Molecular and cellular mechanisms underlying the failure of mitochondrial metabolism drugs in cancer clinical trials

The majority of cancer cells have a functional mitochondrial electron transport chain (ETC). Mitochondrial complex I is the primary entry point into the ETC, where oxidative phosphorylation occurs, generating ATP as an energy source for powering the cell. Electrons are transferred through a chain of mitochondrial protein complexes (complex I, II, III, and IV) to the final electron acceptor, molecular oxygen, while protons are pumped by complexes I, III, and IV to create an electrochemical proton gradient, ultimately driving ATP synthesis through complex V. The ETC can function optimally even in hypoxic conditions, allowing solid tumors, which often have limited oxygen availability, to maintain mitochondrial respiration. Mitochondrial ETC function is intrinsically linked to the oxidative tricyclic acid (TCA) cycle, which supports tumor growth by enabling macromolecule biosynthesis (1). Genetic and pharmacologic inhibition of the ETC prevents de novo pyrimidine synthesis and oxidative TCA cycle flux, supporting lipid, heme, aspartate, and asparagine production, all of which act together to decrease primary tumor growth and metastasis (2). Furthermore, mutations in ETC genes are generally selected against across various types of cancer (3). Thus, mitochondrial metabolism is an essential, dynamic process throughout tumorigenesis, with metabolic flexibility serving the tumor's needs at every stage, from initiation to metastasis. Ultimately, the metabolic demand imposed by driver mutations on specific tissue lineages, coupled with nutrient or [...]