Does platinum bind sulfhydryl groups and disrupt mitochondrial detoxification enzymes?

Platinum-based compounds, such as cisplatin, are highly effective therapeutic agents whose clinical utility is often limited by severe organ-system toxicities, particularly nephrotoxicity. This damage is fundamentally driven by the chemical affinity of platinum for cellular sulfur donors and mitochondrial targets.

Biochemical mechanisms of platinum-thiol binding

• High-affinity thiol binding: Platinum(II) complexes preferentially and irreversibly bind to sulfhydryl (-SH) groups on both cellular proteins and low-molecular-weight thiols like glutathione (GSH), diverting the drug away from nuclear DNA to cellular proteins.
• Mitochondrial bioactivation: In vulnerable tissues like the kidneys, cisplatin forms cysteine S-conjugates that are metabolized by mitochondrial cysteine-S-conjugate β-lyase into highly reactive platinum-thiol species, which selectively accumulate within the mitochondria.

Enzymatic and respiratory disruption

• Inactivation of metabolic enzymes: Covalent platinum-thiol binding inactivates critical TCA cycle enzymes, specifically aconitase and the α-ketoglutarate dehydrogenase complex (KGDHC), by disrupting their essential thiol and iron-sulfur centers.
• Impairment of detoxification pathways: Platinum depletes mitochondrial GSH and directly inhibits glutathione reductase. This halts the regeneration of reduced GSH, crippling cellular antioxidant defenses.
• Mitochondrial DNA (mtDNA) damage: Beyond protein binding, platinum binds directly to mtDNA, forming adducts that block replication and transcription. This impairs the synthesis of essential respiratory chain subunits, leading to the collapse of complexes I–IV, membrane potential depolarization, and extensive reactive oxygen species (ROS) production.

Bottom line

• Platinum complexes bind irreversibly to sulfhydryl groups and mtDNA, inactivating critical metabolic enzymes (KGDHC, aconitase) and detoxification systems (glutathione reductase), which collectively drive profound mitochondrial bioenergetic failure and oxidative stress.