Figure 8.

Mechanisms of cell damage induced by cobalt ions. (A) mitochondrial stress generated by the cobalt-induced opening of the mitochondrial transition pore (MTP). Under normal conditions in aerobic respiration, the H⁺ generated during the tricarboxylic acid cycle in the form of NADH and NAPH are transferred to the intermembrane space by the electron transport chain, generating an electrochemical gradient, in which a high concentration of H⁺ is found in the intermembrane space. By use of this electrochemical gradient, the ATP synthase can phosphorylate ADP into ATP. With the opening of MTP, the electrochemical gradient is lost, then the synthesis of ATP is decreased. (B) cellular effects of the mitochondrial stress. Under normal conditions, the hypoxia induced factor HIF-1α is degraded by the proteasome; similarly, phosphorylated IKK bound in the cytoplasm NF-κB. With a drop in ATP, the degradation of HIF-1α is decreased, allowing HIF-1α to translocate into the nucleus and bind CBP and HRP to enhance transcription of target genes, such as NF-κB and VEGF. The decrease in ATP also reverses the phosphorylation of IKK that in a non-phosphorylated state releases NF-κB, which dimerizes and translocates to the nucleus, binding DNA and enhancing the transcription of target genes, such as IL-6 and IL-8.