Mitochondrial TSPO Deficiency Triggers Retrograde Signaling in MA-10 Mouse Tumor Leydig Cells.

The mitochondrial translocator protein (TSPO) has been shown to bind cholesterol with high affinity and is involved in mediating its availability for steroidogenesis. We recently reported that targeted Tspo gene deletion in MA-10 mouse tumor Leydig cells resulted in reduced cAMP-stimulated steroid formation and significant reduction in the mitochondrial membrane potential (ΔΨm) compared to control cells. We hypothesized that ΔΨm reduction in the absence of TSPO probably reflects the dysregulation and/or maintenance failure of some basic mitochondrial function(s). To explore the consequences of TSPO depletion via CRISPR-Cas9-mediated deletion (indel) mutation in MA-10 cells, we assessed the transcriptome changes in TSPO-mutant versus wild-type (Wt) cells using RNA-seq. Gene expression profiles were validated using real-time PCR. We report herein that there are significant changes in nuclear gene expression in Tspo mutant versus Wt cells. The identified transcriptome changes were mapped to several signaling pathways including the regulation of membrane potential, calcium signaling, extracellular matrix, and phagocytosis. This is a retrograde signaling pathway from the mitochondria to the nucleus and is probably the result of changes in expression of several transcription factors, including key members of the NF-κB pathway. In conclusion, TSPO regulates nuclear gene expression through intracellular signaling. This is the first evidence of a compensatory response to the loss of TSPO with transcriptome changes at the cellular level.

Mouse ovarian tumors--a review including classification and induction of neoplastic lesions and description of several previously unreported types.

The purpose of this study is to review the pertinent literature on the incidence, methods of induction and pathogenesis of ovarian tumors of mice. Strains of mice with a high incidence of spontaneously occurring granulosa cell tumors (gct) and tubular adenomas (ta) are the C3HeB/Fe and C3HeB/De; strain HAN:NMRI developed Sertoli cell tumors and (DBA x Ce)F1 hybrids had a high incidence gct. Ninety-five percent of hybrid (C57BL/6J x C3H/HeJ)F1 WxWv mice which lack germ cells develop complex tubular adenomas. Strain LT, in which a high percentage of ovarian ova develop parthenogenetically, develops has a high incidence of teratomas. The use of hormones, castration and transplantation of the ovaries in a number of inbred strains results in a high incidence of ovarian tumors; in strain Maf/Sp gct and luteomas were induced in 82%. Irradiation with gamma rays produced a similar incidence of ovarian tumors in (C57L x A)F1 hybrids. The chemical inducing the highest incidence (92%) of ovarian tumors of mice is 9,10 Dimethyl 1,2 benzanthracene (DMBA). Recently, 4-Vinylcyclohexene was shown to induce a high incidence of ovarian tumors. A number of rare ovarian tumors were reported. Described are five androblastomas composed of either Leydig or Sertoli cells or a combination of the two cell types and a single undifferentiated androblastoma. Seven teratomas were described, three of which contained large amounts of neural tissue; another was classified as a teratoma with a parieto-visceral yolk-sac carcinoma component.