Role of NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex 4-Like 2 in Clear Cell Renal Cell Carcinoma

Abstract

Purpose We delineated the functions of the HIF1α target NADH Dehydrogenase (Ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) in ccRCC and characterized NDUFA4L2 as a novel molecular target for ccRCC treatment. Experimental Design We evaluated normal kidney and ccRCC patient microarray and RNAseq data from Oncomine and The Cancer Genome Atlas (TCGA) for NDUFA4L2 mRNA levels and the clinical implications of high NDUFA4L2 expression. Additionally, we examined normal kidney and ccRCC patient tissue samples, human ccRCC cell lines, and murine models of ccRCC for NDUFA4L2 mRNA and protein expression. Utilizing shRNA, we performed NDUFA4L2 knockdown experiments and analyzed the proliferation, clonogenicity, metabolite levels, cell structure, and autophagy in ccRCC cell lines in culture. Results We found that NDUFA4L2 mRNA and protein are highly expressed in ccRCC samples but undetectable in normal kidney tissue samples, and that NDUFA4L2 mRNA expression correlates with tumor stage and lower overall survival. Additionally, we demonstrated that NDUFA4L2 is a HIF1α target in ccRCC and that NDUFA4L2 knockdown has a profound anti-proliferative effect, alters metabolic pathways, and causes major stress in cultured RCC cells. Conclusions Collectively, our data show that NDUFA4L2 is a novel molecular target for ccRCC treatment.

Tissue‐ and Condition‐Specific Isoforms of Mammalian Cytochrome c Oxidase Subunits: From Function to Human Disease

“…NDUFA4L2 expression has been shown to be highly induced in clear-cell renal cell carcinoma, whereas normal kidney shows no significant expression [169]. In addition, expression levels were positively correlated with stage, with increasing expression in later-stage renal cancer.…”

Systematic Expression Analysis of Mitochondrial Complex I Identifies NDUFS1 as a Biomarker in Clear-Cell Renal-Cell Carcinoma

“…Some subunits of the electron transport chain have been linked to RCC before: NDUFA4 expression is decreased in ccRCC and may predict unfavorable outcome following nephrectomy. 9 In contrast, NDUFA4L2, a paralogue of NDUFA4, is upregulated in RCC 10,11 and altered gene expression is associated with a poor prognosis. 11 The aim of this study was to develop a better understanding of the expression of the mitochondrial complex I subunits and to determine whether some subunits may have the potential to be used as a new biomarker.…”

“…9 In contrast, NDUFA4L2, a paralogue of NDUFA4, is upregulated in RCC 10,11 and altered gene expression is associated with a poor prognosis. 11 The aim of this study was to develop a better understanding of the expression of the mitochondrial complex I subunits and to determine whether some subunits may have the potential to be used as a new biomarker. Therefore, we reviewed microarray gene expression studies to explore the expression profile of the complex I subunits.…”

MISTR: A conserved MItochondrial STress Response network revealed by signatures of evolutionary conflict

“…In addition, miR-147b functions were recently associated with the TCA cycle (Zhang et al, 2019), but the observation that miR-147b was encoded by the same gene as a MISTR1 paralog had not been reported (Bertero et al, 2012)(Figure 4). Likewise, the overexpression of endogenous MISTRH correlating with loss of MISTR1 protein (Figure 5H) has been observed in c lear c ell R enal C ell C arcinoma (ccRCC) tumor samples and ccRCC cell lines (Minton et al, 2016); a disease characterized by hyperactive HIF signaling (Brugarolas, 2014), but the requirement of HIF in the regulation of this newly proposed circuit had not been tested (Figure 5H).…”