Knowing the mitochondrial content and cell membrane P-glycoprotein (MDR1) pump expression does not explain the molecular basis of 99mTc-sestamibi uptake in renal masses

Abstract

Background: 99mTc-sestamibi uptake in renal masses was hypothetically related to the interplay between the mitochondrial content and cell membrane P-glycoprotein (MDR1) pump expression. A subtractive normalization of mitochondrial content model was proposed to predict how tumors will appear on 99mTc-sestamibi scintigraphy. We aimed to test this model and demonstrate the 99mTc-sestamibi uptake pattern in different renal pathologies. Methods: A preoperative 99mTc-sestamibi SPECT/CT scintigraphy was performed to 86 renal masses. On pathological examination cell membrane P-glycoprotein (MDR1) pump expression and mitochondrial content were determined. Mitochondrial staining scores were normalized by subtracting cell membrane P-glycoprotein (MDR1) immunostaining records from the noted mitochondrial staining scores. The subtractive normalization values ranged between -3/+3, with +3 indicating strong mitochondrial content and no cell membrane P-glycoprotein (MDR1) pump expression and -3 indicating the opposite. These values were analyzed in the light of 99mTc-sestamibi uptake. Results: The majority of benign lesions (11/15) showed a subtractive normalization value of +2/+3, while the rest had 0/+1 value. The majority of malignant lesions (60/71) had value between -1/+1. 11 clear cell RCC cases showed a + 2/+3 value. 99mTc-sestamibi uptake correlated negligibly with subtractive normalization of mitochondrial content (Spearman correlation of 0.279, p = 0.009). This correlation was not able to explain either the positive 99mTc-sestamibi uptake in tumors with zero subtractive normalization value like chromophobe RCC lesions or the negative 99mTc-sestamibi uptake in tumors with positive subtractive normalization value like angiomyolipomas or oncocytic papillary RCC. Conclusions: The hypothesized interplay between mitochondrial content and cell membrane P-glycoprotein (MDR1) pump may not be enough to explain the molecular basis of 99mTc-sestamibi uptake by renal masses. Mitochondrial P-glycoprotein, cell membrane MRP transporters and the functionality of multidrug resistance transporters should be in the scope of future research regarding the kinetics of 99mTc-sestamibi in different pathologies. © 2025 Elsevier B.V., All rights reserved.