Abstract
Oxidative folding in the mitochondrial intermembrane space (IMS) is a key cellular event associated with the folding and import of a large and still undetermined number of proteins. This process is catalyzed by an oxidoreductase, Mia40 that is able to recognize substrates with apparently little or no homology. Following substrate oxidation, Mia40 is reduced and must be reoxidized by Erv1/Alr1 that consequently transfers the electrons to the mitochondrial respiratory chain. Although our understanding of the physiological relevance of this process is still limited, an increasing number of pathologies are being associated with the impairment of this pathway; especially because oxidative folding is fundamental for several of the proteins involved in defense against oxidative stress. Here we review these aspects and discuss recent findings suggesting that oxidative folding in the IMS is modulated by the redox state of the cell.
Highlights
Specific cellular processes cannot be fully understood without considering the multiple pathways that are associated with them
Mitochondria constitute the major source of reactive oxygen species within a cell; it is likely that oxidative stress can itself influence the redox state of Mia40 and the correct import of several proteins
While a significant amount of information has already been obtained on the mechanism using model substrates, its regulation and links to the remaining cellular processes still need to be clearly discerned
Summary
Specific cellular processes cannot be fully understood without considering the multiple pathways that are associated with them. It is known that most mitochondrial proteins (95%) are synthesized in the cytoplasm and imported posttranslationaly to the organelle; a broad perspective on the way this event is regulated or linked to other cellular processes is missing. This issue is relevant considering that the mitochondria, a key organelle, is associated with an increasing number of human pathologies and that impairment of mitochondrial protein import is lethal [2,3]. We review and discuss, in light of recent findings, the impact that misregulation of this pathway has on human health
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