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

Autor:	Sandkuhler SE; Department of Pathology, University of Rochester Medical Center, Rochester, NY., Youngs KS; Department of Neurology, University of Rochester Medical Center, Rochester, NY., Owlett L; Department of Neurology, University of Rochester Medical Center, Rochester, NY., Bandora MB; Morgan State University, Baltimore, MD., Naaz A; Department of Biology, McGill University, Montreal, Canada., Kim ES; Department of Medicine, Brigham and Women's Hospital Harvard Medical School, Boston, MA., Wang L; Department of Pharmacology, Vanderbilt University, Nashville, TN., Wojtovich AP; Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, Rochester, NY., Gupta VA; Department of Medicine, Brigham and Women's Hospital Harvard Medical School, Boston, MA., Sacher M; Department of Biology, McGill University, Montreal, Canada.; Department of Anatomy and Cell Biology, Concordia, Montreal, Canada., Mackenzie SJ; Department of Neurology, University of Rochester Medical Center, Rochester, NY.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Nov 22. Date of Electronic Publication: 2024 Nov 22.
DOI:	10.1101/2023.11.29.569072
Abstrakt:	Mutations in the TANGO2 gene cause severe illness in humans, including life-threatening metabolic crises. However, the function of TANGO2 protein remains unknown. Using Caenorhabditis elegans and other models, 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 heme-related observations in nematodes may be better explained by a previously unreported metabolic phenotype in these worms, 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 key 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. Competing Interests: Competing Interests: The authors declare the following competing interests: The following authors have unpaid roles at the TANGO2 Research Foundation: SES, Early Diagnostic and Detection Committee Member VAG, Scientific Advisor Board Member MS, Executive Board Member SJM, Research Committee Member and Scientific Advisory Board Chair
Databáze:	MEDLINE
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