Multiple Mechanisms Converging on Transcription Factor EB Activation by the Natural Phenol Pterostilbene.

Martina La Spina,Giulietta Di Benedetto,Andrea Salmaso,Martina Chrisam,Marco Schiavone,Sofia Parrasia,Natascia Tiso,Lucia Biasutto,Eva Galletta,Michele Azzolini,Andrea Mattarei,Andrea Ballabio,Mario Zoratti,Franco J L

doi:10.1155/2021/7658501

Abstract

Pterostilbene (Pt) is a potentially beneficial plant phenol. In contrast to many other natural compounds (including the more celebrated resveratrol), Pt concentrations producing significant effects in vitro can also be reached with relative ease in vivo. Here we focus on some of the mechanisms underlying its activity, those involved in the activation of transcription factor EB (TFEB). A set of processes leading to this outcome starts with the generation of ROS, attributed to the interaction of Pt with complex I of the mitochondrial respiratory chain, and spreads to involve Ca2+ mobilization from the ER/mitochondria pool, activation of CREB and AMPK, and inhibition of mTORC1. TFEB migration to the nucleus results in the upregulation of autophagy and lysosomal and mitochondrial biogenesis. Cells exposed to several μM levels of Pt experience a mitochondrial crisis, an indication for using low doses in therapeutic or nutraceutical applications. Pt afforded significant functional improvements in a zebrafish embryo model of ColVI-related myopathy, a pathology which also involves defective autophagy. Furthermore, long-term supplementation with Pt reduced body weight gain and increased transcription levels of Ppargc1a and Tfeb in a mouse model of diet-induced obesity. These in vivo findings strengthen the in vitro observations and highlight the therapeutic potential of this natural compound.

Highlights

Macroautophagy is a tightly regulated celldegradative process leading to the removal of cellular components through lysosomes
We confirmed that Pt induces autophagy in vitro at low concentrations: lipidated LC3 and LC3-positive puncta increased in WT HeLa cells treated with 1-25 μM Pt
This confers Pt the potential to function as a health-improving agent in all conditions which would benefit from the stimulation of autophagy, lysosomal biogenesis and/or mitochondrial turnover

Summary

Introduction

Macroautophagy (degradative/lysosomal autophagy; in this paper “autophagy,” for short) is a tightly regulated celldegradative process leading to the removal of cellular components through lysosomes. Autophagy may lead to cell death under. An example of autophagymediated protective action is given by redox-active toxicants such as CrVI [16, 17], which induce mitochondrial dysfunction and organ damage mediated through generation of excessive amounts of reactive oxygen species (ROS). In these cases, autophagy helps cell survival by eliminating malfunctioning mitochondria, a process called “mitophagy,” which intervenes in other cases, such as neurodegeneration and cardiac myopathies [18–20]. ROS, involved in cell death in this example, are autophagy inducers [21, 22]

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Conclusion