Abstract
Mitochondrial proteases ensure mitochondrial integrity and function after oxidative stress by providing mitochondrial protein quality control. However, the molecular mechanisms that regulate this basic biological function in eukaryotic cells remain largely unknown. Caveolin-1 is a scaffolding protein involved in signal transduction. We find that AFG3L2, a m-AAA type of mitochondrial protease, is a novel caveolin-1-interacting protein in vitro. We show that oxidative stress promotes the translocation of both caveolin-1 and AFG3L2 to mitochondria, enhances the interaction of caveolin-1 with AFG3L2 in mitochondria and stimulates mitochondrial protease activity in wild-type fibroblasts. Localization of AFG3L2 to mitochondria after oxidative stress is inhibited in fibroblasts lacking caveolin-1, which results in impaired mitochondrial protein quality control, an oxidative phosphorylation to aerobic glycolysis switch and reduced ATP production. Mechanistically, we demonstrate that a lack of caveolin-1 does not alter either mitochondrial number or morphology but leads to the cytoplasmic and proteasome-dependent degradation of complexes I, III, IV and V upon oxidant stimulation. Restoration of mitochondrial respiratory chain complexes in caveolin-1 null fibroblasts reverts the enhanced glycolysis observed in these cells. Expression of a mutant form of AFG3L2, which has reduced affinity for caveolin-1, fails to localize to mitochondria and promotes degradation of complex IV after oxidative stress. Thus, caveolin-1 maintains mitochondrial integrity and function when cells are challenged with free radicals by promoting the mitochondrial localization of m-AAA protease and its quality control functions.
Highlights
Mitochondria regulate the bioenergetic capacity of most eukaryotic cells
Localization of AFG3L2 to mitochondria after oxidative stress is inhibited in fibroblasts lacking caveolin‐1, which results in impaired mitochondrial protein quality control, an oxidative phosphorylation to aerobic glycolysis switch and reduced adenosine triphosphate (ATP) production
Given the notion that mitochondria possess quality control systems to avoid oxidant-induced damage, we started to investigate the hypothesis that caveolin-1-mediated signaling is activated under conditions of oxidative stress to maintain mitochondrial function by asking whether sublethal levels of oxidants promote the interaction of caveolin-1 with AFG3L2 in cells
Summary
A major biological function of mitochondria is the production of adenosine triphosphate (ATP) through cellular respiration This is accomplished by transferring electrons through mitochondrial respiratory chain complexes, which is coupled with the transferring of protons out of the matrix space. Since mitochondria are sensitive targets of reactive oxygen species (ROS), eukaryotic cells have developed several mitochondrial protein quality control systems for the maintenance of protein homeostasis and the prevention of oxidant-induced mitochondrial damages [2]. These include mitochondrial proteases, which degrade, process and mediate the assembly and disassembly of mitochondrial macromolecular structures involved in a variety of mitochondrial activities, including oxidative phosphorylation [3]
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