The retrograde response: when mitochondrial quality control is not enough.

Mitochondria are responsible for generating adenosine triphosphate (ATP) and metabolic intermediates for biosynthesis. These dual functions require the activity of the electron transport chain in the mitochondrial inner membrane. The performance of these electron carriers is imperfect, resulting in release of damaging reactive oxygen species. Thus, continued mitochondrial activity requires maintenance. There are numerous means by which this quality control is ensured. Autophagy and selective mitophagy are among them. However, the cell inevitably must compensate for declining quality control by activating a variety of adaptations that entail the signaling of the presence of mitochondrial dysfunction to the nucleus. The best known of these is the retrograde response. This signaling pathway is triggered by the loss of mitochondrial membrane potential, which engages a series of signal transduction proteins, and it culminates in the induction of a broad array of nuclear target genes. One of the hallmarks of the retrograde response is its capacity to extend the replicative life span of the cell. The retrograde signaling pathway interacts with several other signaling pathways, such as target of rapamycin (TOR) and ceramide signaling. All of these pathways respond to stress, including metabolic stress. The retrograde response is also linked to both autophagy and mitophagy at the gene and protein activation levels. Another quality control mechanism involves age-asymmetry in the segregation of dysfunctional mitochondria. One of the processes that impinge on this age-asymmetry is related to biogenesis of the organelle. Altogether, it is apparent that mitochondrial quality control constitutes a complex network of processes, whose full understanding will require a systems approach. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.