Activation of mitochondrial TUFM ameliorates metabolic dysregulation through coordinating autophagy induction

Dasol Kim, Hui Yun Hwang, Eun Sun Ji, Jin Young Kim, Jong Shin Yoo, Ho Jeong Kwon

Research output: Contribution to journalArticlepeer-review

Abstract

Disorders of autophagy, a key regulator of cellular homeostasis, cause a number of human diseases. Due to the role of autophagy in metabolic dysregulation, there is a need to identify autophagy regulators as therapeutic targets. To address this need, we conducted an autophagy phenotype-based screen and identified the natural compound kaempferide (Kaem) as an autophagy enhancer. Kaem promoted autophagy through translocation of transcription factor EB (TFEB) without MTOR perturbation, suggesting it is safe for administration. Moreover, Kaem accelerated lipid droplet degradation in a lysosomal activity-dependent manner in vitro and ameliorated metabolic dysregulation in a diet-induced obesity mouse model. To elucidate the mechanism underlying Kaem’s biological activity, the target protein was identified via combined drug affinity responsive target stability and LC–MS/MS analyses. Kaem directly interacted with the mitochondrial elongation factor TUFM, and TUFM absence reversed Kaem-induced autophagy and lipid degradation. Kaem also induced mitochondrial reactive oxygen species (mtROS) to sequentially promote lysosomal Ca2+ efflux, TFEB translocation and autophagy induction, suggesting a role of TUFM in mtROS regulation. Collectively, these results demonstrate that Kaem is a potential therapeutic candidate/chemical tool for treating metabolic dysregulation and reveal a role for TUFM in autophagy for metabolic regulation with lipid overload.

Original languageEnglish
Article number1
JournalCommunications Biology
Volume4
Issue number1
DOIs
Publication statusPublished - 2021 Dec

Bibliographical note

Funding Information:
This work was partly supported by grants from the National Research Foundation of Korea, by the government of the Republic of Korea (MSIP; 2015K1A1A2028365, 2016K2A9A1A03904900, 2018M3A9C4076477), and by the Brain Korea 21 Plus Project and ICONS (Institute of Convergence Science), Yonsei University.

Publisher Copyright:
© 2021, The Author(s).

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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