Tissue‐specific expression and post‐transcriptional regulation of the ATPase inhibitory factor 1 (IF1) in human and mouse tissues

Abstract

The ATPase inhibitory factor 1 (IF1) is an intrinsically disordered protein that regulates the activity of the mitochondrial ATP synthase. Phosphorylation of S39 in IF1 prevents it from binding to the enzyme and thus abolishes its inhibitory activity. Dysregulation of IF1 is linked to different human diseases, providing a relevant biomarker of cancer progression. However, the tissue content of IF1 relative to the abundance of the ATP synthase is unknown. In this study, we characterized the tissue-specific expression of IF1 in human and mouse tissues and quantitated the content of IF1 and of ATP synthase. We found relevant differences in IF1 expression between human and mouse tissues and found that in high-energy-demanding tissues, the molar content of IF1 exceeds that of the ATP synthase. In these tissues, a fraction of IF1 is bound to the enzyme, and the other fraction is phosphorylated and hence is unable to bind the enzyme. Post-transcriptional control accounts for most of the regulated expression of IF1, especially in mouse heart, where IF1 mRNA translation is repressed by the leucine-rich pentatricopeptide repeat containing protein. Overall, these findings enlighten the cellular biology of IF1 and pave the way to development of additional models that address its role in pathophysiology.-Esparza-Moltó, P. B., Nuevo-Tapioles, C., Chamorro, M., Nájera, L., Torresano, L., Santacatterina, F., Cuezva, J. M. Tissue-specific expression and post-transcriptional regulation of the ATPase inhibitory factor 1 (IF1) in human and mouse tissues.

Overexpression of Mitochondrial IF1 Prevents Metastatic Disease of Colorectal Cancer by Enhancing Anoikis and Tumor Infiltration of NK Cells

“…In contrast, the overexpression of IF1 in colon (this study) and breast carcinomas [13,24] is a biomarker of good prognosis. However, at variance with liver and stomach, colon and breast are tissues with low expression of IF1 under normal physiological conditions (this study and [13,24]), suggesting that IF1, in addition to its structural [14] and inhibitory functions on the ATP synthase [19], has additional tissue-specific functional roles [15,31].…”

“…In this regard, we suggest that the large differences observed in the tissue-specific expression of IF1 might underlie this behavior [15]. For instance, in the case of liver and stomach, IF1 expression is highly abundant in the normal tissue [13,15] and its overexpression in oncogenesis predicts bad patient prognosis [20,22]. In contrast, the overexpression of IF1 in colon (this study) and breast carcinomas [13,24] is a biomarker of good prognosis.…”

“…We should stress the dissimilar behavior reported for IF1 as biomarker in cancer prognosis [31]. In this regard, we suggest that the large differences observed in the tissue-specific expression of IF1 might underlie this behavior [15]. For instance, in the case of liver and stomach, IF1 expression is highly abundant in the normal tissue [13,15] and its overexpression in oncogenesis predicts bad patient prognosis [20,22].…”

“…Since the high expression of IF1 observed in CRC is unrelated to changes in the cellular availability of IF1 mRNA [13], we suggest that its accumulation in carcinomas should result from oncogenic transformation of the mechanisms that regulate IF1 mRNA translation and/or the stability of the protein. Evidence for the operation of both mechanisms of posttranscriptional regulation of IF1 expression has already been provided [6,15], thus emphasizing their potential contribution in the pathophysiology linked to IF1 expression.…”

“…The ATPase Inhibitor Factor 1 (IF1) is a physiological inhibitor [11][12][13] and structural organizer [14] of the mitochondrial ATP synthase in tissues where it is normally expressed [15], as recently stressed in vivo [16][17][18]. IF1 is expressed at low levels in normal human colon, lung and breast tissues [15] but is highly overexpressed in the carcinomas arising in these tissues [13].…”