Title page for ETD etd-12062007-161608


Type of Document Dissertation
Author Rajasimha, Harsha Karur
Author's Email Address hrajasim@vt.edu
URN etd-12062007-161608
Title Insights Into Mitochondrial Genetic and Morphologic Dynamics Gained by Stochastic Simulation
Degree PhD
Department Genetics, Bioinformatics, and Computational Biology
Advisory Committee
Advisor Name Title
Samuels, David C. Committee Chair
Bevan, David R. Committee Member
Onufriev, Alexey V. Committee Member
Tyson, John J. Committee Member
Vullikanti, Anil Kumar S. Committee Member
Keywords
  • heteroplasmy
  • fusion
  • fission
  • blood
  • inheritance
  • model
  • morphology
  • mtDNA
  • stem cells
  • segregation
  • oogenesis
  • ageing
  • mutations
Date of Defense 2007-12-05
Availability unrestricted
Abstract
MtDNA mutations in mammalian cells are implicated in cellular ageing and encephalomyopathies, although mechanisms involved are not completely understood. The mitochondrial genetic bottleneck has puzzled biologists for a long time. Approximate models of genetic bottleneck proposed in the literature do not accurately model underlying biology. Recent studies indicate mitochondrial morphology changes during cellular ageing in culture. In particular, the rates of mitochondrial fission and fusion are shown to be in tight balance, though this rate decreases with age. Some proteins involved in mitochondrial morphology maintenance are implicated in apoptosis. Hence, mitochondrial genetic and morphologic dynamics are critical to the life and death of cells.

By working closely with experimental collaborators and by utilizing data derived from literature, we have developed stochastic simulation models of mitochondrial genetic and morphologic dynamics.

Hypotheses from the mitochondrial genetic dynamics model include: (1) the decay of mtDNA heteroplasmy in blood is exponential and not linear as reported in literature. (2) Blood heteroplasmy measurements are a good proxy for the blood stem cell heteroplasmy. (3) By analyzing our simulation results in tandem with published longitudinal clinical data, we propose for the first time, a way to correct for the patient’s age in the analysis of heteroplasmy data. (4) We develop a direct model of the genetic bottleneck process during mouse embryogenesis. (5) Partitioning of mtDNA into daughter cells during blastocyst formation and relaxed replication of mtDNA during the exponential growth phase of primordial germ cells leads to the variation in heteroplasmy inherited by offspring from the same mother. (6) We develop a “simulation control” for experimental studies on mtDNA heteroplasmy variation in cell cultures.

Hypothesis from the mitochondrial morphologic dynamics model: (7) A cell adjusts the mitochondrial fusion rate to compensate for the fluctuations in the fission rate, but not vice versa. A deterministic model for this control is proposed.

Contributions: extensible simulation models of mitochondrial genetic and morphologic dynamics to aide in the powerful analysis of published and new experimental data. Our results have direct relevance to cell biology and clinical diagnosis. The work also illustrates scientific success by tight integration of theory with practice.

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