RNA-binding protein YBX1 promotes brown adipogenesis and thermogenesis via PINK1/PRKN-mediated mitophagy

Promoting the thermogenic function of brown adipose tissue (BAT) is a promising strategy to combat obesity and metabolic disorders. While much is known about the transcriptional regulation of BAT activation, however, the underlying mechanism of post-transcriptional control by RNA binding proteins remains largely unknown. Here, we found that RNA binding protein Y-box binding protein 1 (YBX1) expression was abundant in BAT and induced by cold exposure and a β-adrenergic agonist in mice. Loss-of-function experiments showed that YBX1 deficiency inhibited mouse primary brown adipocyte differentiation and thermogenic function. Further study showed that YBX1 positively regulates thermogenesis through enhancing Mitophagy. Mechanistically, RNA immunoprecipitation identified that YBX1 directly targeted the transcripts of PTEN-induced kinase 1 (Pink1) and parkin RBR E3 ubiquitin-protein Ligase (Prkn), two key regulators of Mitophagy. RNA decay assay proved that loss of YBX1 decreased mRNA stability of Pink1 and Prkn, leading to reduced protein expression, thereby alleviating Mitophagy and inhibiting thermogenic program. Importantly, in vivo experiments demonstrated that YBX1 overexpression in BAT promoted thermogenesis and Mitophagy in mice. Collectively, our results reveal novel insight into the molecular mechanism of YBX1 in post-transcriptional regulation of PINK1/PRKN-mediated Mitophagy and highlight the critical role of YBX1 in brown adipogenesis and thermogenesis.