Lipopolysaccharide induces placental mitochondrial dysfunction in murine and human systems by reducing MNRR1 levels via a TLR4-independent pathway

Neeraja Purandare; Yusef Kunji; Yue Xi; Roberto Romero; Nardhy Gomez-Lopez; Andrew Fribley; Lawrence I Grossman; Siddhesh Aras

doi:10.1016/j.isci.2022.105342

Lipopolysaccharide induces placental mitochondrial dysfunction in murine and human systems by reducing MNRR1 levels via a TLR4-independent pathway

iScience. 2022 Oct 12;25(11):105342. doi: 10.1016/j.isci.2022.105342. eCollection 2022 Nov 18.

Authors

Neeraja Purandare^{1

2}, Yusef Kunji², Yue Xi³, Roberto Romero^{1

4

5

2

6}, Nardhy Gomez-Lopez^{1

7

8}, Andrew Fribley³, Lawrence I Grossman^{1

2}, Siddhesh Aras^{1

2}

Affiliations

¹ Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD 20892, Detroit, MI 48201, USA.
² Center for Molecular Medicine and Genetics, Wayne State University; Detroit, MI 48201, USA.
³ Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
⁴ Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48104, USA.
⁵ Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI 48824, USA.
⁶ Detroit Medical Center, Detroit, MI 48201, USA.
⁷ Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
⁸ Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA.

Abstract

Mitochondria play a key role in placental growth and development, and mitochondrial dysfunction is associated with inflammation in pregnancy pathologies. However, the mechanisms whereby placental mitochondria sense inflammatory signals are unknown. Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a bi-organellar protein responsible for mitochondrial function, including optimal induction of cellular stress-responsive signaling pathways. Here, in a lipopolysaccharide-induced model of systemic placental inflammation, we show that MNRR1 levels are reduced both in mouse placental tissues in vivo and in human trophoblastic cell lines in vitro. MNRR1 reduction is associated with mitochondrial dysfunction, enhanced oxidative stress, and activation of pro-inflammatory signaling. Mechanistically, we uncover a non-conventional pathway independent of Toll-like receptor 4 (TLR4) that results in ATM kinase-dependent threonine phosphorylation that stabilizes mitochondrial protease YME1L1, which targets MNRR1. Enhancing MNRR1 levels abrogates the bioenergetic defect and induces an anti-inflammatory phenotype. We therefore propose MNRR1 as an anti-inflammatory therapeutic in placental inflammation.

Keywords: Cell biology; Human metabolism; Immunity.

Grants and funding

HHSN275201300006C/HD/NICHD NIH HHS/United States