Enhanced BCAA metabolism improves age-related reproductive function

Mitochondrial dysfunction is linked to the decline in oocyte quality and reproductive aging. However, which mitochondria-related processes are critical for oocyte quality maintenance with age are not understood.

To understand how mitochondria affect oocyte quality and reproductive aging, we isolated mitochondria from young and aged WT worms or the long-reproductive daf-2 mutants for proteomic analysis. We found that the mitochondrial proteomic profiles of young WT and daf-2 (either young or aged) worms are similar, and both demonstrate distinct clustering from mitochondrial proteins of aged WT.

By focusing on proteins that are more abundant in young mitochondria, we found that the branched-chain amino acid (BCAA) degradation pathway, and specifically the first enzyme of the pathway, BCAT-1, is important for reproduction. Upon knockdown of bcat-1 in daf-2, mtROS levels are elevated and mitochondria are shifted to perinuclear distribution within its mature oocytes. Moreover, downregulating bcat-1 decreases daf-2 oocyte quality and reduces reproductive capability in late age, indicating the importance of this pathway in the maintenance of quality with age. By modulating this pathway in wild-type worms we can extend reproduction: both overexpression of BCAT-1 and remarkably, supplementing vitamin B1, a cofactor needed for the pathway, extend reproductive capability.