Mitochondrial dynamics controlled by mitofusins define organelle positioning and movement during mouse oocyte maturation

Abstract

Mitochondria are abundant in fully grown mammalian oocytes with a unique spherical morphology, but the mechanisms controlling mitochondria behavior are not well understood. Here we describe for the first time the control of mitochondrial behavior in mouse oocytes by a fusion/fission mechanism. Mitofusins (Mfn1 and Mfn2) and OPA1 proteins are required for outer and inner mitochondrial membrane fusion, respectively, whereas Drp1 is the key regulator of mitochondrial fission. We show that mouse oocytes express the Mfn1, Mfn2, Opa1 and Drp1 proteins, both in immature and mature oocytes at similar levels. Overexpression of Mfn1 or Mfn2 causes marked mitochondrial aggregation, particularly in the perinuclear region during meiotic progression. Tracking of mitochondria with chromosomes or endoplasmic reticulum (ER) throughout oocyte maturation demonstrates that Mfn1 and Mfn2-promoted mitochondrial aggregation disturbs the spatiotemporal dynamic of the chromosomes and ER, respectively. Our findings suggest that organelle dynamics are co-ordinately controlled during meiotic division, and an imbalance of mitochondrial fusion/fission leads to disorganization of the organelle compartments.

Oocyte mitochondria: role on fertility and disease transmission

“…Mitochondrial dysfunctions that do not affect early oogenesis can indeed impair oocyte maturation, leading to infertility (Thouas et al, 2004;Zhang et al, 2006;Ben-Meir et al, 2015;Boucret et al, 2015;MayPanloup et al, 2016). During oocyte maturation, mitochondria are highly mobile, clustering at specific sites (i.e., around GV and spindles) to assure the energy requirement to be met (Kruip et al, 1983;Yu et al, 2010;Udagawa et al, 2014;Wakai et al, 2014). Thus, the large number of mitochondria possibly counterbalance their decreased activity, assuring energy demand to be supplied locally, without excessive ROS generation (Fig.…”

“…This assumption is supported by the finding that ablation of fission leads to mitochondrial elongation in mouse oocytes (Udagawa et al, 2014). Yet, overexpression of MFN1 or MFN2 does not cause mitochondrial elongation in oocytes (Wakai et al, 2014), suggesting that keeping mitochondria fragmented is critical for the gamete. In fact, mice with oocytes deficient for mitochondrial fission are infertile (Udagawa et al, 2014), whereas overexpression of fusion genes impairs oocyte viability (Wakai et al, 2014).…”

“…Yet, overexpression of MFN1 or MFN2 does not cause mitochondrial elongation in oocytes (Wakai et al, 2014), suggesting that keeping mitochondria fragmented is critical for the gamete. In fact, mice with oocytes deficient for mitochondrial fission are infertile (Udagawa et al, 2014), whereas overexpression of fusion genes impairs oocyte viability (Wakai et al, 2014). This effect was explained by accentuated interaction between organelles (i.e., mitochondrion-mitochondrion and mitochondrionendoplasmic reticulum), possibly mediated by the increased levels of either MFN1 or MFN2.…”

“…Moreover, overexpression of MFN2 markedly disintegrated the endoplasmic reticulum network as this organelle was heavily tethered to mitochondria, thus preventing their proper migration through the cytoplasm. As a result, Ca 2+ stores in the endoplasmic reticulum were severely depleted (Wakai et al, 2014).…”

Oocyte mitochondrial function and reproduction

“…The regulation of mitochondrial dynamics is important for oocyte maturation. Overexpression of mitochondrial fusion proteins leads to the formation of mitochondrial aggregates in oocyte cytoplasm and interferes with spindle organization and spatiotemporal endoplasmic reticulum (ER) distribution [24]. Moreover, oocyte-specific knockout of mitochondrial fission factor Drp1 impairs calcium signalling and intercellular communication, and leads to abnormalities in follicle development and ovulation [25].…”