Cell Reports (Jun 2021)
The heme synthesis-export system regulates the tricarboxylic acid cycle flux and oxidative phosphorylation
- Veronica Fiorito,
- Anna Lucia Allocco,
- Sara Petrillo,
- Elena Gazzano,
- Simone Torretta,
- Saverio Marchi,
- Francesca Destefanis,
- Consiglia Pacelli,
- Valentina Audrito,
- Paolo Provero,
- Enzo Medico,
- Deborah Chiabrando,
- Paolo Ettore Porporato,
- Carlotta Cancelliere,
- Alberto Bardelli,
- Livio Trusolino,
- Nazzareno Capitanio,
- Silvia Deaglio,
- Fiorella Altruda,
- Paolo Pinton,
- Simone Cardaci,
- Chiara Riganti,
- Emanuela Tolosano
Affiliations
- Veronica Fiorito
- Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
- Anna Lucia Allocco
- Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
- Sara Petrillo
- Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
- Elena Gazzano
- Department of Oncology, University of Torino, Torino, Italy
- Simone Torretta
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy
- Saverio Marchi
- Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy
- Francesca Destefanis
- Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
- Consiglia Pacelli
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
- Valentina Audrito
- Immunogenetics Unit, Department of Medical Sciences, University of Torino, Torino, Italy
- Paolo Provero
- Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; Center for Omics Sciences, San Raffaele Scientific Institute IRCSS, Milano, Italy
- Enzo Medico
- Department of Oncology, University of Torino, Candiolo, TO, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO, Italy
- Deborah Chiabrando
- Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
- Paolo Ettore Porporato
- Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
- Carlotta Cancelliere
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO, Italy
- Alberto Bardelli
- Department of Oncology, University of Torino, Candiolo, TO, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO, Italy
- Livio Trusolino
- Department of Oncology, University of Torino, Candiolo, TO, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO, Italy
- Nazzareno Capitanio
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
- Silvia Deaglio
- Immunogenetics Unit, Department of Medical Sciences, University of Torino, Torino, Italy
- Fiorella Altruda
- Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
- Paolo Pinton
- Department of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
- Simone Cardaci
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy
- Chiara Riganti
- Department of Oncology, University of Torino, Torino, Italy
- Emanuela Tolosano
- Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; Corresponding author
- Journal volume & issue
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Vol. 35,
no. 11
p. 109252
Abstract
Summary: Heme is an iron-containing porphyrin of vital importance for cell energetic metabolism. High rates of heme synthesis are commonly observed in proliferating cells. Moreover, the cell-surface heme exporter feline leukemia virus subgroup C receptor 1a (FLVCR1a) is overexpressed in several tumor types. However, the reasons why heme synthesis and export are enhanced in highly proliferating cells remain unknown. Here, we illustrate a functional axis between heme synthesis and heme export: heme efflux through the plasma membrane sustains heme synthesis, and implementation of the two processes down-modulates the tricarboxylic acid (TCA) cycle flux and oxidative phosphorylation. Conversely, inhibition of heme export reduces heme synthesis and promotes the TCA cycle fueling and flux as well as oxidative phosphorylation. These data indicate that the heme synthesis-export system modulates the TCA cycle and oxidative metabolism and provide a mechanistic basis for the observation that both processes are enhanced in cells with high-energy demand.
