Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

Riccardo Turchi, Flavia Tortolici, Giulio Guidobaldi, Federico Iacovelli, Mattia Falconi, Stefano Rufini, Raffaella Faraonio, Viviana Casagrande, Massimo Federici, Lorenzo De Angelis, Simone Carotti, Maria Francesconi, Maria Zingariello, Sergio Morini, Roberta Bernardini, Maurizio Mattei, Piergiorgio La Rosa, Fiorella Piemonte, Daniele Lettieri-Barbato, Katia Aquilano

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Abstract

Decreased expression of mitochondrial frataxin (FXN) causes Friedreich’s ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.

Original languageEnglish
Article number51
JournalCell Death and Disease
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 1 2020

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ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Turchi, R., Tortolici, F., Guidobaldi, G., Iacovelli, F., Falconi, M., Rufini, S., Faraonio, R., Casagrande, V., Federici, M., De Angelis, L., Carotti, S., Francesconi, M., Zingariello, M., Morini, S., Bernardini, R., Mattei, M., Rosa, P. L., Piemonte, F., Lettieri-Barbato, D., & Aquilano, K. (2020). Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue. Cell Death and Disease, 11(1), [51]. https://doi.org/10.1038/s41419-020-2253-2