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Multi-scale Structure-function Analysis of Mitochondrial Network Morphology and Respiratory State in Budding Yeast

  • Author(s): Lim, Swee Siong
  • Advisor(s): Rafelski, Susanne
  • et al.
Creative Commons 'BY' version 4.0 license
Abstract

Remodeling of the mitochondrial network in response to metabolism involves changes to mitochondrial structure from the ultrastructure to the cellular level. Morphological changes in dysfunctional mitochondria that manifest in diseases such as Parkinson’s and Leber’s hereditary optic neuropathy drive the need to have a ’systems’ level understanding of the relationship between mitochondrial structure and function. However, an integrated, quantitative understanding of the mechanisms linking the changes of structure in response to functional state, and vice versa, is lacking in the field. We developed a multi-scale, quantitative image analysis pipeline and database to simultaneously extract structural features and functional markers of mitochondrial networks for further analysis. We applied this pipeline to the budding yeast, Saccharomyces cerevisiae, which we grew in different carbon sources to achieve distinct respiratory states. Our system was able to quantitatively show that the spatial distribution of mitochondrial membrane potential (ΔΨ, an indicator of mitochondrial function) within individual mitochondrial tubules was nonrandom and dependent on the respiratory state of the cell. These differences were consistent with known alterations to the cristae of the mitochondria. We next investigated the relationship between the connectivity of the mitochondrial network and ΔΨ. Network connectivity is generated by fission and fusion events between individual tubules within the mitochondrial network. Mitochondrial fusion and bioenergetic status are known to be interdependent. We were thus surprised that nowhere in our exhaustive network measurement-based analysis was ΔΨ upregulated in more highly connected networks or network regions as we had predicted. We expect that dynamic data will be needed to detect local regions of the network undergoing fusion dynamics and that it may be these highly dynamic regions of the network that could be be upregulated in ΔΨ. We also investigated the asymmetry of ΔΨ between the mother and daughter bud (future daughter cell) and found that ΔΨ was maintained at a higher level in the daughter throughout the cell division cycle. We detected an increasing gradient in the

distribution of ΔΨ along the mother-daughter axis and speculate that this might indicate an increasing ΔΨ-dependent process in the direction of the daughter bud during cell growth.

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