Autophagy is an intracellular degenerative pathway which is responsible for neuronal survival. Under the condition of nutrient deprivation, autophagy can lead to dysfunction in memory consolidation. AMPK/mTOR pathway ...Autophagy is an intracellular degenerative pathway which is responsible for neuronal survival. Under the condition of nutrient deprivation, autophagy can lead to dysfunction in memory consolidation. AMPK/mTOR pathway is currently the most studied autophagy mechanism, while recently researchers have proved ACSS2 can also affect autophagy. ACSS2 is phosphorylated at Ser659 by AMPK and then forms a translocation complex with Importin α5 to translocate into the nucleus. This process interacts with TFEB, resulting in upregulated expression of lysosomal and autophagosomal genes. These upregulations inhibit synaptic plasticity and hence memory functions. On the other hand, ACSS2 is also recognized as a regulator of histone acetylation. After recruiting CBP/p300 and activating CBP's HAT activity in the nucleus, ACSS2 maintains the level of localized histone acetylation by recapturing acetate from histone deacetylation to reform acetyl-CoA, providing substrates for HAT. The increase of histone acetylation locally enhanced immediate early gene transcription, including Egr2, Fos, Nr2f2, Sgk1, and Arc, to benefit neuronal plasticity and memory in many ways.展开更多
The symbiotic relationship between the host and microbiota is widely acknowledged as mutually beneficial.However,due to significant differences in metabolic substrates and products between prokaryotic bacteria and mam...The symbiotic relationship between the host and microbiota is widely acknowledged as mutually beneficial.However,due to significant differences in metabolic substrates and products between prokaryotic bacteria and mammalian cells,mechanisms must exist to reconcile the metabolic incompatibility between the host and microbiota.We report that host enzymes are required to detoxify gut microbiota-derived acetate to maintain male fertility in mice.The combined deletion of acetyl-CoA synthetase short-chain family member 1 and 2(ACSS1 and ACSS2),two enzymes consuming acetate in mammals,leads to excessive accumulation of acetate in circulation.This accumulation causes metabolic acidosis,blocking spermatogenesis and rendering male mice infertile.ACSS1/2-deficient germ cells exhibit comprehensive metabolic alterations with nicotinamide adenine dinucleotide(NAD+)deficiency that impairs betaine production.Supplementation with betaine restores spermatogenesis and fertility in ACSS1/2-deficient mice.Thus,the inevitable production of acetate by gut bacteria and its reproductive toxicity to the host represents an unappreciated metabolic incompatibility between the host and microbiota,which is reconciled by ACSS1/2.展开更多
文摘Autophagy is an intracellular degenerative pathway which is responsible for neuronal survival. Under the condition of nutrient deprivation, autophagy can lead to dysfunction in memory consolidation. AMPK/mTOR pathway is currently the most studied autophagy mechanism, while recently researchers have proved ACSS2 can also affect autophagy. ACSS2 is phosphorylated at Ser659 by AMPK and then forms a translocation complex with Importin α5 to translocate into the nucleus. This process interacts with TFEB, resulting in upregulated expression of lysosomal and autophagosomal genes. These upregulations inhibit synaptic plasticity and hence memory functions. On the other hand, ACSS2 is also recognized as a regulator of histone acetylation. After recruiting CBP/p300 and activating CBP's HAT activity in the nucleus, ACSS2 maintains the level of localized histone acetylation by recapturing acetate from histone deacetylation to reform acetyl-CoA, providing substrates for HAT. The increase of histone acetylation locally enhanced immediate early gene transcription, including Egr2, Fos, Nr2f2, Sgk1, and Arc, to benefit neuronal plasticity and memory in many ways.
基金This research was supported by Tsinghua University Initiative Scientific Research Program (to M.P.) and funds from Tsinghua-Peking Center for Life Sciences and Institute forImmunology at Tsinghua University (to M.P.).
文摘The symbiotic relationship between the host and microbiota is widely acknowledged as mutually beneficial.However,due to significant differences in metabolic substrates and products between prokaryotic bacteria and mammalian cells,mechanisms must exist to reconcile the metabolic incompatibility between the host and microbiota.We report that host enzymes are required to detoxify gut microbiota-derived acetate to maintain male fertility in mice.The combined deletion of acetyl-CoA synthetase short-chain family member 1 and 2(ACSS1 and ACSS2),two enzymes consuming acetate in mammals,leads to excessive accumulation of acetate in circulation.This accumulation causes metabolic acidosis,blocking spermatogenesis and rendering male mice infertile.ACSS1/2-deficient germ cells exhibit comprehensive metabolic alterations with nicotinamide adenine dinucleotide(NAD+)deficiency that impairs betaine production.Supplementation with betaine restores spermatogenesis and fertility in ACSS1/2-deficient mice.Thus,the inevitable production of acetate by gut bacteria and its reproductive toxicity to the host represents an unappreciated metabolic incompatibility between the host and microbiota,which is reconciled by ACSS1/2.
