HIF1\u03b1-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia

Claudio Laquatra,Giorgio Colombo,Giuseppe Cannino,Andrea Rasola,Marco Schiavone,Silvio Tosatto,Alberto Dinarello,Carlos Sanchez-Martin,Elisabetta Moroni,Giovanni Minervini,Paolo Bernardi,Francesco Argenton,Ionica Masgras

doi:10.1038/s41419-021-03716-6

Abstract

The mitochondrial paralog of the Hsp90 chaperone family TRAP1 is often induced in tumors, but the mechanisms controlling its expression, as well as its physiological functions remain poorly understood. Here, we find that TRAP1 is highly expressed in the early stages of Zebrafish development, and its ablation delays embryogenesis while increasing mitochondrial respiration of fish larvae. TRAP1 expression is enhanced by hypoxic conditions both in developing embryos and in cancer models of Zebrafish and mammals. The TRAP1 promoter contains evolutionary conserved hypoxic responsive elements, and HIF1α stabilization increases TRAP1 levels. TRAP1 inhibition by selective compounds or by genetic knock-out maintains a high level of respiration in Zebrafish embryos after exposure to hypoxia. Our data identify TRAP1 as a primary regulator of mitochondrial bioenergetics in highly proliferating cells following reduction in oxygen tension and HIF1α stabilization.

Highlights

Changes in metabolic circuities are required by highly proliferating cells during development or tumorigenesis to fuel biosynthetic pathways[1,2], and central carbon metabolism coordinates a variety of reactions to ensure the generation of energetic molecules and anabolic building blocks even in conditions of scarce oxygen availability[3,4]
We have demonstrated that HIF1α can be stabilized by TRAP1, the mitochondrial paralog of the HSP90 chaperone family, through inhibition of succinate dehydrogenase (SDH) and the subsequent increase in intracellular succinate concentration that abrogates the priming for proteasomal degradation of HIF1α16,17
The absence of TRAP1 does not affect the structure and fiber organization of muscle, as no differences were detected in muscle birefringence (Fig. 1b and Supplementary Fig. 1f), a physical property of light that indicates the integrity of muscle sarcomeres[25]

Summary

Introduction

Changes in metabolic circuities are required by highly proliferating cells during development or tumorigenesis to fuel biosynthetic pathways[1,2], and central carbon metabolism coordinates a variety of reactions to ensure the generation of energetic molecules and anabolic building blocks even in conditions of scarce oxygen availability[3,4]. TRAP1 induction of HIF1α is pseudohypoxic, as it occurs independently of oxygen availability, and supports a proneoplastic metabolic shift toward aerobic glycolysis in a variety of tumor cell types[16]. It constitutes an example of how mitochondria can tune the metabolism of proliferating cells, allowing their rapid adaptations to fluctuating environmental conditions. It remains poorly investigated the role played by TRAP1 in determining the metabolic changes of cells under physiological conditions, as well as the molecular mechanisms regulating its expression. Embryonic development, in which cells undergo a fast proliferation rate under varying conditions of oxygen tension[2], represents an interesting field of investigation for TRAP1dependent regulation of cell bioenergetics

Methods

Results

Conclusion