Intrinsic oxidative phosphorylation limitations underlie cellular bioenergetics in leukemia.

Abstract

Currently there is great interest in developing cytotoxic pharmacotherapies that disrupt mitochondrial energy transduction in cancer. Given that mitochondria are critical to mammalian energy homeostasis, clinical success of a given therapeutic will undoubtedly hinge upon its cancer cell selectivity. That said, how the mitochondrial network is intrinsically remodeled to drive/enable the cancer phenotype remains a biological black box, largely due to limitations in analytical approaches. Herein, we leveraged an in-house diagnostic biochemical workflow to comprehensively evaluate mitochondrial bioenergetic efficiency and capacity in human leukemia. Using this platform, we provide direct evidence that despite minimal changes in absolute respiratory kinetics, leukemic mitochondria are hallmarked by intrinsic limitations in oxidative phosphorylation (OXPHOS) that constrain the network’s ability to contribute to cellular ATP free energy (i.e, ΔGATP) charge. Together, these findings link accelerated oxidative metabolism in leukemia to intrinsic OXPHOS deficiency and provide proof-of-concept that restoring, rather than disrupting, OXPHOS across the leukemic mitochondrial network may represent an untapped, but highly feasible, therapeutic avenue.

Pan-tissue mitochondrial phenotyping reveals lower OXPHOS expression and function across tumor types

“…Quantitative determination of respiratory capacity per unit of mitochondrial protein: Having established that mitochondrial proteome composition varies widely across both normal and malignant mouse tissues, we next wanted to investigate changes in respiratory flux. To do this, we made use of a technique that integrates in situ functional readouts of mitochondrial flux with quantitative determination of mitochondrial content using mass-spectrometry, effectively allowing for measurements of both respiratory capacity and OXPHOS kinetics to be interpreted both on a per cell and per mitochondrion basis 25,[36][37][38] . Experiments were performed in permeabilized colorectal cancer (CRC) cells (e.g., CT26.WT) with results being compared to either permeabilized mouse colon or permeabilized heart myofibers (Fig.…”