About the Program
Given how crucial energy is at all stages of development, and the central role of mitochondria in generating that energy during most stages of development, the Maternal-Fetal Mitochondrial Metabolism Unit investigates normal function and dysfunction of mitochondria in development. Emphasis is on the role of mitochondrial dysfunction that leads to preterm birth as well as the role of inflammation in mitochondrial dysfunction. 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.
- Development of drug therapies to restore mitochondrial function.
- Energy supply during pregnancy. Since the metabolic source of energy changes during pregnancy and mitochondrial dysfunction can promote preterm birth, we are focused on regulation of metabolism and on interventions to improve outcomes by restoring mitochondrial function.
- Mitochondrial role in inflammation. As mitochondria have a special role in the placental response to inflammatory stimulus, we seek to identify linchpin mitochondrial targets to ameliorate placental inflammation.
- Oxygen responsive genes. Given the role of oxygen level changes during development, we are focused on cellular regulators of hypoxic response and their role in mitochondrial function.
- 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. Proc Natl 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
- Mitochondrial complex IV subunit 4 isoform 2 is essential for acute pulmonary oxygen sensing. 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. Circ Res. 2017 Aug 4; 121:424-438. PMID: 28620066
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