1: Defining the Independence of the Liver Circadian Clock.

Cell,

2019 May 30; 177 (6) : 1448-1462.e14.

Koronowski K. B., Kinouchi K., Welz P. S., Smith J. G., Zinna V. M., Shi J., Samad M., Chen S., Magnan C. N., Kinchen J. M., Li W., Baldi P., Benitah S. A., Sassone-Corsi P.

Circadian rhythms are persistent oscillations with a cycle of approximately 24 hours that synchronize with environmental factors such as light and food. They are considered an adaptive mechanism that allows the body to maintain homeostasis by anticipating and responding to diurnal changes. It has been pointed out that excessive light exposure at night or late-night eating can disrupt circadian rhythms, becoming a risk factor for various diseases such as diabetes and cancer. The body's internal circadian clock is crucial for the expression of circadian rhythms. In this study, we reconstituted the endogenous expression of the clock gene Bmal1 specifically in the liver of mice that lack Bmal1 and thus have no circadian rhythm, revealing that the liver's circadian clock oscillates autonomously. This autonomous oscillation of the circadian clock reconstituted autonomous diurnal variations of about 10% in genes and 20% in metabolites, centered on glucose and NAD+ metabolism in the liver. On the other hand, the approximately 80-90% of non-autonomous diurnal variations that were not reconstituted in the liver are thought to be driven by periodic signals originating from the circadian clocks of other organs, suggesting the importance of circadian rhythms in inter-organ communication. The results of this study are expected to contribute to the development of prevention and treatment methods for lifestyle-related diseases such as diabetes and hypertension, for which circadian rhythm disruption is a risk factor.

(Kenichiro Kiuchi, Division of Nephrology, Endocrinology and Metabolism, 85th Graduating Class)

Cancer Cell,

Volume 35, Issue 5, 13 May 2019, Pages 707-708

Jo Ishizawa, Sarah F. Zarabi, R. Eric Davis, Ondrej Halgas, Takenobu Nii, Yulia Jitkova, Ran Zhao, Jonathan St-Germain, Lauren E. Heese, Grace Egan, Vivian R. Ruvolo, Samir H. Barghout, Yuki Nishida, Rose Hurren, Wencai Ma, Marcela Gronda, Todd Link, Keith Wong, …Michae Andreeff

The origin of mitochondria is believed to be the result of a type of bacterium being incorporated into and coexisting with a primitive eukaryotic cell (the endosymbiotic theory). This is thought to have enabled eukaryotes to evolve more advanced energy production, respiration, and metabolism, which was advantageous for survival. It has recently become clear that certain types of cancer cells hijack this symbiotic relationship with mitochondria, entering a state of dependence that exceeds the original symbiosis. Based on this, as we aim to establish "mitochondria-targeted therapy" as a next-generation cancer treatment concept, this paper focuses specifically on the mitochondrial protease ClpP. We demonstrated a mechanism whereby the overactivation of ClpP leads to the excessive degradation of multiple essential proteins within the mitochondria, causing a decline in mitochondrial function and, as a result, the selective death of cancer and leukemia cells compared to normal cells. Furthermore, in an international collaborative study with a group from Canada, we identified the new drug imipridone (ONC201, ONC212) as a ClpP agonist and, using crystal structure analysis, reported its binding mode and the activation mechanism involving a three-dimensional structural change in ClpP (Figure). The results of this study have contributed to the planning and design improvement of clinical trials for ONC201 in the United States for multiple cancer types, and it is expected to be clinically applied as a next-generation mitochondria-targeted therapy.

(Jo Ishizawa, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Internal Medicine, 83rd Graduating Class)

MOLECULAR PSYCHIATRY,

24 (7):952-964; 10.1038/s41380-018-0252-9 JUL 2019

Moriguchi S, Takamiya A, Noda Y, Horita N, Wada M, Tsugawa S , Plitman E, Sano Y, Tarumi R, El Salhy M, Katayama N, Ogyu K, Miyazaki T, Kishimoto T, Graff-Guerrero A, Meyer JH, Blumberger DM, Daskalakis ZJ, Mimura M, Nakajima S.