Mitochondria and lipid metabolism in mammalian oocytes and early embryos

Abstract

Mammalian oocytes and early cleavage-stage embryos are critically dependent on their ˜100,000 mitochondria to develop from ovulation to compacted morula stage. They rely almost solely on oxidative phosphorylation of multiple intracellular substrates- namely pyruvate, fatty acids and glutamine- for production of ATP. Increasing evidence exists for the requirement of both fatty acids and pyruvate for mammalian developmental potential. Fatty acids are stored as neutral lipids in lipid droplets, which are liberated into the cytoplasm as free fatty acids and taken up into mitochondria for metabolism. Different mammalian species exhibit different amounts of stored and free lipid, while the types of lipid present tend to remain constant. It is thought that the amount of lipid contained in the oocytes of mammalian species reflects the extent of β-oxidation, but it is unclear why large differences are seen in lipid content. Maternal high fat diet or obesity causes negative intracellular effects such as the ER stress response, and oxidative mitochondrial and DNA damage. While some mechanisms have been established, it is still unclear exactly how high fat leads to compromised oocyte and embryo quality. It is proposed that healthy mammalian oocyte mitochondria require a balance of pyruvate and fatty acid oxidation in order to maintain a low level of otherwise damaging ROS production. This balance is disrupted in conditions of excess or insufficient substrate.

Mitofusin 1 is required for oocyte growth and communication with follicular somatic cells

“…Then, we determined whether stimulation of the PI3K‐Akt signaling (through treatment with bpV‐HOpic 51,52 ) could rescue the development of Mfn1 ‐cKO oocytes. ATP content was used in this experiment as a readout for oocyte viability as, besides being markedly decreased in Mfn1 ‐cKO oocytes (Figure 3J), it has been shown to be intimately linked with oocyte quality 9,53 . Although the treatment with bpV‐HOpic failed to increase oocyte diameter (Figure 5E), it did increase ATP content in Mfn1 ‐cKO oocytes (Figure 5F).…”

A Comparative Analysis of Oocyte Development in Mammals

“…Pyruvate is the main energy substrate oxidized in follicles, where both glycolysis and mitochondrial pyruvate oxidation occur, and pyruvate is required to meet oocyte energetic requirement for the resumption of meiosis (reviewed by [193,194]). Moreover, dietary glycemic load (quality/amount of carbohydrate) is related to anovulation [195].…”

“…Oocytes of cows and ewes also contain a high albeit lower level of lipids (63 ng and 89 ng respectively), and they exhibit fewer and smaller lipids droplets. Finally, oocytes from mice and humans contain the lowest amount of lipids [194]. The abundance of neutral lipids in lipid droplets correlates with dark inclusions in the ooplasm, and was quantified by lipid-specific fluorescence [202,229].…”

“…In contrast, in species where the oocyte contains a high level of lipids, as in swine, the dependency on lipid metabolism seems to be high, and even a partial inhibition of fatty acid β-oxidation is sufficient to block oocyte maturation. Mouse oocytes should be less sensitive to fatty acid β-oxidation impairment than swine oocytes, with an intermediate status for human, cows and ewes [194]. The oocyte capacity for lipid storage may also vary between species.…”

“…Indeed, the expression level of diacylglycerol O-acyltransferase 1 (DGAT1), and therefore, the rate of TAG synthesis and storage vary between species, and are the highest in the swine oocyte. The cause of such variations between species is not known at the moment, but it is thought to be related to the extended duration of embryo development before implantation, and to the litter size in high lipid containing pig and dog oocytes [194]. However, this correlation between time to implantation and lipid content is correct for extreme species (high or low lipid content), but not with intermediate species (cows, ewes, goats).…”