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

Abstract

Mitochondrial function, largely regulated by the dynamics of this organelle, is inextricably linked to the oocyte health. In comparison with most somatic cells, mitochondria in oocytes are smaller and rounder in appearance, suggesting limited fusion. The functional implications of this distinct morphology, and how changes in the mitochondrial shape translate to mitochondrial function in oogenesis is little understood. We, therefore, asked whether the pro‐fusion proteins mitofusins 1 (MFN1) and 2 (MFN2) are required for the oocyte development. Here we show that oocyte‐specific deletion of Mfn1, but not Mfn2, prevents the oocyte growth and ovulation due to a block in folliculogenesis. We pinpoint the loss of oocyte growth and ovulation to impaired PI3K‐Akt signaling and disrupted oocyte‐somatic cell communication. In support, the double loss of Mfn1 and Mfn2 partially rescues the impaired PI3K‐Akt signaling and defects in oocyte development secondary to the single loss of Mfn1. Together, this work demonstrates that the mitochondrial function influences the cellular signaling during the oocyte development, and highlights the importance of distinct, nonredundant roles of MFN1 and MFN2 in oogenesis.

Melatonin improves the quality of maternally aged oocytes by maintaining intercellular communication and antioxidant metabolite supply

“…An improved mitochondria function, in turn, act on melatonin synthetic enzymes, regulating melatonin biosynthesis and free radical scavenger, thus completing a feedback regulatory loop [ 25 ]. Our observations are perfectly aligned with these studies demonstrating the requirement of the restoration of mitochondrial dysfunction for melatonin-mediated enhancement of oocyte quality and the developmental competence [ 42 ]. The loss of oocyte the developmental competence is not only considered to be associated with the germ cells but also the defective granulosa cells in aged individuals [ [43] , [44] , [45] , [46] ].…”

“…The gap junction coupling architecture provides a functional channel for metabolites and ensures that the oocyte developmental needs are met [ 16 ]. The loss of this coupling with the granulosa cells has severe consequences for ATP production, meiotic progression, and oocyte developmental competence [ 39 , 42 , 48 ]. Here, we found that melatonin supplementation promotes ATP production in aged mice.…”

Mitochondrial Dynamics in the Drosophila Ovary Regulates Germ Stem Cell Number, Cell Fate, and Female Fertility

“…Therefore, incorrect egg morphology indicates that egg chambers and oocyte did not develop as normal. Consistently, mitochondria morphology was also found to be important for proper oocyte development in mice, highlighting the critical role of mitochondria in oogenesis (Udagawa et al, 2014;Liu et al, 2016;Carvalho et al, 2020). Strikingly, decreasing the levels of OxPhos/TCA cycle enzymes in germ cells does not cause the same defects in late egg chamber development, nor in nurse cell morphology.…”

The Role of Mitochondria in Human Fertility and Early Embryo Development: What Can We Learn for Clinical Application of Assessing and Improving Mitochondrial DNA?

“…Mice models demonstrated that targeted deletion of either Mfn1 or Mfn2 leads to phenotype consistent with female reproductive aging (e.g., apoptotic cell loss resulting in accelerated follicular depletion). The absence of Mfn1 additionally caused the interruption of oocyte growth and ovulation due to a block in folliculogenesis, whereas Mfn2-lacking oocytes revealed shortened telomeres [ 12 , 13 , 14 ]. On the other hand, cells lacking Opa1 do undergo outer membrane fusion, however cannot progress to inner membrane fusion.…”