Hypoxia can cause stress and structural changes to the epithelial cytoskeleton. The intermediate filament (IF) network is known to reorganize in response to stress. We examined whether rats exposed to
hypoxia had altered
keratin IF expression in their alveolar epithelial type II (ATII) cells. There was a significant decrease in
keratin protein levels in hypoxic ATII cells compared with those in ATII cells isolated from normoxic rats. To define the mechanisms regulating this process we studied changes to the
keratin IF network in A549 cells (an alveolar epithelial cell line) exposed to 1.5%
oxygen. We observed a time-dependent disassembly-degradation of
keratin 8 and 18
proteins, which was associated with an increase in
reactive oxygen species (ROS).
Hypoxia-treated A549 cells deficient in
mitochondrial DNA or A549 cells treated with a
small interfering RNA against the
Rieske iron-sulfur protein of mitochondrial
complex III did not have increased levels of ROS nor was the
keratin IF network disassembled and degraded. The
superoxide dismutase (SOD)/
catalase mimetic (EUK-134) prevented the
hypoxia-mediated
keratin IF degradation as did the overexpression of SOD1 but not of SOD2. Accordingly, we provide evidence that
hypoxia promotes the disassembly and degradation of the
keratin IF network via mitochondrial
complex III-generated
reactive oxygen species.-Na, N., Chandel, N. S., Litvan, J., Ridge, K. M. Mitochondrial
reactive oxygen species are required for
hypoxia-induced degradation of
keratin intermediate filaments.