Biophysical Significance of Mitochondrial Properties on Mitochondrial Function:Experimental-Computational Approach.

Mitochondria;Mechanical Engineering;Engineering;Mechanical Engineering

Song, Dong HoonPark, Jonghyun ;

University of Michigan

关键词: Mitochondria;    Mechanical Engineering;    Engineering;    Mechanical Engineering;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/99868/dhsong_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

With the increase in average life expectancy over the last few decades, the importance of research on central nervous system (CNS) diseases has continuously grown. In one effort to reveal the mechanisms of these diseases, mitochondria have been extensively studied in close relation to neurodegeneration and aging because of their decisive roles in apoptosis and cellular bioenergetics. However, the precise mechanisms behind mitochondrial functions in the development and progression of CNS diseases as well as how mitochondrial properties may reflect the functional states of mitochondria have not yet been elucidated.Throughout the dissertation, we started our mitochondrial research at the level of individual mitochondria. The scope of the research was then extended to the properties of the mitochondrial population. Finally, we shifted our attention into the internal structure and corresponding electrochemistry of mitochondria.First, we introduced image analysis methods in order to simultaneously quantify the changes in mitochondrial properties under 1,3-DNB exposure. By using these image analysis techniques, we presented that major membrane potential fluctuations are mostly accompanied by abrupt changes in mitochondrial morphology. Additionally, we found that 1,3-DNB can induce statistically significant changes in mitochondrial morphology and membrane potential, and that theses alterations may not be related to the mitochondrial permeability transition.Next, we developed a mitochondrion model simulating the electrochemical potential gradient across the inner mitochondrial membrane (IMM) and investigated the biophysical significance of the IMM. By performing simulations with various morphological parameters, we showed that a crista can enhance the capacity for ATP synthesis. Moreover, we identified key morphological parameters that may potentially represent the energy state of mitochondria.Finally, we investigated the effects of the local pH gradient on the IMM dynamics. A numerical model was developed to simulate the morphological evolution of the cristae membrane at the given pH profile. By using this model, we demonstrated that a tubular crista structure can be formed and regulated by the local pH gradient. The simulation results also suggested that the cristae membrane may contain a higher composition of cardiolipin than the other parts of the IMM.