Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism

Abstract

Butyrate (BT) is a ubiquitous short-chain fatty acid (SCFA) principally derived from the enteric microbiome. BT positively modulates mitochondrial function, including enhancing oxidative phosphorylation and beta-oxidation and has been proposed as a neuroprotectant. BT and other SCFAs have also been associated with autism spectrum disorders (ASD), a condition associated with mitochondrial dysfunction. We have developed a lymphoblastoid cell line (LCL) model of ASD, with a subset of LCLs demonstrating mitochondrial dysfunction (AD-A) and another subset of LCLs demonstrating normal mitochondrial function (AD-N). Given the positive modulation of BT on mitochondrial function, we hypothesized that BT would have a preferential positive effect on AD-A LCLs. To this end, we measured mitochondrial function in ASD and age-matched control (CNT) LCLs, all derived from boys, following 24 and 48 h exposure to BT (0, 0.1, 0.5, and 1 mM) both with and without an in vitro increase in reactive oxygen species (ROS). We also examined the expression of key genes involved in cellular and mitochondrial response to stress. In CNT LCLs, respiratory parameters linked to adenosine triphosphate (ATP) production were attenuated by 1 mM BT. In contrast, BT significantly increased respiratory parameters linked to ATP production in AD-A LCLs but not in AD-N LCLs. In the context of ROS exposure, BT increased respiratory parameters linked to ATP production for all groups. BT was found to modulate individual LCL mitochondrial respiration to a common set-point, with this set-point slightly higher for the AD-A LCLs as compared to the other groups. The highest concentration of BT (1 mM) increased the expression of genes involved in mitochondrial fission (PINK1, DRP1, FIS1) and physiological stress (UCP2, mTOR, HIF1α, PGC1α) as well as genes thought to be linked to cognition and behavior (CREB1, CamKinase II). These data show that the enteric microbiome-derived SCFA BT modulates mitochondrial activity, with this modulation dependent on concentration, microenvironment redox state, and the underlying mitochondrial function of the cell. In general, these data suggest that BT can enhance mitochondrial function in the context of physiological stress and/or mitochondrial dysfunction, and may be an important metabolite that can help rescue energy metabolism during disease states. Thus, insight into this metabolic modulator may have wide applications for both health and disease since BT has been implicated in a wide variety of conditions including ASD. However, future clinical studies in humans are needed to help define the practical implications of these physiological findings.

Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder

“…In our study, evaluation of mitochondrial bioenergetics activity using a metabolic flux analyzer showed that ASD fibroblasts presented altered parameters of mitochondrial respiration including higher maximal respiratory capacity, reserve capacity, and proton‐leak respiration. These data are in agreement with other recent studies in which Rose and colleagues demonstrated that immortalized lymphoblastoid cells derived from children with ASD present significant abnormalities in mitochondrial respiration at baseline, with these abnormalities worsening following exposure to different pro‐oxidant stimuli 22‐25 . Indeed, similarly to our results, when examined in basal condition, ASD lymphoblastoid cells exhibited abnormally high maximal respiratory capacity, reserve capacity, and proton‐leak respiration coupled with higher glycolysis and glycolytic reserve 22‐25 .…”

Causal roles of mitochondrial dynamics in longevity and healthy aging

“…Butyrate increases the expression of the mitochondrial master regulator, PGC1‐α α, to induce mitochondrial biogenesis and oxidative metabolism in cells and in skeletal muscle of C57BL/6 mice . Furthermore, butyrate induced the expression of genes involved in both mitochondrial fission ( Drp‐1 , Fis‐1 ) and mitophagy ( Pink‐1 , Lc3 , Pten), in vitro , suggesting that SCFAs produced primarily from gut microbiome can fine‐tune mitochondrial function, biogenesis, and dynamics .…”

Mitochondria could be a potential key mediator linking the intestinal microbiota to depression

“…76 The intestinal microbiota is also known to produce SCFAs, which include acetate, butyrate, and propionate from dietary fiber. 81 The important role of butyrate in mitochondrial functionality has been demonstrated in colonocytes. Moreover, acetate and butyrate have been demonstrated to systemically circulate to the brain, increasing brain mitochondrial function.…”