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

Author:

La Spina Martina1ORCID,Azzolini Michele123ORCID,Salmaso Andrea124,Parrasia Sofia1ORCID,Galletta Eva14ORCID,Schiavone Marco15ORCID,Chrisam Martina6ORCID,Mattarei Andrea7ORCID,Di Benedetto Giulietta2ORCID,Ballabio Andrea891011ORCID,Tiso Natascia4ORCID,Zoratti Mario12ORCID,Biasutto Lucia12ORCID

Affiliation:

1. Department of Biomedical Sciences, University of Padova, Padova, Italy

2. CNR Neuroscience Institute, Padova, Italy

3. Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden

4. Department of Biology, University of Padova, Padova, Italy

5. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

6. Department of Molecular Medicine, University of Padova, Padova, Italy

7. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy

8. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy

9. Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy

10. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

11. Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA

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.

Funder

Telethon

Publisher

Hindawi Limited

Subject

Cell Biology,Aging,General Medicine,Biochemistry

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