A fraction of yeast Cu,Zn-superoxide dismutase and its metallochaperone, CCS, localize to the intermembrane space of mitochondria - A physiological role for SOD1 in guarding against mitochondrial oxidative damage

Cu,Zn-superoxide dismutase (SOD1) is an abundant, largely cytosolic enzyme that scavenges superoxide anions. The biological role of SOD1 is somewhat c ontroversial because superoxide is thought to arise largely from the mitoch ondria where a second SOD (manganese SOD) already resides. Using bakers'yea st as a model, we demonstrate that Cu,Zn-SOD1 helps protect mitochondria fr om oxidative damage, as sod1 Delta mutants show elevated protein carbonyls in this organelle. In accordance with this connection to mitochondria, a fr action of active SOD1 localizes within the intermembrane space (IMS) of mit ochondria together with its copper chaperone, CCS. Neither CCS nor SOD1 con tains typical Nterminal presequences for mitochondrial uptake; however, the mitochondrial accumulation of SOD1 is strongly influenced by CCS. When CCS synthesis is repressed, mitochondrial SOD1 is of low abundance, and conver sely IMS SOD1 is very high when CCS is largely mitochondrial. The mitochond rial form of SOD1 is indeed protective against oxidative damage because yea st cells enriched for IMS SOD1 exhibit prolonged survival in the stationary phase, an established marker of mitochondrial oxidative stress. Cu,Zn-SOD1 in the mitochondria appears important for reactive oxygen physiology and m ay have critical implications for SOD1 mutations linked to the fatal neurod egenerative disorder, amyotrophic lateral sclerosis.