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The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR

Citation:

Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, Diep S, Lomenick B, Meli VS, Monsalve GC, et al. The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. NatureNatureNature. 2014;510 :397-401.

Date Published:

Jun 19

Abstract:

Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that alpha-ketoglutarate (alpha-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit beta is identified as a novel binding protein of alpha-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that alpha-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by alpha-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by alpha-KG requires ATP synthase subunit beta and is dependent on target of rapamycin (TOR) downstream. Endogenous alpha-KG levels are increased on starvation and alpha-KG does not extend the lifespan of dietary-restricted animals, indicating that alpha-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.

Notes:

Chin, Randall MFu, XudongPai, Melody YVergnes, LaurentHwang, HeejunDeng, GangDiep, SimonLomenick, BrettMeli, Vijaykumar SMonsalve, Gabriela CHu, EileenWhelan, Stephen AWang, Jennifer XJung, GwanghyunSolis, Gregory MFazlollahi, FarbodKaweeteerawat, ChitradaQuach, AustinNili, MahtaKrall, Abby SGodwin, Hilary AChang, Helena RFaull, Kym FGuo, FengJiang, MeishengTrauger, Sunia ASaghatelian, AlanBraas, DanielChristofk, Heather RClarke, Catherine FTeitell, Michael APetrascheck, MichaelReue, KarenJung, Michael EFrand, Alison RHuang, JingP40 OD010440/OD/NIH HHS/T32 CA009120/CA/NCI NIH HHS/T32 GM007104/GM/NIGMS NIH HHS/T32 GM007185/GM/NIGMS NIH HHS/T32 GM008496/GM/NIGMS NIH HHS/EnglandNature. 2014 Jun 19;510(7505):397-401. doi: 10.1038/nature13264. Epub 2014 May 14.