Figure 9.

Proposed mechanism for MnSOD-mediated mitochondria to nucleus signaling and crosstalk with the IIS pathway. The data suggest a model in which MnSOD catalyzed detoxification of superoxide results in increased intracellular hydrogen peroxide levels that mediate various signaling events. Such events include the activation of the JNK and NF-κB pathways. Pathway components that demonstrate increased expression due to MnSOD over-expression are highlighted in yellow. Note that genes up-regulated at both time points are indicated by black text, those up-regulated only at the first time point assayed are indicated by grey text, whereas those up-regulated only at the later time point are denoted by blue text. Solid lines indicate direct interactions, dashed lines indicate indirect interactions, dotted lines indicate translocation events, and '?' indicates hypothetical or speculative elements. The proposed retrograde signal from the mitochondria to the nucleus mediated by hydrogen peroxide is shown in red. Numerous genes are up-regulated as a result of these signaling events and some were also identified as being similarly altered in long-lived C. elegans IIS mutants, suggesting their role as species-general lifespan effectors. These genes are indicated as are the biological processes that they contribute to. Hydrogen peroxide reversibly inhibits PTEN [105], an upstream inhibitor of IIS, resulting in activation of phosphoinositide 3-kinase (PI3K) signaling. In accordance with this, Pk61C gene expression levels are up-regulated as are some downstream components of the IIS pathway in response to MnSOD over-expression. Increased IIS activity results in dFOXO inactivation and since MnSOD may be a direct transcriptional target, this suggests that feedback regulation may occur. The proposed feedback loop between MnSOD and the IIS pathway is also shown in red. Crosstalk between TOR and its binding partner, raptor, with the mitochondrion has been suggested [111], although the molecular basis has not been elucidated. As shown here, hydrogen peroxide may participate in this mechanism. ET, electron transport; ILP, insulin-like peptide.