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

doi:10.1016/j.cmet.2023.06.019

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

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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 language	English (US)
Pages (from-to)	1441-1456.e9
Journal	Cell Metabolism
Volume	35
Issue number	8
DOIs	https://doi.org/10.1016/j.cmet.2023.06.019
State	Published - Aug 8 2023
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2023.06.019

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Shmuel-Galia, L., Humphries, F., Vierbuchen, T., Jiang, Z., Santos, N., Johnson, J., Shklyar, B., Joannas, L., Mustone, N., Sherman, S., Ward, D., Houghton, J. M., Baer, C. E., O'Hara, A., Henao-Mejia, J., Hoebe, K., & Fitzgerald, K. A. (2023). The lncRNA HOXA11os regulates mitochondrial function in myeloid cells to maintain intestinal homeostasis. Cell Metabolism, 35(8), 1441-1456.e9. https://doi.org/10.1016/j.cmet.2023.06.019

Shmuel-Galia, L, Humphries, F, Vierbuchen, T, Jiang, Z, Santos, N, Johnson, J, Shklyar, B, Joannas, L, Mustone, N, Sherman, S, Ward, D, Houghton, JM, Baer, CE, O'Hara, A, Henao-Mejia, J, Hoebe, K & Fitzgerald, KA 2023, 'The lncRNA HOXA11os regulates mitochondrial function in myeloid cells to maintain intestinal homeostasis', Cell Metabolism, vol. 35, no. 8, pp. 1441-1456.e9. https://doi.org/10.1016/j.cmet.2023.06.019

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title = "The lncRNA HOXA11os regulates mitochondrial function in myeloid cells to maintain intestinal homeostasis",

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.",

keywords = "IBD, Krebs cycle, OXPHOS, colitis, complex I, intestinal inflammation, lncRNA, mitochondria, mtROS, mucosal inflammation, ncRNA",

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

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doi = "10.1016/j.cmet.2023.06.019",

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AU - Shmuel-Galia, Liraz

AU - Humphries, Fiachra

AU - Vierbuchen, Tim

AU - Jiang, Zhaozhao

AU - Santos, Nolan

AU - Johnson, John

AU - Shklyar, Boris

AU - Joannas, Leonel

AU - Mustone, Nicholas

AU - Sherman, Shany

AU - Ward, Doyle

AU - Houghton, Jean Marie

AU - Baer, Christina E.

AU - O'Hara, Aisling

AU - Henao-Mejia, Jorge

AU - Hoebe, Kasper

AU - Fitzgerald, Katherine A.

PY - 2023/8/8

Y1 - 2023/8/8

N2 - 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.

AB - 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.

KW - IBD

KW - Krebs cycle

KW - OXPHOS

KW - colitis

KW - complex I

KW - intestinal inflammation

KW - lncRNA

KW - mitochondria

KW - mtROS

KW - mucosal inflammation

KW - ncRNA

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

Abstract

Keywords

ASJC Scopus subject areas

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