About the Program
Few processes are as energy-demanding as the development of a fetus and it is the cell's mitochondria that play a central role in generating the energy that powers this development. Mitochondria are also a hub for inflammatory response to infection and other threats to a developing fetus. It is thus crucial to understand the role of mitochondria in preterm birth syndromes and consequently the Maternal-Fetal Mitochondrial Metabolism Unit investigates both normal function and dysfunction of mitochondria in development. Members of the unit include Siddhesh Aras, MBBS, PhD, and Neeraja Purandare, PhD.
- Study of mitochondrial metabolism during development.
- Analysis of mitochondrial function during preterm birth syndromes using animal models, cultured cells, and human samples.
- Determination of mechanism by which mitochondria become dysfunctional in inflammation.
- We have shown that reduced levels of Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) are responsible for inflammation-induced mitochondrial dysfunction. Increasing the levels of MNRR1 either genetically or via specific activators rescues the defect. MNRR1 therefore is an attractive target for inflammatory mitochondrial pathologies.
- MNRR1 rescues dysfunctional mitochondria owing to its biorganellar function as an activator of multiple homeostatic cellular pathways. These include: i) enhancing respiration (oxidative phosphorylation), ii) stimulating the mitochondrial unfolded protein response, ii) inhibiting apoptosis, a form of cell death, and iv) transcriptionally regulating stress-responsive genes.
- Currently, we are investigating the subcellular mechanism by which MNRR1 functions as an anti-inflammatory target in placental pathologies using in vitro and in vivo
- Lipopolysaccharide induces placental mitochondrial dysfunction by reducing MNRR1 levels via a TLR4-independent pathway. Purandare, Neeraja, Yusef Kunji, Yue Xi, Roberto Romero, Nardhy Gomez-Lopez, Andrew Fribley, Lawrence I. Grossman, and Siddhesh Aras. bioRxiv (2021) (in revision).
- Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) rescues the cellular phenotype in MELAS by inducing stress responsive homeostatic mechanisms. Aras S, Purandare N, Gladyck S, Somayajulu-Nitu M, Zhang K, Wallace DC, Grossman LI. ProcNatl Acad Sci USA, 2020in press.
- Acute O2 sensing through HIF2α-dependent expression of atypical cytochrome oxidase subunits in arterial chemoreceptors.Moreno-Domínguez A, Ortega-Sáenz P, Gao L, Colinas O, García-Flores P, Bonilla-Henao V, Aragonés J, Hüttemann M, Grossman LI, Weissmann N, Sommer N, López-Barneo J. Sci Signal. 2020 Jan 21; 13:eaay9452. PMID: 31848220
- The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction.Purandare N, Somayajulu M, Hüttemann M, Grossman LI, Aras S. J Biol Chem. 2018 Apr 27; 293:6517-6529. PMID: 29540477
- Metformin, the aspirin of the 21st century: its role in gestational diabetes, prevention of preeclampsia and cancer, and the promotion of longevity.Romero R, Erez O, Hüttemann M, Maymon E, Panaitescu B, Conde-Agudelo A, Pacora P, Yoon BH, Grossman LI. Am J Obstet Gynecol. 2017 Sep; 217:282-302. PMID: 28619690
ABOUT THE PROGRAM
- The regulation of mitochondrial function during normal placental development
- Delineation of the effects of inflammation on mitochondrial function in a cell and tissue culture model and characterization of a pathway for the observed effects
- To understand how MNRR1 mediated mitochondrial function relates to organellar activity throughout pregnancy, and therefore the repercussions of an inflammatory insult on MNRR1-mediated mitochondrial dysfunction
- How do inflammatory stimuli induce mitochondrial dysfunction?
- What is the pathway by which LPS affects mitochondrial function?
- How does stress regulator MNRR1 (CHCHD2) function during plaental inflammation?
IMPORTANT POINTS & DISCOVERIES
- In preliminary data, MNRR1 decreases duering placental inflammation, inhibiting mitochondrial function.
- Aras S, Arrabi H, Purandare N, Hüttemann M, Kamholz J, Züchner S, Grossman LI. (2017). Abl2 kinase phosphorylates bi-organellar regulator MNRR1 in mitochondria, stimulating respiration. Biochim Biophys Acta 1864, 440-448.
- Sommer N, Hüttemann M, Pak O, Scheibe S, Knoepp F, Sinkler C, Malczyk M, Gierhardt M, Esfandiary A, Kraut S, Jonas F, Veith C, Aras S, Sydykov A, Alebrahimdehkordi N, Giehl K, Hecker M, Brandes RP, Seeger W, Grimminger F, Ghofrani HA, Schermuly RT, Grossman LI, Weissmann N (2017). Mitochondrial complex IV subunit 4 isoform 2 is essential for acute pulmonary oxygen sensing. Circ Res 121, 424-438.
- Purandare N, Somayajulu M, Hüttemann M, Grossman LI, Aras S. (2018). The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction. J Biol Chem 293, 6517-6529