Human Ovarian Cancer Tissue Exhibits Increase of Mitochondrial Biogenesis and Cristae Remodeling

Abstract

Ovarian cancer (OC) is the most lethal gynecologic cancer characterized by an elevated apoptosis resistance that, potentially, leads to chemo-resistance in the recurrent disease. Mitochondrial oxidative phosphorylation was found altered in OC, and mitochondria were proposed as a target for therapy. Molecular evidence suggests that the deregulation of mitochondrial biogenesis, morphology, dynamics, and apoptosis is involved in carcinogenesis. However, these mitochondrial processes remain to be investigated in OC. Eighteen controls and 16 OC tissues (serous and mucinous) were collected. Enzymatic activities were performed spectrophotometrically, mitochondrial DNA (mtDNA) content was measured by real-time-PCR, protein levels were determined by Western blotting, and mitochondrial number and structure were measured by electron microscopy. Statistical analysis was performed using Student’s t-test, Mann-Whitney U test, and principal component analysis (PCA). We found, in OC, that increased mitochondrial number associated with increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and mitochondrial transcription factor A (TFAM) protein levels, as well as mtDNA content. The OC mitochondria presented an increased maximum length, as well as reduced cristae width and junction diameter, associated with increased optic atrophy 1 protein (OPA1) and prohibitin 2 (PHB2) protein levels. In addition, in OC tissues, augmented cAMP and sirtuin 3 (SIRT3) protein levels were observed. PCA of the 25 analyzed biochemical parameters classified OC patients in a distinct group from controls. We highlight a “mitochondrial signature” in OC that could result from cooperation of the cAMP pathway with the SIRT3, OPA1, and PHB2 proteins.

Development of a novel transcription factors-related prognostic signature for serous ovarian cancer

“…Mainly expressed in plasma cells, IRF4 was reported to be associated with tumor stage, histological grade, and completeness of chemotherapy 44 . Multiple evidence has shown that TEAD1 and TFAM are oncogenes in OC, which is concordant with our results 45 , 46 . The role of ZNF124 in OC is little known, but it was found to inhibit apoptotic death and function as an oncogene in hematopoietic cells 47 .…”

Development of a novel transcription factors-related prognostic signature for serous ovarian cancer

“…Mainly expressed in plasma cells, IRF4 was reported to be associated with tumor stage, histological grade, and completeness of chemotherapy [55]. Multiply evidence has shown that TEAD1 and TFAM are oncogenes in OC, which is concordant with our results [56,57]. The role of ZNF124 in OC is little known, but it was found to inhibit apoptotic death and function as an oncogene in hematopoietic cells [58].…”

Potential relationship between Sirt3 and autophagy in ovarian cancer (Review)

“…These findings suggested that overexpression of Sirt3 can induce OC cell death. In terms of mitochondrial dynamics, a previous study revealed that stabilization of Sirt3 can increase mitochondrial biogenesis and cristae remodeling in OC tissues (38). Additionally, stabilization of optic atrophy protein 1, which increased resistance to apoptosis, was demonstrated to be regulated by increasing the expression of Sirt3 and prohibitin 2 (38).…”

“…In terms of mitochondrial dynamics, a previous study revealed that stabilization of Sirt3 can increase mitochondrial biogenesis and cristae remodeling in OC tissues (38). Additionally, stabilization of optic atrophy protein 1, which increased resistance to apoptosis, was demonstrated to be regulated by increasing the expression of Sirt3 and prohibitin 2 (38). Activation of Sirt3 has also been found to enhance the sensitivity of OC cells to cisplatin (39), rendering Sirt3 to be a novel therapeutic target.…”