The lactate transporter MCT4 drives age-related decline in mouse oocytes, and blocking it partially restores their fertilization capacity
The lactate transporter MCT4 drives age-related decline in mouse oocytes, and blocking it partially restores their fertilization capacity
On 21 September 2026, Nature Communications published a study by researchers at Zhejiang University that, for the first time, measured two molecular layers simultaneously (proteins and RNA) in the same oocyte, both mouse and human, at immature and mature stages. Among all measured changes, MCT4 shifted the most in aged oocytes of both species: artificially raising it in young mouse oocytes reproduced age-related defects, while blocking it in old oocytes partially reversed them. In women undergoing IVF, lactate output from a single oocyte correlated with donor age, AMH level (a marker of ovarian reserve), and the number of oocytes retrieved.
An oocyte spends most of its life running on supplies laid down in advance: the RNA it needs is deposited during follicle growth, and for years afterward the cell subsists on that stockpile, translating it into protein while producing almost no new RNA. Earlier studies of oocyte aging that measured only RNA could therefore miss what is actually happening at the protein level, where the cell's functional machinery resides. In both species, mouse and human, these two layers diverge with age: protein changes do not reduce to RNA changes.
Among the thousands of proteins measured, with no hypothesis imposed beforehand, MCT4 showed the strongest and most consistent age-related shift in both mouse and human oocytes.
The rise in MCT4 is itself sufficient to cause part of the aging phenotype: artificially elevating it in young mouse oocytes reproduces the same defects seen in old cells. In such an oocyte, intracellular pH rises because lactate leaves the cell together with a proton that had been keeping it acidic. The exported lactate is taken up by surrounding cumulus cells, while the oocyte itself is left short of mitochondrial fuel: pyruvate and ATP reserves drop, oxidative stress and DNA damage increase, and spindle assembly errors become more frequent. Blocking MCT4 in aged oocytes with the compound VB124 partially relieved these defects, up to and including a partial restoration of fertilization capacity. The effect was reproduced in isolated oocytes, in oocytes within their natural cumulus cell environment, and in live aged mice, which rules out a cell-culture artifact.
To separate the effect of MCT4 specifically from lactate metabolism in general, the authors tested the related transporter MCT1, which under normal conditions moves lactate in the opposite direction, into the cell: its abundance did not change with age, and knocking it out had no effect on oocyte quality. MCT4 accumulates in aged oocytes because there are more transporter molecules, not because each one is more active: its mRNA synthesis increases, and degradation of the finished protein by the proteasome (the cell's disposal machinery for spent proteins) weakens.
In women undergoing IVF, the amount of lactate secreted per oocyte also rose with donor age and tracked with AMH level and the number of oocytes retrieved. In humans, however, this association remains correlational: a causal experiment blocking MCT4, as was done in mice, has not been performed on human oocytes. The human oocytes in this study were matured in a laboratory dish, because naturally matured oocytes are reserved by clinics for the IVF procedure itself, and they were collected during hormonally stimulated cycles.