Enhanced Branched-Chain Amino Acid Metabolism Improves Age-related Reproductive Function

Abstract

SummaryReproductive aging is one of the earliest aging phenotypes, and mitochondrial dysfunction has been linked to a decline in oocyte quality. However, the mitochondria-related processes that are critical for oocyte quality maintenance with age have not been fully identified. We isolated mitochondria from young and aged wild-type and long-reproductivedaf-2mutantC. elegansfor proteomic analysis. We found that the mitochondrial proteomic profiles of young wild-type anddaf-2worms are similar and are distinct from mitochondrial proteins of aged wild-type animals. The first enzyme of the branched-chain amino acid (BCAA) metabolism pathway, BCAT-1, is more abundant in young anddaf-2mitochondria. Upon knockdown ofbcat-1indaf-2, reproduction is shortened, mitochondrial ROS levels are elevated, and mitochondria shift to a perinuclear distribution within the mature oocytes. Moreover,bcat-1knockdown decreasesdaf-2oocyte quality and reduces reproductive capability in late age, indicating the importance of this pathway in the maintenance of oocyte quality with age. Importantly, we can extend reproduction in wild-type animals both bybcat-1overexpression and by supplementing vitamin B1, a cofactor needed for the BCAA metabolism.HighlightsBCAT-1 is abundant in mitochondria isolated from young wild-type worms and the long-lived mutantdaf-2.Downregulatingbcat-1indaf-2mutants reducesdaf-2reproductive span, alters mitochondrial oocyte distribution, and elevates mtROS in mature oocytes.Overexpression ofbcat-1extends reproductive capability.Supplementation with thiamine (vitamin B1) extends reproductive capability.