Dissertations, Theses, and Capstone Projects

Date of Degree


Document Type


Degree Name





Patricia Rockwell

Committee Members

Maria E. Figueiredo-Pereira

Peter Serrano

Dan McCloskey

Luena Papa


mitochondrial dysfunction, mito UPR, neuroprotection, mitochondrial respiration, ERK, glycolysis


Mitochondrial dysfunction has been recognized to play a central role in the pathogenesis of neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease. Transcription factor ATF5 has been shown to mediate an endogenous stress pathway known as the UPRmt, a prosurvival mechanism amidst malfunctioning mitochondria. However, the ATF5/UPRmt protective pathway associated with mitochondrial impairment in neurons remains to be elucidated. To decipher the regulatory mechanisms involved with mediating neuroprotection, the effect of ATF5 was examined on the mitochondrial dysfunction induced by the proinflammatory prostaglandin PGJ2 in rat cortical neurons. ATF5 overexpression protected the effects induced by PGJ2 by attenuating HO-1 induction, Caspase-3 cleavage, cell loss, ROS production, and a collapse of the mitochondrial membrane potential ΔΨm. With the exception of Capsase-3 activation, silencing ATF5 escalated PGJ2 induced toxicity thereby attenuating the prosurvival effects of ATF5 overexpression. Detecting protein expression only in the presence of PGJ2 treatment along with constant levels of ATF5 transcript, whether PGJ2 stress is present or not, proposes PGJ2 stress induces protein expression by stabilizing ATF5 transcript for translation. PGJ2 stress elicited ATF5 trafficking between the mitochondria and nucleus suggests organelle partitioning accompanies the protection promoted by ATF5. Inhibition of the MEK/ERK signaling pathway with the selective inhibitor U0126 revealed yet another level of anti-apoptotic regulation by ATF5. A blockade of ERK activation prevented the protection by ATF5 by increasing the loss in cell viability induced by PGJ2. These findings suggest that ERK activation plays a role in AFT5 mediated protection in cortical neurons. In assessing mitochondrial function and glycolysis respiration, our findings suggest ATF5 protection against PGJ2 toxicity involves modulating mitochondrial functions. Reduction of cellular respiration demand by ATF5 observed in PGJ2 stressed neurons may relieve damaged mitochondria from the pressure of maintaining unsustainable energy production levels. Glycolysis contribution towards cellular energy demands remained the same regardless of ATF5 overexpression or silencing supporting the ability of ATF5 to alter overall cellular expenditure requirements through mitochondrial respiration. Mediating ATF5 protection by improving mitochondrial efficacy provides a possible pathway towards re-establishing homeostasis and recovery of the mitochondria.