Dissertation Defense Announcement
To:  The George Mason University Community

Candidate: Sangeeta Shukla
Program: PhD in Bioinformatics & Computational Biology
Date:   Thursday August 20, 2015
Time:   12:00 Noon
Place:  George Mason University
             Fairfax Campus
             Krasnow Institute, Room 229
Title: "Multiscale Modeling of the Regulation of Mitochondrial Function by Metabolites and Ultrastructure"

Committee Chair: Dr. Saleet Jafri

Committee Members:  Dr. Iosif Vaisman, Dr. Kim Blackwell
A copy of the dissertation is available in the Johnson Center Library.  All are invited to attend the defense.

Mitochondria are responsible for producing ATP, the energy currency in all cells.  To do this, the mitochondria has a complex microarchitecture upon which occur biomolecular processes that break down energy substrate to produce ATP.  In a heart which is constantly beating, mitochondrial energy metabolism is well regulated, allowing for increases during exercise. Energy metabolism is thought to be regulated both by changes in metabolite concentration as well as the microarchitecture of the cristae which are the folds in the mitochondrial inner membrane.  The two questions addressed here are 1) how is calcium in the mitochondria regulated and what effect does this have on energy metabolism and 2) how does the cristae structure contribute to the regulation of energy metabolism.  To this end, a multiscale computational modeling approach has been used to integrate experimental information across disparate scales and gain an understanding of the complex dynamics of this system. 

Calcium activates three dehydrogenases in the mitochondria and the ATP synthase all of which are involved in energy metabolism.  In the experimental literature there is disagreement upon whether calcium dynamics in the mitochondrial is fast or slow.  Fast dynamics lead to large beat-to-beat changes in mitochondrial calcium.  Slow dynamics result in a time averaging of the calcium transients similar to a low pass filter. The computational studies suggest that slow calcium dynamics are more efficient at stimulating ATP production than fast dynamics.

The cristae structure in mitochondria varies in different cells, under different physiological conditions, and during disease.  We hypothesize that these changes might play role in the efficiency of energy metabolism.  The computational studies suggest that there are gradients in the intercristae spaces of metabolites such as calcium, ATP, and ADP.  These gradients change when mitochondria structure changes.  The computational models also suggest that the changes in gradient affect the efficiency of energy metabolism. With greater accumulation of calcium in mitochondrial matrix, activation of TCA cycle dehydrogenases and ATP synthase produces more ATP. Our model simulations suggest that  depending on the structure, gradients across the length of mitochondrial crista change as does the matrix volume. Such variation in the localized concentrations of metabolites may dictate the overall function of mitochondria.