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

  1. Chen Lesnik
  2. Salman Sohrabi
  3. Jasmine M. Ashraf
  4. Rachel Kaletsky
  5. Vanessa Cota
  6. Titas Sengupta
  7. William Keyes
  8. Coleen T. Murphy
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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.

Highlights

  • BCAT-1 is abundant in mitochondria isolated from young wild-type worms and the long-lived mutant daf-2 .

  • Downregulating bcat-1 in daf-2 mutants reduces daf-2 reproductive span, alters mitochondrial oocyte distribution, and elevates mtROS in mature oocytes.

  • Overexpression of bcat-1 extends reproductive capability.

  • Supplementation with thiamine (vitamin B1) extends reproductive capability.

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  1. Life Science Editors

    Review coordinated by Life Science Editors.

    Reviewed by: Dr. Angela Andersen, Life Science Editors

    Potential Conflicts of Interest: None

    Background: The ability to reproduce decreases with age in many animals - including humans and worms. Oocytes age earlier than other tissues, and their decline in quality contributes to reduced reproduction. Diminished mitochondria number/activity in human oocytes correlates with age-related decline.

    Question: Does mitochondrial dysfunction cause (or just correlate with) reduced egg quality?

    Summary: The authors compared the proteomes of mitochondria isolated from young worms, old worms and daf-2 mutant worms (c. elegans) (insulin/igf-1 receptor mutant) that have longer lifespans & longer reproductive lifespan.

    • Mitochondria from young & mutant worms had high levels of BCAT-1 (branched chain aminotransferase).
    • RNAi of bcat-1 reduced the longevity, reproductive longevity & egg quality of daf2 mutants, and increased mitochondrial activity/mtROS.
    • Similar effects of bcat-1 kd in wt worms, but interestingly the effects on reproductive longevity were more severe in wt than daf2 mutants (from a quick look), but there was no effect on lifespan in wt animals.
    • Overexpressing bcat-1 in wt extended reproduction & egg quality but not lifespan.
    • Treating animals with vitamin B1 (a cofactor downstream of BCAT1 in BCAA metabolism) delayed reproductive aging, slightly extended lifespan, improved oocyte quality, reduced mtROS in aged worms..

    Advance: BCAT-1 levels/BCAA metabolism correlate with mitochondrial quality & reproductive longevity. Vit B1, which promotes BCAA metabolism, can extended reproductive longevity.

    Significance: More/strong evidence that dysfunctional mitochondria cause a decline oocyte quality, reduce reproductive longevity. If vitamin B1 supplements are a safe way to delay age-related decline of eggs in female mammals (humans) that would be amazing. .

    Ang asks:

    • is this effectively dietary restriction of BCAA? Would that be a better (albeit perhaps more difficult to sustain) approach?

    • How does this relate to some recent papers pointing out that mitochondria in eggs are special (e.g. Cheng et al. Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment, Science 2022; Rodriguez-Nuevo et al., Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I, Nature 2022) and a role for BCAA in longevity (e.g. Richardson et al., Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and life span in mice, Nature Aging 2021).

    • How does low BCAA metabolism lead to mitochondrial dysfunction/oocyte aging? Is it related to accumulation of amino acids in the cytosol and toxicity to mitochondria? (e.g. Hughes et al., Cysteine toxicity drives age-related mitochondrial decline by altering iron homeostasis, Cell 2020).

    • Overall these data support the idea that oocytes are particularly vulnerable to conditions that drive aging, and conserved aging mechanisms in the soma and germline as well as across species.

  2. Version 1 published on bioRxiv