Abstract
Mitochondrial redox metabolism is the central component in the cellular metabolic landscape, where anabolic and catabolic pathways are reprogrammed to maintain optimum redox homeostasis. During different stages of cancer, the mitochondrial redox status plays an active role in navigating cancer cells’ progression and regulating metabolic adaptation according to the constraints of each stage. Mitochondrial reactive oxygen species (ROS) accumulation induces malignant transformation. Once vigorous cell proliferation renders the core of the solid tumor hypoxic, the mitochondrial electron transport chain mediates ROS signaling for bringing about cellular adaptation to hypoxia. Highly aggressive cells are selected in this process, which are capable of progressing through the enhanced oxidative stress encountered during different stages of metastasis for distant colonization. Mitochondrial oxidative metabolism is suppressed to lower ROS generation, and the overall cellular metabolism is reprogrammed to maintain the optimum NADPH level in the mitochondria required for redox homeostasis. After reaching the distant organ, the intrinsic metabolic limitations of that organ dictate the success of colonization and flexibility of the mitochondrial metabolism of cancer cells plays a pivotal role in their adaptation to the new environment.
Highlights
The dynamics of reactive oxygen species (ROS) during cancer progression are reciprocated in the level of TIGAR (TP53-induced glycolysis and apoptosis regulator), which is the P53-induced modulator for cellular adaptation to oxidative stress-increasing NADPH production and heightening the antioxidant defense
This review focuses on the various aspects of mitochondrial redox metabolism and ROS generation during different stages of tumor development and metastasis, with an emphasis on how it plays a central role in reprogramming cellular metabolism for efficient transition and adaptation in each stage
NADPH is primarily generated in mitochondria via mitochondrial inner membrane enzyme nicotinamide nucleotide transhydrogenase (NNT), which catalyzes the transfer of a hydride from NADH to NADP+, producing NADPH and NAD+, coupled to the translocation of one proton across the membrane (Figure 1) [22]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The dynamics of oxidative stress navigates the cancer cell throughout its progression in different stages- where higher reactive oxygen species (ROS) favor malignant transformation, decrease during tumor formation to the optimum level required for maintaining cellular redox homeostasis. It again increases during hypoxia and selects for aggressive metastatic cells. Antioxidants 2021, 10, 1838 metabolism resides at the epicenter of this process and orchestrates different aspects of cellular metabolism for adaptation and, in association with generating ROS signaling actively, drives cancer cells’ progression through tumor development, metastasis and colonization in distant organs [10,11]. This review focuses on the various aspects of mitochondrial redox metabolism and ROS generation during different stages of tumor development and metastasis, with an emphasis on how it plays a central role in reprogramming cellular metabolism for efficient transition and adaptation in each stage
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