Ketogenic Diet Consumption Inhibited Mitochondrial One-Carbon Metabolism

Abstract

Given the popularity of ketogenic diets, their potential long-term consequences deserve to be more carefully monitored. Mitochondrially derived formate has a critical role in mammalian one-carbon (1C) metabolism and development. The glycine cleavage system (GCS) accounts for another substantial source for mitochondrially derived 1C units. Objective: We investigated how the ketogenic state modulates mitochondrial formate generation and partitioning of 1C metabolic fluxes. Design: HepG2 cells treated with physiological doses (1 mM and 10 mM) of β-hydroxybutyrate (βHB) were utilized as the in vitro ketogenic model. Eight-week male C57BL/6JNarl mice received either a medium-chain fatty-acid-enriched ketogenic diet (MCT-KD) or a control diet AIN 93M for 8 weeks. Stable isotopic labeling experiments were conducted. Results and Conclusions: MCT-KD is effective in weight and fat loss. Deoxythymidine (dTMP) synthesis from the mitochondrial GCS-derived formate was significantly suppressed by βHB and consumption of MCT-KD. Consistently, plasma formate concentrations, as well as the metabolic fluxes from serine and glycine, were suppressed by MCT-KD. MCT-KD also decreased the fractional contribution of mitochondrially derived formate in methionine synthesis from serine. With the worldwide application, people and medical professionals should be more aware of the potential metabolic perturbations when practicing a long-term ketogenic diet.

A Metabolic Signature to Monitor Endothelial Cell Differentiation, Activation, and Vascular Organization

“…This is in agreement with the decreased folate metabolism observed in aortic rings, whose sprouting was inhibited by propranolol ( Figure 6 G,H). The decreased levels of 3-hydroxybutyrate also reinforced the impairment of one-carbon metabolism by cysteine ( Figure 4 J), since the ketone body degradation was recently indicated as responsible for one-carbon metabolism downregulation [ 33 ]. Additionally, the decreased acetate levels in monocytes are accentuated by cysteine, because in cells that are not in the differentiation process, and may be more proliferative, acetate supplies fatty acid synthesis [ 30 , 31 , 32 ] ( Figure 1 ).…”

A ketogenic diet alters mTOR activity, systemic metabolism and potentially prevents collagen degradation associated with chronic alcohol consumption in mice

“…In support, others have shown that a KD results in the downregulation of a subset of genes involved in one-carbon metabolism in mouse liver (Pissios et al, 2013 ) and an inhibition of one-carbon metabolism in HepG2 cells and mice (Hsu et al, 2022 ). This inhibitory effect on one-carbon metabolism has been ascribed to the reduced mTOR signalling associated with a KD (Hsu et al, 2022 ). Chronic alcohol intake during a ND significantly increased the excretion of the same essential amino acids lowered by a KD, likely reflecting altered protein turnover (Bernal et al, 1993 ; Lang et al, 2010 ).…”

“…We therefore postulate that the marked reduction observed in mouse urinary one-carbon metabolites while on a KD, reflect a perturbation in this pathway. In support, others have shown that a KD results in the downregulation of a subset of genes involved in one-carbon metabolism in mouse liver (Pissios et al, 2013) and an inhibition of one-carbon metabolism in HepG2 cells and mice (Hsu et al, 2022). This inhibitory effect on one-carbon metabolism has been ascribed to the reduced mTOR signalling associated with a KD (Hsu et al, 2022).…”