The lncRNA HOXA11os regulates mitochondrial function in myeloid cells to maintain intestinal homeostasis

Liraz Shmuel-Galia*, Fiachra Humphries, Tim Vierbuchen, Zhaozhao Jiang, Nolan Santos, John Johnson, Boris Shklyar, Leonel Joannas, Nicholas Mustone, Shany Sherman, Doyle Ward, Jean Marie Houghton, Christina E. Baer, Aisling O'Hara, Jorge Henao-Mejia, Kasper Hoebe, Katherine A. Fitzgerald*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

This study reveals a previously uncharacterized mechanism to restrict intestinal inflammation via a regulatory RNA transcribed from a noncoding genomic locus. We identified a novel transcript of the lncRNA HOXA11os specifically expressed in the distal colon that is reduced to undetectable levels in colitis. HOXA11os is localized to mitochondria under basal conditions and interacts with a core subunit of complex 1 of the electron transport chain (ETC) to maintain its activity. Deficiency of HOXA11os in colonic myeloid cells results in complex I deficiency, dysfunctional oxidative phosphorylation (OXPHOS), and the production of mitochondrial reactive oxygen species (mtROS). As a result, HOXA11os-deficient mice develop spontaneous intestinal inflammation and are hypersusceptible to colitis. Collectively, these studies identify a new regulatory axis whereby a lncRNA maintains intestinal homeostasis and restricts inflammation in the colon through the regulation of complex I activity.

Original languageEnglish
Pages (from-to)1441-1456.e9
JournalCell Metabolism
Volume35
Issue number8
DOIs
StatePublished - 8 Aug 2023

Funding

FundersFunder number
UMass Chan Medical School Animal FacilityS10 OD025113-01, S10RR021043
National Center for Research Resources
Crohn's and Colitis Foundation of America708946, 882711
European Molecular Biology OrganizationALT-534-2017
Janssen Research and Development
Janssen Pharmaceuticals
Kenneth Rainin Foundation20230031

    Keywords

    • IBD
    • Krebs cycle
    • OXPHOS
    • colitis
    • complex I
    • intestinal inflammation
    • lncRNA
    • mitochondria
    • mtROS
    • mucosal inflammation
    • ncRNA

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