Abstract
Mitochondrial dysfunction activates intracellular signaling pathways that impact yeast longevity, and the best known of these pathways is the retrograde response. More recently, similar responses have been discerned in other systems, from invertebrates to human cells. However, the identity of the signal transducers is either unknown or apparently diverse, contrasting with the well-established signaling module of the yeast retrograde response. On the other hand, it has become equally clear that several other pathways and processes interact with the retrograde response, embedding it in a network responsive to a variety of cellular states. An examination of this network supports the notion that the master regulator NFκB aggregated a variety of mitochondria-related cellular responses at some point in evolution and has become the retrograde transcription factor. This has significant consequences for how we view some of the deficits associated with aging, such as inflammation. The support for NFκB as the retrograde response transcription factor is not only based on functional analyses. It is bolstered by the fact that NFκB can regulate Myc–Max, which is activated in human cells with dysfunctional mitochondria and impacts cellular metabolism. Myc–Max is homologous to the yeast retrograde response transcription factor Rtg1–Rtg3. Further research will be needed to disentangle the pro-aging from the anti-aging effects of NFκB. Interestingly, this is also a challenge for the complete understanding of the yeast retrograde response.
Highlights
Mitochondrial dysfunction underlies the spectacular manifestations of a class of diseases known as mitochondrial encephalomyopathy
Cells often respond to mitochondrial stress with specific responses, allowing them to survive in some cases
The best known of these cellular responses to mitochondrial dysfunction is the yeast (Saccharomyces cerevisiae) retrograde response (Liu and Butow, 2006), which plays a role in determining replicative lifespan (Kirchman et al, 1999)
Summary
Mitochondrial dysfunction underlies the spectacular manifestations of a class of diseases known as mitochondrial encephalomyopathy. Similar responses have been described in Caenorhabditis elegans, Drosophila melanogaster, and the mouse (Jazwinski, 2012) They have even been found in human cells in tissue culture, demonstrating their pervasiveness. It is embedded in a mesh of signal transduction events that adapt the cell to a variety of internal and external environments This range of interactions has recently expanded, and it is our purpose to review them here to provide clues to the signaling modules that may operate in the response of mammalian cells to mitochondrial dysfunction. This augments the bioinformatics approach we have taken earlier to identify the retrograde response transcription factors in mammalian cells (Srinivasan et al, 2010). The first three reactions of the TCA cycle remain intact, and this part www.frontiersin.org
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