Mitochondria at the crossroads: drug selectivity challenges, organelle vulnerabilities, and emerging strategies for restoring rather than destroying metabolic pathways

Mitochondria stand at the centre of redox balance, metabolism, and cellular defense, yet their bacterial ancestry makes them vulnerable to therapeutic interventions that were never meant to reach them. Antioxidants, antibiotics, antifungals, antiparasitic agents, and metabolic modulators designed to inhibit pathogens, modulate oxidative stress, or repair mitochondrial dysfunction may inadvertently affect host redox signaling, damage beneficial microbiota, or impair organelles of shared origin such as plastids or peroxisomes. This review explores how structural homology among proteins (i.e. FAD/NAD(P)H-dependent dehydrogenases, mitochondrial carriers, acyl-CoA/carnitine transferases) playing crucial roles in mitochondrial function, might complicate selective drug design. Historical and emerging examples of drugs that exploit or disrupt redox networks are analysed. Computational strategies, ranging from drug repurposing to structure-based screening and fold recognition, that can improve target selectivity, are also briefly presented. It is also examined the known biological cases of intracellular bacteria (Midichloria mitochondrii) or viruses (notably SARS-CoV-2 and flaviviruses) for their ability to invade/interact with mitochondria, blurring the line between host and pathogen metabolism. In addition, new paradigms in “rescue pharmacology”, are explored, where drugs aim to restore rather than inhibit mitochondrial functions, with potential implications for aging and longevity research. Recognizing mitochondria as both targets and victims of therapeutic intervention calls for an integrated view of evolution, metabolism, and drug selectivity in the age of mitochondrial medicine.