HIF1α-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia |
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| Authors: | Claudio Laquatra Carlos Sanchez-Martin Alberto Dinarello Giuseppe Cannino Giovanni Minervini Elisabetta Moroni Marco Schiavone Silvio Tosatto Francesco Argenton Giorgio Colombo Paolo Bernardi Ionica Masgras Andrea Rasola |
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| Institution: | 1.Dipartimento di Scienze Biomediche, Università di Padova, viale G. Colombo 3, 35131 Padova, Italy ;2.Dipartimento di Biologia, Università di Padova, viale G. Colombo 3, 35131 Padova, Italy ;3.Istituto di Scienze e Tecnologie Chimiche, CNR, Via Mario Bianco 9, 20131 Milano, Italy ;4.Dipartimento di Chimica, Università di Pavia, via Taramelli 12, 27100 Pavia, Italy ;5.Istituto di Neuroscienze, CNR, Viale G. Colombo 3, 35131 Padova, Italy |
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| 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.Subject terms: Cancer metabolism, Cell signalling |
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