Rat liver mitochondrial dysfunction by addition of copper(II) or iron(III) ions

Increased copper (Cu) and iron (Fe) levels in liver and brain are associated to oxidative stress and damage with increased phospholipid oxidation process. The aim of this work was to assess the toxic effects of Cu²⁺ and Fe³⁺ addition to rat liver mitochondria by determining mitochondrial respiration in states 3 (active respiration) and 4 (resting respiration), and phospholipid peroxidation. Both, Cu²⁺ and Fe³⁺ produced decreases in O₂ consumption in a concentration-dependent manner in active state 3: both ions by 42% with malate-glutamate as complex I substrate (concentration for half maximal response (C₅₀) 60μM Cu²⁺ and 1.25mM Fe³⁺), and with succinate as complex II substrate: 64-69% with C₅₀ of 50μM Cu²⁺ and with C₅₀ of 1.25mM of Fe³⁺. Respiratory control decreased with Cu²⁺ (C₅₀ 50μM) and Fe³⁺ (C₅₀ 1.25-1-75mM) with both substrates. Cu²⁺ produced a 2-fold increase and Fe³⁺ a 5-fold increase of thiobarbituric acid-reactive substances (TBARS) content from 25μM Cu²⁺ (C₅₀ 40μM) and from 100μM Fe³⁺ (C₅₀ 1.75mM). Supplementations with Cu²⁺ and Fe³⁺ ions induce mitochondrial dysfunction with phospholipid peroxidation in rat liver mitochondria. Although is proved that a Fenton/Haber Weiss mechanism of oxidative damage occurs in metal-ion induced mitochondrial toxicity, slightly different responses to the metal ions suggest some differences in the mechanism of intracellular toxicity. The decreased rates of mitochondrial respiration and the alteration of mitochondrial function by phospholipid and protein oxidations lead to mitochondrial dysfunction, cellular dyshomeostasis and cell death.