The mitochondriotropic antioxidants AntiOxBEN2 and AntiOxCIN4 are structurally-similar but differentially alter energy homeostasis in human skin fibroblasts.

Mitochondrial dysfunction and increased reactive oxygen species (ROS) generation play an import role in different human pathologies. In this context, mitochondrial targeting of potentially protective antioxidants by their coupling to the lipophilic triphenylphosphonium cation (TPP) is widely applied. Employing a six‑carbon (C₆) linker, we recently demonstrated that mitochondria-targeted phenolic antioxidants derived from gallic acid (AntiOxBEN₂) and caffeic acid (AntiOxCIN₄) counterbalance oxidative stress in primary human skin fibroblasts by activating ROS-protective mechanisms. Here we demonstrate that C₆-TPP (but not AntiOxBEN₂ and AntiOxCIN₄) induce cell death in human skin fibroblasts. This indicates that C₆-TPP cytoxocity is counterbalanced by the antioxidant moieties of AntiOxBEN₂ and AntiOxCIN₄. Remarkably, C₆-TPP and AntiOxBEN₂ (but not AntiOxCIN₄) induced a glycolytic switch, as exemplified by a reduced cellular oxygen consumption rate (OCR), increased extracellular acidification rate (ECAR), elevated extracellular lactate levels, and higher protein levels of glucose transporter 1 (GLUT-1). This switch involved activation of AMP-activated protein kinase (AMPK) and fully compensated for the loss in mitochondrial ATP production by sustaining cellular ATP content. When glycolytic switch induction was prevented (i.e. by using a glucose-free, galactose-containing medium), AntiOxBEN₂ induced cell death whereas AntiOxCIN₄ did not. We conclude that, despite their similar chemical structure and antioxidant capacity, AntiOxBEN₂ and AntiOxCIN₄ display both common (redox-adaptive) and specific (bioenergetic-adaptive) effects.