Genetic dysfunction of the mitochondrial respiratory chain impairs proteasome activity

Background: Mitochondria are the central energy producers and signaling platforms of the cell. Recent evidence links mitochondrial function to the main protein degradation machinery of the cell – the ubiquitin proteasome system. Pharmacological inhibition of mitochondrial respiratory chain results in reduced ATP production and excessive formation of reactive oxygen species (ROS) which both impair proteasome function [1]. Objective: We here analyzed the ROS-independent effect of impaired oxidative phosphorylation on proteasome function. Methodology and results: We used embryonic fibroblast from mutator mice that accumulate mutations in mitochondrial DNA resulting in loss of mitochondrial respiration [2] as well as human skin fibroblasts from patients with mitochondrial complex I mutations and comprehensively analyzed expression and activity of cellular proteasome complexes. Mutations in the mitochondrial DNA caused respiratory chain dysfunction and resulted in diminished assembly and activity of 26S and PA28γ-associated proteasome complexes [3] in mutator cells. Dampening of the proteasome activity was independent of excessive ROS production and ATP supply and made them less sensitive towards proteasome inhibition. Conclusion: Disturbed proteasomal function may represent a confounding factor for progression of severe hereditary mitochondrial respiratory chain disorders.