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; JeanMarie 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

Cell Metab. 2023 Aug 8;35(8):1441-1456.e9. doi: 10.1016/j.cmet.2023.06.019. Epub 2023 Jul 25.

Authors

Liraz Shmuel-Galia¹, Fiachra Humphries², Tim Vierbuchen², Zhaozhao Jiang², Nolan Santos², John Johnson³, Boris Shklyar⁴, Leonel Joannas⁵, Nicholas Mustone², Shany Sherman⁶, Doyle Ward⁷, JeanMarie Houghton⁸, Christina E Baer⁹, Aisling O'Hara³, Jorge Henao-Mejia¹⁰, Kasper Hoebe³, Katherine A Fitzgerald¹¹

Affiliations

¹ Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: liraz.galia@umassmed.edu.
² Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
³ Immunology Discovery, Janssen Research and Development LLC, Spring House, PA 19477, USA.
⁴ Bioimaging Unit, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
⁵ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁷ Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Center for Microbiome Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
⁸ Division of Gastroenterology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
⁹ Sanderson Center for Optical Imaging and Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
¹⁰ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹¹ Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: kate.fitzgerald@umassmed.edu.

PMID: 37494932
DOI: 10.1016/j.cmet.2023.06.019

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Colitis* / genetics
Colitis* / metabolism
Homeostasis
Inflammation / metabolism
Intestinal Mucosa / metabolism
Mice
Mitochondria / genetics
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism

Substances

RNA, Long Noncoding

Abstract

Publication types

MeSH terms

Substances

Grants and funding