Mitochondrial Dysfunction in Mechanisms of Ethanol Toxicity in the Spinal Neural Crest

Date of Award


Document Type


Degree Name

Doctor of Philosophy (Ph.D.)

Institution Granting Degree

University of Michigan

Cedarville University School or Department

Pharmaceutical Sciences

First Advisor

Craig Harris

Second Advisor

Martin Philbert

Third Advisor

Kathryn Tosney


Mitochondria, toxicity, toxicology


It was hypothesized that ethanol inhibits neural crest cell (NCC) migration and differentiation through induction of the mitochondrial permeability transition (MPT). Cultures of spinal NCCs contained mixtures of polarized and unpolarized mitochondria. Migration of NCCs was enhanced following establishment of mitochondrial potentials. Most control NCCs either remained undifferentiated or expressed Schwann cell markers. Differentiated cells exhibited greater mitochondrial polarization but lower migration rates than their undifferentiated counterparts. Ethanol decreased mitochondrial transmembrane potential. Ethanol ultimately inhibited NCC migration. Death of NCCs and loss of mitochondrial membrane potential by ethanol was prevented by the MPT inhibitor, bongkrekic acid (BKA), but BKA-pretreatment did not alter Updated 1/12/15 ethanol-induced changes in NCC migration. In utero exposure to ethanol decreased embryonic mitochondrial glutathione but increased embryonic ATP content. These data suggest that the MPT is unrelated to ethanolinduced perturbation of migration. However, MPT pore opening mediates death of undifferentiated NCCs in vitro, and depletion of mitochondrial glutathione may initiate opening of the pore in vivo. The high degree of correlation between mitochondrial polarization states and NCC migration and differentiation suggests that genetic and environmental factors that coordinate NCC function also play a central role in mitochondrial maturation.