Systematic Analysis of the Expression of the Mitochondrial ATP Synthase (Complex V) Subunits in Clear Cell Renal Cell Carcinoma

Abstract

Mitochondrial dysfunction is common in cancer and the mitochondrial electron transport chain is often affected in carcinogenesis. To date, little is known about the expression of the ATP synthase subunits in clear cell renal cell carcinoma (ccRCC). The NextBio database was used to determine an expression profile of the ATP synthase subunits based on published microarray studies. We observed down-regulation of 23 out of 29 subunits of the ATP synthase. Differential expression was validated exemplarily for 12 genes (ATP5A1, ATP5B, ATPAF1, ATP5C1, ATP5D, ATP5O, ATP5F1, ATP5G1, ATP5G2, ATP5G3, ATP5I, ATP5S; screening cohort ccRCC n = 18 and normal renal tissue n = 10) using real-time PCR. Additional eight genes (ATP5A1, ATP5B, ATPAF1, ATP5F1, ATP5G1, ATP5G2, ATP5G3, ATP5S) were internally validated within an enlarged cohort (ccRCC n = 74; normal renal tissue n = 36). Furthermore, down-regulation of ATP5A1, ATPAF1, ATP5G1/G2/G3 was confirmed on the protein level using Western Blot and immunohistochemistry. We observed that altered expression of ATPAF1 and ATP5G1/G2/G3 was correlated with overall survival in patients with ccRCC. In conclusion, down-regulation of many ATP Synthase subunits occurs in ccRCC and is the basis for the reduced activity of the mitochondrial electron chain. Alteration of the expression of ATP5A1, ATPAF1, and ATP5G1/G2/G3 is characteristic for ccRCC and may be prognostic for ccRCC patients' outcome.

Systematic expression analysis of the mitochondrial respiratory chain protein subunits identifies COX5B as a prognostic marker in clear cell renal cell carcinoma

“…In previous studies, we were able to show the dysregulation of specific subunits of the different respiratory chain complexes. Interestingly, a correlation of dysregulation and survival could be shown for some subunits . Taking up this idea, we carried out an extensive in silico analysis based on the TCGA data with a focus on the prognostic relevance.…”

“…In previous studies, it could be demonstrated that various subunits are downregulated in renal cell clear cell carcinoma. In addition, it has already been shown that the dysregulation of specific subunits is associated with a shortened survival . These findings prompted us to carry out a comprehensive expression analysis of the subunits, focusing on the prognostic impact.…”

Proteogenomic view of cancer epigenetics: the impact of DNA methylation on the cancer proteome

“…HMGB3 promotes cell proliferation in colorectal cancer cells through regulation of MYC, where genes from same family have been linked to decreased MYC expression which is unique to proliferative subtypes of ovarian cancer (26). Lastly, ProteoMix also identifies hypo-methylation in two mitochondrial genes ATP5D and SPG7, speculatively linked to cancer through metabolic function (52).…”

Severe Pantothenic Acid Deficiency Induces Alterations in the Intestinal Mucosal Proteome of Starter Pekin Ducks

“…NDUFA5 and NDUFA6 are two subunits of complex I, which play a direct role in complex I assembly [61,62]. ATP5F1, ATP5H, and ATP5PO are three subunits of complex V, which play a direct role in complex V assembly [63][64][65]. The downregulated expression of proteins involved in the oxidative phosphorylation process, including complex I and complex V, likely indicates that mitochondrial oxidative phosphorylation is impaired by PAD.…”