Abstract
Recent evidence suggests that neural stem cell (NSC) fate is highly dependent on mitochondrial bioenergetics. Tauroursodeoxycholic acid (TUDCA), an endogenous neuroprotective bile acid and a metabolic regulator, stimulates NSC proliferation and enhances adult NSC pool in vitro and in vivo. In this study, we dissected the mechanism triggered by this proliferation-inducing molecule, namely in mediating metabolic reprogramming. Liquid chromatography coupled with mass spectrometry (LC-MS) based detection of differential proteomics revealed that TUDCA reduces the mitochondrial levels of the long-chain acyl-CoA dehydrogenase (LCAD), an enzyme crucial for β-oxidation of long-chain fatty acids (FA). TUDCA impact on NSC mitochondrial proteome was further confirmed, including in neurogenic regions of adult rats. We show that LCAD raises throughout NSC differentiation, while its silencing promotes NSC proliferation. In contrast, nuclear levels of sterol regulatory element-binding protein (SREBP-1), a major transcription factor of lipid biosynthesis, changes in the opposite manner of LCAD, being upregulated by TUDCA. In addition, alterations in some metabolic intermediates, such as palmitic acid, also supported the TUDCA-induced de novo lipogenesis. More interestingly, a metabolic shift from FA to glucose catabolism appears to occur in TUDCA-treated NSCs, since mitochondrial levels of pyruvate dehydrogenase E1-α (PDHE1-α) were significant enhanced by TUDCA. At last, the mitochondria-nucleus translocation of PDHE1-α was potentiated by TUDCA, associated with an increase of H3-histones and acetylated forms. In conclusion, TUDCA-induced proliferation of NSCs involves metabolic plasticity and mitochondria-nucleus crosstalk, in which nuclear PDHE1-α might be required to assure pyruvate-derived acetyl-CoA for histone acetylation and NSC cycle progression.
Highlights
Over the past few years, our perception of neural stem cell (NSC) potential has greatly increased, we are only beginning to understand their metabolic profile in physiological and pathological context (Ottoboni et al, 2017)
We have shown that the endogenous bile acid Tauroursodeoxycholic acid (TUDCA) is a well-known mitochondrion protecting agent in early stages of neural differentiation (Xavier et al, 2015), while promoting the proliferation of NSCs, both in vitro and in vivo, to increase NSC pool (Xavier et al, 2014; Soares et al, 2018)
We identified proteins involved in cell metabolism, such as aldehyde dehydrogenase 2 (ALDH2) responsible for converting acetaldehyde metabolized from ethanol to acetate, and the acetylCoA acetyltransferase (ACAT1, known as β-thiolase) that catalyzes the condensation of two acetyl-CoA to acetoacetyl-CoA, as well as the reverse reaction, by breaking down acetoacetyl-CoA (Fukao et al, 1990)
Summary
Over the past few years, our perception of neural stem cell (NSC) potential has greatly increased, we are only beginning to understand their metabolic profile in physiological and pathological context (Ottoboni et al, 2017). GRAPHICAL ABSTRACT | TUDCA induces a metabolic shift to boost NSC proliferation. In early-differentiating NSCs, TUDCA increases de novo lipogenesis and proliferation by inducing a metabolic shift from FA to glucose catabolism that facilitates NSC cell cycle-associated H3 acetylation. Mitochondrial dynamics and bioenergetics are closely associated to NSC fate and behavior (Kann and Kovács, 2007; Wanet et al, 2015; Xavier et al, 2015). In this regard, mitochondrial dysfunction can be an underlying problem in the depletion of the stem cell pool and impaired neurogenesis (Wallace, 2005; Khacho et al, 2017). Mitochondria and its regulatory network have major implications toward a more efficient use of neural regeneration therapies (Casarosa et al, 2014)
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