Pendleton 2023 Front Cell Dev Biol

Pendleton KE, Wang K, Echeverria GV (2023) Rewiring of mitochondrial metabolism in therapy-resistant cancers: permanent and plastic adaptations. Front Cell Dev Biol 11:1254313. https://doi.org/10.3389/fcell.2023.1254313

» PMID: 37779896 Open Access

Pendleton KE, Wang K, Echeverria GV (2023) Front Cell Dev Biol

Abstract: Deregulation of tumor cell metabolism is widely recognized as a "hallmark of cancer." Many of the selective pressures encountered by tumor cells, such as exposure to anticancer therapies, navigation of the metastatic cascade, and communication with the tumor microenvironment, can elicit further rewiring of tumor cell metabolism. Furthermore, phenotypic plasticity has been recently appreciated as an emerging "hallmark of cancer." Mitochondria are dynamic organelles and central hubs of metabolism whose roles in cancers have been a major focus of numerous studies. Importantly, therapeutic approaches targeting mitochondria are being developed. Interestingly, both plastic (i.e., reversible) and permanent (i.e., stable) metabolic adaptations have been observed following exposure to anticancer therapeutics. Understanding the plastic or permanent nature of these mechanisms is of crucial importance for devising the initiation, duration, and sequential nature of metabolism-targeting therapies. In this review, we compare permanent and plastic mitochondrial mechanisms driving therapy resistance. We also discuss experimental models of therapy-induced metabolic adaptation, therapeutic implications for targeting permanent and plastic metabolic states, and clinical implications of metabolic adaptations. While the plasticity of metabolic adaptations can make effective therapeutic treatment challenging, understanding the mechanisms behind these plastic phenotypes may lead to promising clinical interventions that will ultimately lead to better overall care for cancer patients.

• Bioblast editor: Gnaiger E

Correction: FADH₂ and Complex II

FADH₂ is shown as the substrate feeding electrons into Complex II (CII). This is wrong and requires correction - for details see Gnaiger (2024).

Gnaiger E (2024) Complex II ambiguities ― FADH₂ in the electron transfer system. J Biol Chem 300:105470. https://doi.org/10.1016/j.jbc.2023.105470 - »Bioblast link«

Hydrogen ion ambiguities in the electron transfer system

Communicated by Gnaiger E (2023-10-08) last update 2023-11-10

Electron (e^-) transfer linked to hydrogen ion (hydron; H⁺) transfer is a fundamental concept in the field of bioenergetics, critical for understanding redox-coupled energy transformations.

However, the current literature contains inconsistencies regarding H⁺ formation on the negative side of bioenergetic membranes, such as the matrix side of the mitochondrial inner membrane, when NADH is oxidized during oxidative phosphorylation (OXPHOS). Ambiguities arise when examining the oxidation of NADH by respiratory Complex I or succinate by Complex II.

Oxidation of NADH or succinate involves a two-electron transfer of 2{H⁺+e^-} to FMN or FAD, respectively. Figures indicating a single electron e^- transferred from NADH or succinate lack accuracy.

The oxidized NAD⁺ is distinguished from NAD indicating nicotinamide adenine dinucleotide independent of oxidation state.

NADH + H⁺ → NAD⁺ +2{H⁺+e^-} is the oxidation half-reaction in this H⁺-linked electron transfer represented as 2{H⁺+e^-} (Gnaiger 2023). Putative H⁺ formation shown as NADH → NAD⁺ + H⁺ conflicts with chemiosmotic coupling stoichiometries between H⁺ translocation across the coupling membrane and electron transfer to oxygen. Ensuring clarity in this complex field is imperative to tackle the apparent ambiguity crisis and prevent confusion, particularly in light of the increasing number of interdisciplinary publications on bioenergetics concerning diagnostic and clinical applications of OXPHOS analysis.

Labels: Pathology: Cancer