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

Abstract

26Decreased expression of the mitochondrial protein frataxin (FXN) causes Friedreich's ataxia 27 (FRDA). FRDA is a neurodegenerative disease also characterized by systemic metabolic alterations 28 that increase the risk of developing type 2 diabetes thus aggravating FRDA prognosis. Brown adipose 29 tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that, in addition to its 30 thermoregulatory role, turns excess energy into heat to maintain energy balance. Here we report that 31FXN knock-in/knock-out (KIKO) mouse shows reduced energy expenditure and VO2, 32 hyperlipidemia, decreased insulin sensitivity and enhanced circulating levels of leptin, recapitulating 33 diabetes-like signatures. FXN deficiency leads to alteration of mitochondrial structure and oxygen 34 consumption, decreased lipolysis and lipid accumulation in BAT. Transcriptomic data highlighted a 35 blunted thermogenesis response, as several biological processes related to thermogenesis (e.g. 36 response to temperature stimuli, mitochondrial gene transcription, triglyceride metabolism, 37 adipogenesis) resulted affected in BAT of KIKO mice upon cold exposure. Decreased adaptation to 38 cool temperature in association with limited PKA-mediated lipolysis and downregulation of the 39 expression of the genes controlling mitochondrial metabolism and lipid catabolism were observed in 40 KIKO mice. T37i brown adipocytes and primary adipocytes with FXN deficiency showed reduced 41 thermogenesis and adipogenesis markers respectively recapitulating the molecular signatures 42 detected in KIKO mice. 43 Collectively our data point to BAT dysfunction in FRDA and suggest BAT as a promising target to 44 overcome metabolic complications in FRDA. 45 46

Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue

“…Then, 1 mg of RNA was treated with genomic DNase and retro-transcripted using PrimeScript RT Reagent Kit (Takara Bio Inc., Japan). qPCR was performed in triplicate on 50 ng of cDNA using validated qPCR primers (BLAST), Applied BiosystemsÔ PowerÔ SYBRÔ Green Master Mix, and the QuantStudio3 Real-Time PCR System (Thermo Fisher, Waltam, MA, USA), as described by Turchi et al (2020). The primers used for qPCR are listed below:…”