S‐adenosylmethionine: A metabolite critical to the regulation of autophagy

Abstract

Autophagy is a mechanism that enables cells to maintain cellular homeostasis by removing damaged materials and mobilizing energy reserves in conditions of starvation. Although nutrient availability strongly impacts the process of autophagy, the specific metabolites that regulate autophagic responses have not yet been determined. Recent results indicate that S‐adenosylmethionine (SAM) represents a critical inhibitor of methionine starvation–induced autophagy. SAM is primarily involved in four key metabolic pathways: transmethylation, transsulphuration, polyamine synthesis and 5′‐deoxyadenosyl 5′‐radical–mediated biochemical transformations. SAM is the sole methyl group donor involved in the methylation of DNA, RNA and histones, modulating the autophagic process by mediating epigenetic effects. Moreover, the metabolites of SAM, such as homocysteine, glutathione, decarboxylated SAM and spermidine, also exert important influences on the regulation of autophagy. From our perspective, nuclear‐cytosolic SAM is a conserved metabolic inhibitor that connects cellular metabolic status and the regulation of autophagy. In the future, SAM might be a new target of autophagy regulators and be widely used in the treatment of various diseases.

SAM homeostasis is regulated by CFIm-mediated splicing of MAT2A

“…Too much or too little methylation of substrates by SAM has been associated with cancer, diabetes, along with other diseases ( Gharipour et al, 2020 ; McMahon et al, 2017 ; Zhu et al, 2020 ). Therefore, intracellular SAM levels are tightly controlled to maintain homeostasis, with loss of regulation resulting in cellular dysfunction ( Gao et al, 2019 ; Lio and Huang, 2020 ; Ouyang et al, 2020 ; Parkhitko et al, 2019 ).…”

SAM homeostasis is regulated by CFIm-mediated splicing of MAT2A

“…The continual turnover of SAM in the cell by methyltransferases and its central importance to a wide variety of cellular pathways requires that its levels be constantly monitored. Indeed, disruption of the methionine-SAM homeostasis has widespread consequences for health and disease (Gao et al, 2019; Lio and Huang, 2020; Ouyang et al, 2020; Parkhitko et al, 2019).…”

The Co-occurrence of Chronic Hepatitis B and Fibrosis Is Associated With a Decrease in Hepatic Global DNA Methylation Levels in Patients With Non-alcoholic Fatty Liver Disease

“…One underlying mechanism is the reduction of methylation capacity because of intracellular depletion of SAM. SAM is an essential and critical methyl donor for cellular transmethylation reactions including DNA, RNA, and histone methylation (Ouyang et al, 2020). Diet low in source of methyl donors, high in fat can lead to global DNA hypomethylation in the livers by impairing synthesis of SAM, which could be reversed by methyl donor supplementation (Medici et al, 2013;Wang et al, 2014;Bakir et al, 2019).…”