EPA Science Inventory

The Impact of Mitochondrial Complex Inhibition on mESC Differentiation

Citation:

Royland, J., S. Warren, S. Jeffay, M. Hoopes, H. Nichols, AND S. Hunter. The Impact of Mitochondrial Complex Inhibition on mESC Differentiation. Presented at Keystone Symposia, Sante Fe, NM, February 18 - 23, 2014.

Description:

The Impact of Mitochondrial Complex Inhibition on mESC Differentiation JE Royland, SH Warren, S Jeffay, MR Hoopes, HP Nichols, ES Hunter U.S. Environmental Protection Agency, Integrated Systems Toxicology Division, Research Triangle Park, NC The importance of mitochondrial function on mouse embryonic stem cell (mESC) proliferation and cell fate determination was determined. Differentiating ESCs undergo mitochondrial maturation leading to a metabolic switch from a system dependent upon glycolysis to reliance on oxidative phosphorylation. Thus genetic or environmental modulation of mitochondria and cellular metabolism can adversely affect cell maintenance and differentiation. To better understand the effects of chemical-induced perturbations in mitochondrial metabolism on the differentiation of mESCs, the impact of inhibition of the five complexes of electron transport was determined using the differentiation biomarker, Goosecoid (GSC), a transcription factor highly expressed during embryonic gastrulation. Additional bioassays were used to monitor cell number, mitochondria number and cell death. At the highest doses used, the effect on cell proliferation was complex I inhibition (91% decrease) > complex V (69% decrease) ≈ complex IV (66% decrease) > complex III (25% decrease) ≈ complex II (21% decrease). GSC expression/cell also showed the greatest impact with complex I inhibition (97% decrease), a somewhat less effect in complexes IV and V (~50% decrease), with little effect in complexes II and III (12 and <1% decreases, respectively). In contrast, inhibition of electron transport at complexes I, IV and V showed an increase in mitochondria/cell, increasing as proliferation decreased. Mitochondria/cell decreased following inhibition of complexes II and III (~56%). These data will contribute to the development of a possible adverse outcome pathway (AOP) based on mitochondrial dysfunction and its consequences in embryogenesis. (This abstract does not necessarily reflect USEPA policy).

Purpose/Objective:

The importance of mitochondrial function on mouse embryonic stem cell (mESC) proliferation and cell fate determination was determined. Differentiating ESCs undergo mitochondrial maturation leading to a metabolic switch from a system dependent upon glycolysis to reliance on oxidative phosphorylation.

URLs/Downloads:

JROYLANDABSTRACT.DOC

Record Details:

Record Type: DOCUMENT (PRESENTATION/POSTER)
Completion Date: 03/17/2014
Record Last Revised: 03/17/2014
Record Created: 03/17/2014
Record Released: 03/17/2014
OMB Category: Other
Record ID: 271083

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

INTEGRATED SYSTEMS TOXICOLOGY DIVISION

GENETIC AND CELLULAR TOXICOLOGY BRANCH