Insulin/IGF1 signaling regulates the mitochondrial biogenesis markers in steroidogenic cells of prepubertal testis, but not ovary†

Abstract

Controlled changes in mitochondrial biogenesis and morphology are required for cell survival and homeostasis, but the molecular mechanisms are largely unknown. Here, male and female prepubertal mice (P21) with insulin and IGF1 receptors deletions in steroidogenic tissues (Insr/Igf1r-DKO) were used to investigate transcription of the key regulators of mitochondrial biogenesis (Ppargc1a, Ppargc1b, Pparg, Nrf1, Tfam) and architecture (Opa1, Mfn1, Mfn2) in Leydig cells, ovaries and adrenals. Results showed that the expression of PGC1, a master regulator of mitochondrial biogenesis and integrator of environmental signals, and its downstream target Tfam, significantly decreased in androgen-producing Leydig cells. This is followed by reduction of Mtnd1, an mtDNA encoded transcript whose core subunit belongs to the minimal assembly required for catalysis. The same markers remained unchanged in ovaries. In contrast, in adrenals, the pattern of transcripts for mitochondrial biogenesis markers was the same in both sexes, but opposite from that observed in Leydig cells. The level of transcripts for markers of mitochondrial architecture (Mfn1, Mfn2) significantly increased in Leydig cells from Insr/Igf1r-DKO, but not in ovaries. This was followed by mitochondrial morphology disturbance, suggesting that the mitochondrial phase of steroidogenesis could be affected. Indeed, basal and pregnenolone stimulated progesterone productions in the mitochondria of Leydig cells from Insr/Igf1r-DKO decreased more than androgen production, and were barely detectable. Our results are the first to show that INSR and IGF1R are important for mitochondrial biogenesis in gonadal steroidogenic cells of prepubertal males, but not females and they serve as important regulators of mitochondrial architecture and biogenesis markers in Leydig cells.

Growth Hormone Receptor Gene is Essential for Chicken Mitochondrial Function In Vivo and In Vitro

“…The results of this study showed that knockdown of GHR and the accompanying low expression of IGF1 could reduce the number of mitochondria and alter the structure of mitochondria, as observed in DF-1 cells as increased mitochondrial vacuolation, an absence of dense matrix granules and the disappearance of mitochondria cristae. Our results are in agreement with a previous study showing that a change in IGF1 signaling could alter the morphology and structure of mitochondria in mice Leydig cells [10].…”

“…Knockout of GHR (GHRKO) in mice could also alter the expression of key regulators of mitochondrial biogenesis [8,9]. Furthermore, previous studies have reported that insulin-like growth factor 1 (IGF1) signaling can regulate mitochondrial biogenesis markers in the steroidogenic cells of prepubertal testis [10], and is essential for mitochondrial biogenesis in cancer cells [11]. These findings suggest that the GHR gene plays a pivotal role in mammalian mitochondrial function both in vivo and in vitro.…”

Reduced spermatozoa functionality during stress is the consequence of adrenergic-mediated disturbance of mitochondrial dynamics markers

“…Most of the methods used in the present study were previously reported by our group in more detail (for all references please see 16,17,64 as well as in Supplemental Material and Methods, and are outlined briefly here.…”

Testicular STAC3 regulates Leydig cell steroidogenesis through potentiating mitochondrial membrane potential and StAR processing

“…Testicular steroidogenesis is under a delicate control of a cohort of signals from mitochondria. The changes in the intratesticular environment have been observed to influence the mitochondrial homeostasis and dynamics in testicular steroidogenesis (Bjelic, et al, 2015;Radovic, et al, 2019;Shen, et al, 2016;Strauss, et al, 2009). Nevertheless, the key factors responsible for the modulation of mitochondrial homeostasis in activated LCs remain largely unexplored.…”