Mitochondrial Research

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 Mitochondrial 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.

Objectives

  • Study of mitochondrial metabolism during development.
  • Analysis of mitochondrial function during preterm birth syndrome.
  • Use of 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.

Research Focus

  • Energy supply, whose source changes during pregnancy, is a major factor in development and mitochondrial dysfunction can result in preterm birth.
  • The characterization of mitochondrial function in placental pathophysiology.
  • Interventions to improve outcomes by restoring mitochondrial function.
  • As mitochondria have a special role in placental response to inflammatory stimulus we also seek to identify linchpin mitochondrial targets to ameliorate placental inflammation.

Highlights

  • Mitochondrial function varies throughout gestation.
  • Oxygen levels change during development and cellular regulators of hypoxic response are vital to mitochondrial function.

Selected Publications

  • 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. Acute O2 sensing through HIF2α-dependent expression of atypical cytochrome oxidase subunits in arterial chemoreceptors. Sci Signal. 2020 Jan 21; 13:eaay9452. PMID: 31848220
  • Purandare N, Somayajulu M, Hüttemann M, Grossman LI, Aras S. The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction. J Biol Chem. 2018 Apr 27; 293:6517-6529. PMID: 29540477
  • Romero R, Erez O, Hüttemann M, Maymon E, Panaitescu B, Conde-Agudelo A, Pacora P, Yoon BH, Grossman LI (2017). Metformin, the aspirin of the 21st century: its role in gestational diabetes, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol. 2017 Sep; 217:282-302. PMID:  28619690
  • 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. Mitochondrial complex IV subunit 4 isoform 2 is essential for acute pulmonary oxygen sensing. Circ Res. 2017 Aug 4; 121:424-438. PMID: 28620066
  • Aras S, Arrabi H, Purandare N, Hüttemann M, Kamholz J, Züchner S, Grossman LI. Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration. Biochim Biophys Acta Mol Cell Res. 2017 Feb; 1864:440-448.  PMID: 27913209
  • Aras S, Bai M, Lee I, Springett R, Hüttemann M, Grossman LI. MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism. Mitochondrion. 2015 Jan; 20:43-51. PMID: 25315652
  • Aras S, Pak O, Sommer N, Finley R Jr, Hüttemann M, Weissmann N, Grossman LI. Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2.  Nucleic Acids Res. 2013 Feb 1; 41:2255-66. PMID: 23303788

Mitochondrial Section

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

OBJECTIVES

  • 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

Research Focus

  • 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.

SELECTED PUBLICATIONS

Distinguished Faculty

 

DIRECTOR
Lawrence I. Grossman, Ph.D

Henry L. Brasza Professor of Molecular Medicine and Genetics, Professor of Internal Medicine, Director, Center for Molecular Medicine and Genetics

FULL BIO