The discovery of a regulatory role of prohibitin-1 in testosterone production and the intracellular cholesterol pool in basal steroidogenesis
| dc.contributor.author | Geetika, . | |
| dc.contributor.examiningcommittee | Dodd, Janice (Physiology and Pathophysiology) | en_US |
| dc.contributor.examiningcommittee | Mizuno, Tooru (Physiology and Pathophysiology) | en_US |
| dc.contributor.examiningcommittee | Chelikani, Prashen (Oral Biology) | en_US |
| dc.contributor.examiningcommittee | Kolonin, Mikhail (University of Texas Health Science Center at Houston) | en_US |
| dc.contributor.supervisor | Mishra, Suresh | |
| dc.date.accessioned | 2022-08-04T16:35:06Z | |
| dc.date.available | 2022-08-04T16:35:06Z | |
| dc.date.copyright | 2022-08-03 | |
| dc.date.issued | 2022-07-28 | |
| dc.date.submitted | 2022-08-03T17:30:39Z | en_US |
| dc.degree.discipline | Physiology and Pathophysiology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | The fundamental framework of steroidogenesis across steroidogenic cells is similar, especially the initial mitochondrial steps involving cholesterol translocation across outer mitochondrial membrane (OMM) by the START domain containing proteins (e.g., StAR) and subsequent conversion to pregnenolone by the enzyme P450scc in the inner mitochondrial membrane (IMM). Thus, cholesterol and mitochondria are essential and highly interconnected in steroidogenesis. However, our understanding of this conserved process in steroidogenesis remains limited. Particularly, the transport of cholesterol from the OMM to the IMM. Moreover, growing evidence suggest an important role of autophagy/lipophagy and mitochondrial dynamics in regulating steroidogenic cholesterol homeostasis. However, a potential role the intracellular cholesterol pool in itself in the regulation steroidogenic events remains unexplored. I investigated an unexpected testicular phenotype of two transgenic mouse models and found that the male transgenic mice that expressed a mutant form of a mitochondrial protein prohibitin-1 (PHB1Tyr114Phe) from the Fabp-4 gene promoter displayed smaller testes, higher testosterone levels and lower gonadotropin levels as compared with age matched PHB-1 overexpressing and wild-type mice. Additionally, I found StAR and P450scc as interacting partners of PHB1 in Leydig cell mitochondria. Further analysis of testis and Leydig cells from the transgenic mice revealed that PHB1 plays a regulatory role in coordinating cell signaling, cholesterol homeostasis, and mitochondrial biology pertaining to steroidogenesis. Moreover, I tested the hypothesis that intracellular cholesterol pool in steroidogenic cells plays a role in regulating cell-intrinsic factors and events pertaining steroidogenesis. I found that the depletion of intracellular cholesterol pool in steroidogenic cells (i.e., MA-10, Y-1 and BeWo cells) induces autophagy, affects mitochondrial dynamics, and upregulates steroidogenic factors and basal steroidogenesis. Interestingly, cholesterol depletion-induced changes in steroidogenic cells were found to occur independent of hormone stimulation suggesting a role of cholesterol in basal steroidogenesis. In conclusion, my findings provide novel insights into the role of PHB1 in coordinating steroidogenesis in Leydig cell and a role of the intracellular cholesterol pool in basal steroidogenesis. The implications of my findings are broad as cholesterol is the common substrate for all steroid hormones and the initial stages of steroidogenesis are indistinguishable across steroidogenic cells. | en_US |
| dc.description.note | October 2022 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/36664 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Steroidogenesis | en_US |
| dc.subject | Leydig cell | en_US |
| dc.subject | Mitochondria | en_US |
| dc.subject | Cholesterol | en_US |
| dc.title | The discovery of a regulatory role of prohibitin-1 in testosterone production and the intracellular cholesterol pool in basal steroidogenesis | en_US |
| dc.type | doctoral thesis | en_US |
| local.subject.manitoba | no | en_US |