Decoding the Mechanistic Principles of Gene Regulation by Mitochondrial 3D Spatial Organization
Mitochondria are key organelles within the cell involved in the production of ATP, serve as a hub for biological reactions, and regulate many aspects of cellular activity such as cell senescence (aging), cancer, and stressful conditions. Mitochondria are also very dynamic structures with fluctuating morphologic transitions in response to cellular and environmental perturbations. While there have been many studies investigating the pathways and conditions that alter mitochondrial morphology, the connection between these morphological changes and gene expression regulation is still a poorly explored question. How does changing mitochondrial morphology during aging, cancer, and stress impact gene regulation? How do mitochondria regulate mRNA localization and control translation in response to the metabolic needs of the cell?
1. Decipher the mechanistic basis of enhanced protein synthesis on the mitochondria surface
2. Investigate how fluctuating mitochondrial morphology during stress and disease affects gene expression of yeast and mammalian cells
3. Pursue application method from the understanding of fluctuating mitochondrial morphology, such as screening of anti-aging drugs
As a model system, I will study mRNA localization and mitochondrial morphology in budding yeast and mammalian cells using an interdisciplinary approach combining quantitative microscopy, computational modeling, biochemistry, and molecular genetics. By focusing on a systems-level view of gene expression, I will advance our understanding of how organelle morphology impacts the physiology of the cell. My multi-pronged, quantitative approach toward mRNA and mitochondrial morphological measurements will also allow me to tackle questions about the spatial relationship between biomolecules and other organelles, such as the vacuole and endoplasmic reticulum.
Tatsuhisa Tsuboi Ph.D.
Assistant Professor (tenure-track)
Institute of Biopharmaceutical and Health Engineering
I am exploring single cell and single-molecule analysis of mitochondrial mRNA localization during stress conditions in yeast with techniques of microscopic analysis, microfluidics, and biochemistry. I grew up in Tokyo, Japan, and obtained my Ph.D. from Tohoku University in 2014. During my Ph.D., I worked on mRNA quality control systems under the supervision of Dr. Toshifumi Inada. I spend my postdoc period with Dr. Susanne Rafelski at the University of California Irvine and Dr. Brian Zid at the University of California San Diego, where I worked on mitochondrial mRNA regulatory mechanisms. I love yeast in many ways ;)
TIM50 mRNA associates with mitochondria
Trajectories of ideal Brownian particles in in the space between the cell wall and mitochondria surface
Reconstruction of the spatial relationship between mRNAs and mitochondria
We measured the distances between mRNA foci and closest points on the mitochondrial surface.
Mitochondrial volume fraction and binding affinity regulates mRNA localization
Each mRNA species (colored lines) shows distinctive correlative patterns between localization and mitochondrial volume fraction upon respiratory condition change according to its unique binding affinity.
Guo T, Modi O, Hirano J, Guzman H, Tsuboi T*. (2022) Single-chain models illustrate the 3D RNA folding shape during translation. Biophysical Reports, 100065.
Tsuboi T*, Leff J, Zid BM*. Post-transcriptional control of mitochondrial protein composition in changing environmental conditions. (2020) Biochem Soc Trans. BST20200250. [*co-correspondence authors] Review
Tsuboi T*, Viana MP, Xu F, Yu J, Chanchani R, Arceo XG, Tutucci E, Choi J, Chen YS, Singer RH, Rafelski SM*, Zid BM*. (2020) Mitochondrial volume fraction and translation duration impact mitochondrial mRNA localization and protein synthesis. Elife, 9, e57814. https://doi.org/10.7554/eLife.57814. [*co-correspondence authors]
Tsuboi T, Yamazaki R, Nobuta R, Ikeuchi K, Makino S, Ohtaki A, Suzuki Y, Yoshihisa T, Trotta C, Inada T. (2015) The tRNA Splicing Endonuclease Complex Cleaves the Mitochondria-localized CBP1 mRNA. The Journal of Biological Chemistry, 290(26), 16021-16030.
Izawa T, Tsuboi T, Kuroha K, Inada T, Nishikawa S, Endo T. (2012) Roles of dom34:hbs1 in nonstop protein clearance from translocators for normal organelle protein influx. Cell Reports, 2(3), 447-453
Tsuboi T, Kuroha K, Kudo K, Makino S, Inoue E, Kashima I, Inada T. (2012) Dom34:hbs1 plays a general role in quality-control systems by dissociation of a stalled ribosome at the 3' end of aberrant mRNA. Molecular Cell, 46(4), 518-529.
Tsuboi T, Inada T. (2010) Tethering of poly(A)-binding protein interferes with non-translated mRNA decay from the 5' end in yeast. The Journal of Biological Chemistry, 285(44), 33589-33601.
December 2016 - July 2021
Assistant Project Scientist and Postdoctoral Scholar with Prof. Brian M. Zid
University of California, San Diego: Department of Chemistry and Biochemistry
Interdisciplinary research on mRNA localization and translation in S. cerevisiae combining computation, image processing, genetics, cell biology, and biochemistry
April 2014 - November 2016
Postdoctoral Scholar with Prof. Susanne M. Rafelski
University of California, Irvine: Department of Developmental & Cell Biology
Development of live cell imaging system for mRNA and mitochondria in S. cerevisiae combining computation, image processing, genetics, and cell biology
Doctor of Philosophy (Ph.D.) in Pharmaceutical Sciences
Tohoku University, Japan: Graduate School of Pharmaceutical Sciences
Thesis: “Analysis of molecular mechanism of No-Go Decay and Dom34:Hbs1 targeting mRNA”
Advisor: Prof. Toshifumi Inada
Master of Science
Nagoya University, Japan: Graduate School of Science
Thesis: “Analysis of translational regulator Pab1p on non-translating mRNA”
Advisor: Prof. Toshifumi Inada
Bachelor of Science
Nagoya University, Japan: School of Science
Tsinghua Shenzhen International Graduate School
Building L-304, University Town of Shenzhen, Nanshan District, Shenzhen 518055 P.R. China