Mitochondrial metabolism-regulated epigenetic modification is a driving force of aging and a promising target for therapeutic intervention.Mitochondrial malate dehydrogenase(MDH2),an enzyme in the TCA cycle,was identi...Mitochondrial metabolism-regulated epigenetic modification is a driving force of aging and a promising target for therapeutic intervention.Mitochondrial malate dehydrogenase(MDH2),an enzyme in the TCA cycle,was identified as an anti-aging target through activity-based protein profiling in present study.The expression level of MDH2 was positively correlated with the cellular senescence in Mdh2 knockdown or overexpression fibroblasts.Glibenclamide(Gli),a classic anti-glycemic drug,was found to inhibit the activity of MDH2 and relieve fibroblast senescence in an MDH2-dependent manner.The anti-aging effects of Gli were also further validated in vivo,as it extended the lifespan and reduced the frailty index of naturally aged mice.Liver specific Mdh2 knockdown eliminated Gli’s beneficial effects in naturally aged mice,reducing p^(16INK4a) expression and hepatic fibrosis.Mechanistically,MDH2 inhibition or knockdown disrupted central carbon metabolism,then enhanced the methionine cycle flux,and subsequently promoted histone methylation.Notably,the tri-methylation of H3K27,identified as a crucial methylation site in reversing cellular senescence,was significantly elevated in hepatic tissues of naturally aged mice with Mdh2 knockdown.Taken together,these findings reveal that MDH2 inhibition or knockdown delays the aging process through metabolic-epigenetic regulation.Our research not only identified MDH2 as a potential therapeutic target and Gli as a lead compound for anti-aging drug development,but also shed light on the intricate interplay of metabolism and epigenetic modifications in aging.展开更多
基金the National Natural Science Foundation of China(grants 32121005 to J.L.,22277028 to Z.L.H.,22437002 to J.L,22467010 to B.L.L.,and 22207026 to W.W.L.)the Innovation Program of Shanghai Municipal Education Commission(grant 2021-01-07-00-02-E00104 to J.L.)+3 种基金the Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism(grant 2021 Sci&Tech 03-28 to J.L.)the Innovative Research Team of High-level Local Universities in Shanghai(grant SHSMU-ZDCX20212702 to J.L.)the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering(2060204 to J.L.)the innovative research project of graduate students in Hainan Province(SA2400003375 to L.S.)。
文摘Mitochondrial metabolism-regulated epigenetic modification is a driving force of aging and a promising target for therapeutic intervention.Mitochondrial malate dehydrogenase(MDH2),an enzyme in the TCA cycle,was identified as an anti-aging target through activity-based protein profiling in present study.The expression level of MDH2 was positively correlated with the cellular senescence in Mdh2 knockdown or overexpression fibroblasts.Glibenclamide(Gli),a classic anti-glycemic drug,was found to inhibit the activity of MDH2 and relieve fibroblast senescence in an MDH2-dependent manner.The anti-aging effects of Gli were also further validated in vivo,as it extended the lifespan and reduced the frailty index of naturally aged mice.Liver specific Mdh2 knockdown eliminated Gli’s beneficial effects in naturally aged mice,reducing p^(16INK4a) expression and hepatic fibrosis.Mechanistically,MDH2 inhibition or knockdown disrupted central carbon metabolism,then enhanced the methionine cycle flux,and subsequently promoted histone methylation.Notably,the tri-methylation of H3K27,identified as a crucial methylation site in reversing cellular senescence,was significantly elevated in hepatic tissues of naturally aged mice with Mdh2 knockdown.Taken together,these findings reveal that MDH2 inhibition or knockdown delays the aging process through metabolic-epigenetic regulation.Our research not only identified MDH2 as a potential therapeutic target and Gli as a lead compound for anti-aging drug development,but also shed light on the intricate interplay of metabolism and epigenetic modifications in aging.
