Immunolocalization of beclin 1, a bcl-2-binding, autophagy-related protein, in the human ovary: possible relation to life span of corpus luteum

Abstract

Ovarian tissue homeostasis is maintained by highly regulated cyclic phases of cell proliferation/differentiation and programmed cell death. Compelling evidence indicates that both apoptotic and autophagic types of programmed cell death are involved in the regression of the corpus luteum (CL) in primate species. Beclin 1 is an autophagy-related protein that is involved in the inter-relationships between apoptosis and autophagy, through interaction with the anti-apoptotic protein bcl-2. We studied the presence and expression pattern of beclin 1 in the adult human ovary. In ovarian follicles, beclin 1 immunostaining was found in the theca layer, whereas granulosa cells were negative. After ovulation, beclin 1 immunostaining was present in both theca-lutein and granulosa-lutein areas. The expression of beclin 1 in granulosa-lutein cells was related to the functional and structural status of the CL, being strong at the early and mid luteal phases, barely detectable at the late luteal phase, and absent in granulosa-lutein cells in subsequent cycles. Our results indicated that beclin 1 expression was related to luteal cell survival rather than to cell death. Accordingly, persistent beclin 1 expression was found in granulosa-lutein cells under either physiological (i.e., CL of pregnancy) or pathological (irregularly regressing CL in climacteric women) conditions involving prolonged CL life span. Strong beclin 1 immunostaining was also found in ovarian androgen-producing cells (i.e., secondary interstitial and hilus cells). Our data thus suggest that beclin 1 plays important roles in the regulation of the life span of human CL and ovarian androgen-secreting cells, by maintaining autophagy at levels promoting cell survival rather than cell death.

Autophagy is a cell survival program for female germ cells in the murine ovary

“…In vitro analyses of murine prepubertal oocytes showed that both apoptotic and autophagic processes were involved in the cell death of the oocytes (Lobascio et al 2007, Escobar et al 2008a, 2008b. The importance of autophagy in follicular atresia has been demonstrated across multiple species including Drosophila, teleostei, caecilians, stingray, dove, quail, sheep, rats, and humans (Rosales--Torres et al 2000, Velentzas et al 2007, Gaytan et al 2008, Santos et al 2008, Zarnescu 2004.…”

Leptin-deficient (ob/ob) mouse ovaries show fatty degeneration, enhanced apoptosis and decreased expression of steroidogenic acute regulatory enzyme

“…Notably, autophagy is suggested to promote cell survival rather than cell death in the corpus luteum life span. 34,35 It is conceivable that survival autophagy occurs in addition to apoptosis in regressing ovary follicles. This suggestion is supported by findings of autophagosomes in freshly harvested human granulosa cells.…”

Autophagy in the endocrine glands

“…At the molecular level, there is a specific endocrine voltage-activated sodium channel in the human ovary from which downstream signalling induces autophagy in CL regression (Bulling et al 2000). Conversely, there is increased beclin-1 expression in CL cells during pregnancy as well as in pathological conditions when the CL survives longer than normal, implicating autophagy in granulosa cell survival as well (Gaytán et al 2008). True to the double-edged reputation of autophagy, these findings suggest opposing roles for autophagy in CL dynamics.…”