Autophagy-dependent disruption of beta-FAO-mediated histone acetylation in embryos during maternal aging

With advancing maternal age, embryonic autophagic activity and early embryonic development decline in mammals, yet the underlying mechanisms remain elusive. Here, we show that decreased autophagy exacerbates fatty acid beta-oxidation (beta-FAO), leading to the depletion of lipid droplets (LDs) and impairs early embryonic development. Through RIP-qPCR and RNA pull-down assays, we found that decreased autophagy disrupts LC3B-dependent degradation of Acox1, thereby enhancing beta-FAO in embryos. Mechanistically, enhanced beta-FAO consumes oxidized nicotinamide adenine dinucleotide (NAD+), impeding H3K9ac erasure required for minor ZGA exit. Moreover, we verified enhanced beta-FAO, H3K9ac, and disruption of minor ZGA in embryos from aged female mice and humans. Supplementation with the autophagic agonist rapamycin (Rapa) rescues beta-FAO, H3K9ac, and minor ZGA in embryos from aged female mice, ultimately improving early embryonic development. In sum, our findings demonstrate that decreased autophagy compromises the beta-FAO-mediated histone acetylation, disrupting minor ZGA and ultimately impairing the developmental potential of embryos during maternal aging in mice and humans.