Activation of mitochondrial TUFM ameliorates metabolic dysregulation through coordinating autophagy induction

Commun Biol. 2021 Jan 4;4(1):1. doi: 10.1038/s42003-020-01566-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects
  • Animals
  • Autophagy / drug effects*
  • Autophagy-Related Protein 12 / metabolism
  • Autophagy-Related Protein 5 / metabolism
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Drug Evaluation, Preclinical
  • HeLa Cells
  • Humans
  • Kaempferols / pharmacology
  • Kaempferols / therapeutic use*
  • Lipid Metabolism / drug effects*
  • Metabolic Syndrome / drug therapy*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Proteins / metabolism*
  • Peptide Elongation Factor Tu / metabolism*

Substances

  • Autophagy-Related Protein 12
  • Autophagy-Related Protein 5
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Kaempferols
  • Mitochondrial Proteins
  • TFEB protein, human
  • kaempferide
  • Peptide Elongation Factor Tu
  • Tufm protein, mouse