Page 8 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-4]

Role of mitochondrial TUFM in alleviating metabolic

dysregulation through enhancing autophagy

Dasol Kim¹, Yunyeong Jang¹, Hui-Yun Hwang¹, Eun Sun Ji², Jin Young Kim², Jong Shin Yoo², Ho Jeong Kwon¹

¹Chemical genomics Global Research Laboratory, Department of Biotechnology, Yonsei University, Seoul 03722,

Korea, ²Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongwon 28115, Korea

Autophagy is a key regulatory mechanism for systemic homeostasis, thus disorder of which causes a number of
human metabolic diseases. Accordingly, discovery of new autophagy regulators and elucidation of underlying

mechanism have been highly attracted recently. We identified a natural compound K as a novel autophagy inducer

from our in-lab natural chemical library through cell based phenotypic screening. Through enhancing autophagy,
compound K promoted lipid droplets degradation, which is suppressed by lysosomal inhibitor chloroquine. In
addition, compound K exhibited anti-obesity effect such as prevention of weight gain or hyperglycemia in diet

induced obese mice in vivo. To elucidate the mode of action for compound K, we applied a combined method of
drug affinity responsive target stability (DARTS) with LC-MS/MS analysis, revealing mitochondrial TUFM as a target

protein of compound K. Direct interaction between compound K and TUFM was validated via bio-physical, and bio-
informatic methods. Biological relevancy with metabolic regulation was validated through genetic modulation study.

Collectively, these results suggest new role of TUFM in metabolic fitness, and demonstrate that compound K could
be utilized as a new chemical tool for autophagy related metabolism study.