Mitochondrial ETC dysfunctions have long been associated with aging and aging related diseases. Accumulating evidence in various model organisms, including C. elegans, indicates that mutants with a moderate reduction of mitochondrial electron transport chain (ETC) function exhibit lifespan extension. The mechanism accounting for this lifespan extension is poorly understood. Our lab recently identified
ceh-23, encoding a homeodomain protein, to be an important factor in mediating the longevity effect of mitochondrial ETC mutants in C. elegans. Inactivating
ceh-23 specifically suppresses the lifespan extension of several mitochondrial ETC mutants, but has no effects on the lifespan of other longevity mutants tested. Interestingly,
ceh-23 mutation does not affect the developmental and reproductive defects, which are normally associated with mitochondrial ETC dysfunctions. Moreover,
ceh-23 expression is induced in long-lived mitochondrial ETC mutants, suggesting that
ceh-23 is able to respond to mitochondrial dysfunction. We found that overexpression of CEH-23 extends lifespan in wild type worms, indicating that
ceh-23 is a novel longevity modulator. CEH-23 is expressed in the nuclei of a subset of neurons and intestinal cells and has been implicated in the transcriptional cascade regulating thermosensory neuron differentiation in C. elegans, but not much is known about its role in longevity. Recent studies suggest that lifespan extension in some mitochondrial ETC mutants depends on a small increase in reactive oxygen species (ROS) production (1,2), and activation of the mitochondrial unfolded protein response (mtUPR)(3). To further probe the function of
ceh-23, I tested whether it may be involved in ROS-mediated lifespan extension and/or mtUPR. My preliminary data suggest that
ceh-23 is not required for lifespan extension due to small increase in ROS, and is also not required for downstream components of the mtUPR pathway to be induced in mitochondrial ETC dysfunctioned worms. Together, our data suggest a model in which mitochondrial ETC dysfunction triggers
ceh-23 expression, which in turn extends lifespan through a novel pathway. Further study will provide new insights into CEH-23 function and will shed light on the molecular mechanism whereby altered mitochondrial ETC function modulates longevity. References: 1. Yang, W., et al., PLoS Biol, 2011 2. Lee, S., et al., Curr. Biol, 2011 3. Durieux, J., el al., Cell, 2011.