-9 and HRG-10 may be better explained by a previously unreported metabolic phenotype, characterized by reduced feeding, decreased lifespan and brood sizes, and poor motility. We also show that several genes not implicated in heme transport are upregulated in the low heme state and conversely demonstrate that hrg-9 in particular is highly responsive to oxidative stress, independent of heme status. Collectively, these data implicate bioenergetic failure and oxidative stress as potential factors in the pathophysiology of TANGO2 deficiency, in alignment with observations from human patients. Our group performed several experiments in yeast and zebrafish deficient in TANGO2 homologs and was unable to replicate prior findings from these models. Overall, we believe there is insufficient evidence to support heme transport as the primary function for TANGO2.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping