Yuji Sakai

Program-Specific Associate Professor, Institute for Life and Medical Sciences, Kyoto University *Profile is at the time of the award.

2023Inamori Research GrantsBiology & Life sciences

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Research topics: Theoretical study of intracellular degradation mechanisms

Keyword

Summary: Intracellular degradation systems are essential for cellular homeostasis. In autophagy, the membrane changes the morphology to form autophagosome, which surround degradation substrates, then fuse with lysosomes for degradation. This means that understanding membrane dynamics is necessary to elucidate the intracellular degradation mechanism. Regulatory molecules have been identified, but how these regulate macroscopic membrane dynamics remains a mystery. In this study, I use mathematical methods to elucidate complex intracellular degradation systems as simple physical phenomena such as membrane deformation and fusion.

Comment

I am very honored to be selected for the Inamori Foundation Research Grant. Encouraged by this grant, I would like to take on new challenges and innovate research on intracellular dynamics from mathematical perspectives.

Outline of Research Achievments

Autophagy is an autophagosome-mediated intracellular degradation system that is important for cellular homeostasis. Although autophagosome formation is a fundamental process in autophagy, its characteristic morphological changes have not been systematically and quantitatively described. Therefore, the underlying physical basis has remained largely unexplored.

In this study, we determined the standard morphology of forming autophagosomes by comprehensively and statistically investigating them using three-dimensional electron microscopy. To understand this morphological feature, a mathematical model based on the bending elastic energy of the membrane was constructed. The model quantitatively reproduced the morphology of forming autophagosomes observed by electron microscopy. The model also predicts a factor that stabilizes the opening of autophagosomes, and the Atg20-24 complex is found to be the regulator of this factor. The mathematical model explains the morphological changes of forming autophagosomes upon loss of Atg20-24 complex.

Our results suggest that the seemingly complex membrane dynamics of autophagy can be analyzed by a simple physical mechanism. It is expected to lead to further understanding of the mechanism of autophagosome formation in the future.

Yuji Sakai, Satoru Takahashi et al. (2024) Experimental determination and mathematical modeling of standard shapes of forming autophagosomes Nature Communications 15 (91) doi: 10.1038/s41467-023-44442-1

Tetsuya Kotani, Yuji Sakai et al. (2023) A mechanism that ensures non-selective cytoplasm degradation by autophagy Nature Communications 14 (5815) doi: 10.1038/s41467-023-41525-x

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