Effect of the Ketone Body, D-β-Hydroxybutyrate, on Sirtuin2-Mediated Regulation of Mitochondrial Quality Control and the Autophagy–Lysosomal Pathway

Abstract

Mitochondrial activity and quality control are essential for neuronal homeostasis as neurons rely on glucose oxidative metabolism. The ketone body, D-β-hydroxybutyrate (D-BHB), is metabolized to acetyl-CoA in brain mitochondria and used as an energy fuel alternative to glucose. We have previously reported that D-BHB sustains ATP production and stimulates the autophagic flux under glucose deprivation in neurons; however, the effects of D-BHB on mitochondrial turnover under physiological conditions are still unknown. Sirtuins (SIRTs) are NAD+-activated protein deacetylases involved in the regulation of mitochondrial biogenesis and mitophagy through the activation of transcription factors FOXO1, FOXO3a, TFEB and PGC1α coactivator. Here, we aimed to investigate the effect of D-BHB on mitochondrial turnover in cultured neurons and the mechanisms involved. Results show that D-BHB increased mitochondrial membrane potential and regulated the NAD+/NADH ratio. D-BHB enhanced FOXO1, FOXO3a and PGC1α nuclear levels in an SIRT2-dependent manner and stimulated autophagy, mitophagy and mitochondrial biogenesis. These effects increased neuronal resistance to energy stress. D-BHB also stimulated the autophagic–lysosomal pathway through AMPK activation and TFEB-mediated lysosomal biogenesis. Upregulation of SIRT2, FOXOs, PGC1α and TFEB was confirmed in the brain of ketogenic diet (KD)-treated mice. Altogether, the results identify SIRT2, for the first time, as a target of D-BHB in neurons, which is involved in the regulation of autophagy/mitophagy and mitochondrial quality control.

Treatment with sodium butyrate induces autophagy resulting in therapeutic benefits for spinocerebellar ataxia type 3

“…Therefore, butyrate‐related treatments, or exploiting the gut microbiome to increase butyrate production, may have therapeutic potential for SCA3. While not explored within a SCA3 model, a recent study found that placing healthy mice on a ketogenic (low carbohydrate, high fat) diet resulted in increased levels of D‐β‐hydroxybutyrate in the blood and activation of the autophagy pathway 79 . Further, combined treatment of taurursodiol, a soluble form of bile acid, and phenylbutyrate, a derivative of butyric acid, has been found to improve survival in clinical cohorts of ALS patients 41 and received FDA approval for the treatment of ALS.…”

“…Interestingly, the FOXO family of transcription factors has been reported to have pro‐longevity effects 75,76 and are reported to be downregulated with aging, 77 suggesting a potential benefit of FOXO1‐related therapeutics in age‐linked neurodegenerative diseases 78 . Most recently, it has been demonstrated that treatment with ketone body, D‐β‐hydroxybutyrate, can activate the autophagy pathway through the AMPK pathway and activate transcription factors FOXO1 and FOXO3a in healthy rat cortical neurons 79 . Previously, overexpression of DAF‐16, the equivalent gene of FOXO in C. elegans , prevented motor impairment in a C. elegans model of SCA3 80 .…”

“…78 Most recently, it has been demonstrated that treatment with ketone body, D-βhydroxybutyrate, can activate the autophagy pathway through the AMPK pathway and activate transcription factors FOXO1 and FOXO3a in healthy rat cortical neurons. 79 Previously, overexpression of DAF-16, the equivalent gene of FOXO in C. elegans, prevented motor impairment in a C. elegans model of SCA3. 80 From these studies, alongside our results, the relationship between AMPK-mediated autophagy induction and downstream activation of FOXO transcription factors warrants further investigation as a potential target for SCA3 treatment.…”

Nutrition and autophagy deficiency in critical illness

“…Intermittent fasting remains promising, as it improved behavioral performance and neuronal survival at the injured segment after spinal cord injury, which was prevented with autophagy inhibition, and exerted neuroprotective effects after TBI [127,128 ▪ ]. Ketone bodies, which rise upon fasting, stimulate autophagy [126,129]. However, protection against sepsis-induced muscle weakness with ketone-bodies infusion appeared not mediated via autophagy stimulation [130].…”

Ketogenic diet administration later in life improves memory and regulates the synaptic cortical proteome through the cAMP/PKA signaling pathway in aging mice

“…Indeed, β-hydroxybutyrate (BHB), the main ketone body produced in a KD, has a relevant influence on hallmarks of aging as it reduces the production of reactive oxygen species (Shimazu et al 2013), enhances cell proteostasis (Finn and Dice 2005), activates mitochondrial biogenesis (Hasan-Olive et al 2019), and prevents cell senescence (Han et al 2018) and inflammation (Youm et al 2015). Moreover, ex vivo and in vitro studies indicate that ketone bodies counteract neuronal hyperexcitability (Kadowaki et al 2017), stimulate Aβ 1-40 clearance (Versele et al 2020) and activate autophagy in cortical neurons (Gomora-García et al 2023). Additionally, the administration of ketone esters as an alternative way to deliver ketone bodies to the brain, improves cognition in humans (Fortier et al 2021).…”