Targeting the respiratory chain: from bioenergetic inhibition to metabolic reprogramming

The respiratory chain has traditionally been viewed as a central bioenergetic system responsible for ATP production through oxidative phosphorylation. However, emerging evidence now supports a broader framework in which respiratory complexes function not merely as energy-generating machinery, but as dynamic regulatory nodes integrating metabolism, redox balance, signaling, and cellular fate decisions. This conceptual shift has transformed the respiratory chain from a classical target of bioenergetic inhibition into a programmable therapeutic system capable of inducing context-dependent biological outcomes. Small molecules targeting the respiratory chain act through multiple mechanistic modes, including inhibition of electron transfer, disruption of proton coupling, modulation of reactive oxygen species, and large-scale metabolic rewiring. Depending on cellular context and degree of respiratory perturbation, these interventions can produce outcomes ranging from acute energetic collapse to adaptive metabolic remodeling and cell-state transitions. Such mechanisms have broad therapeutic relevance across antibacterial, antifungal, antiparasitic, anticancer, and metabolic diseases. Recent advances in cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) have further redefined respiratory-chain druggability by revealing high-resolution architectures of individual complexes, supercomplexes, lipid-mediated interfaces, quinone-binding networks, and transient conformational states. These structural insights expose previously inaccessible regulatory features and provide a framework for state-selective and context-specific therapeutic targeting. In this review, we synthesize current understanding of respiratory-chain pharmacology from mechanistic, structural, and systems-level perspectives. We discuss how classical inhibition paradigms are evolving toward precision bioenergetic modulation, highlight emerging opportunities in targeting dynamic respiratory states and supercomplex organization, and outline future strategies for selective therapeutic intervention across diverse disease contexts.