Mitochondria are the major organelles that produce
reactive oxygen species (ROS) and the main target of
ROS-induced damage as observed in various pathological
states including aging. Production of NADPH required
for the regeneration of glutathione in the mitochondria
is critical for scavenging mitochondrial ROS
through glutathione reductase and peroxidase systems.
We investigated the role of mitochondrial NADP1-dependent
isocitrate dehydrogenase (IDPm) in controlling
the mitochondrial redox balance and subsequent cellular
defense against oxidative damage. We demonstrate
in this report that IDPm is induced by ROS and that
decreased expression of IDPm markedly elevates the
ROS generation, DNA fragmentation, lipid peroxidation,
and concurrent mitochondrial damage with a significant
reduction in ATP level. Conversely, overproduction
of IDPm protein efficiently protected the cells
from ROS-induced damage. The protective role of IDPm
against oxidative damage may be attributed to increased
levels of a reducing equivalent, NADPH, needed
for regeneration of glutathione in the mitochondria.
Our results strongly indicate that IDPm is a major
NADPH producer in the mitochondria and thus plays a
key role in cellular