Enhanced Branched-Chain Amino Acid Metabolism Improves Age-Related Reproduction inC. elegans

Abstract

Reproductive 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-reproductive daf-2 mutant C. elegans for proteomic analysis. We found that the mitochondrial proteomic profiles of young wild-type and daf-2 worms 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 and daf-2 mitochondria. Upon knockdown of bcat-1 in daf-2, reproduction is shortened, mitochondrial ROS levels are elevated, and mitochondria shift to a perinuclear distribution within the mature oocytes. Moreover, bcat-1 knockdown decreases daf-2 oocyte 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 by bcat-1 overexpression and by supplementing vitamin B1, a cofactor needed for the BCAA metabolism.