Rapamycin partially rescues oocyte dysfunction in mice deficient for mitochondrial stress response protein CLPP

Wang, T.; Babayev, Elnur; Jiang, Zongliang; Zhang, M.; Esencan, Ecem; Seli, Emre

doi:10.1016/j.fertnstert.2018.07.298

Cited by 1 publication

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“…The number of mature oocytes and two-cell embryos in mice is lower, with no blastocysts. These deficiencies in oocyte and embryo development are related to impaired mitochondrial function and dynamics (Wang et al, 2018). Meanwhile, the apoptotic signals in the follicular granulosa cell layer are significantly increased and show accelerated depletion of follicular reserves and hearing loss, consistent with the symptoms of Perrault syndrome (Gispert et al, 2013;Wang et al, 2018).…”

Section: Discussionmentioning

confidence: 78%

“…These deficiencies in oocyte and embryo development are related to impaired mitochondrial function and dynamics (Wang et al, 2018). Meanwhile, the apoptotic signals in the follicular granulosa cell layer are significantly increased and show accelerated depletion of follicular reserves and hearing loss, consistent with the symptoms of Perrault syndrome (Gispert et al, 2013;Wang et al, 2018). Lower proliferation or excessive apoptosis of ovarian granulosa cells may result in a decrease in the number of cell connections or damage to cell connections, which leads to a lack of nutrients and factors necessary for oocyte growth, causing follicular atresia (Nesvizhskii, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…A reduced number of granulosa cell layers and a higher number of apoptotic bodies were observed in Clpp −/− mouse follicles (Gispert et al, 2013). Furthermore, both cellular energy metabolism and mitochondrial dynamics seem to be severely affected in Clpp −/− mouse oocytes (Wang et al, 2018). Folliculogenesis was not affected by the loss of Clpp in granulosa/cumulus cells (Esencan et al, 2020).…”

Section: Introductionmentioning

confidence: 97%

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CLPP inhibition triggers apoptosis in human ovarian granulosa cells via COX5A abnormality–Mediated mitochondrial dysfunction

Yuan

Chen

et al. 2023

Front. Genet.

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Premature ovarian insufficiency (POI) is characterized by early loss of ovarian function before the age of 40 years. It is confirmed to have a strong and indispensable genetic component. Caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) is a key inducer of mitochondrial protein quality control for the clearance of misfolded or damaged proteins, which is necessary to maintain mitochondrial function. Previous findings have shown that the variation in CLPP is closely related to the occurrence of POI, which is consistent with our findings. This study identified a novel CLPP missense variant (c.628G > A) in a woman with POI who presented with secondary amenorrhea, ovarian dysfunction, and primary infertility. The variant was located in exon 5 and resulted in a change from alanine to threonine (p.Ala210Thr). Importantly, Clpp was mainly localized in the cytoplasm of mouse ovarian granulosa cells and oocytes, and was relatively highly expressed in granulosa cells. Moreover, the overexpression of c.628G > A variant in human ovarian granulosa cells decreased the proliferative capacity. Functional experiments revealed that the inhibition of CLPP decreased the content and activity of oxidative respiratory chain complex IV by affecting the degradation of aggregated or misfolded COX5A, leading to the accumulation of reactive oxygen species and reduction of mitochondrial membrane potential, ultimately activating the intrinsic apoptotic pathways. The present study demonstrated that CLPP affected the apoptosis of granulosa cells, which might be one of the mechanisms by which CLPP aberrations led to the development of POI.

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Section: Discussionmentioning

confidence: 78%