Mitochondrial and Cytoplasmic Oxidative Stress Have Opposing Effects on Lifespan in Nematode Worms

Oxidative stress refers to higher levels of oxidizing molecules present in and around cells, causing more damage by reacting with protein machinery that must then be repaired. Work over the past two decades has show that raising or lowering levels of reactive oxygen species (ROS) produced by the mitochondria within a cell can extend or shorten life in lower animals such as nematode worms: the outcome obtained depends on the details of the process. Cells react to the presence of ROS with increased housekeeping activities, so a modest increase can lead to a net reduction in damage while a large increase overwhelms repair systems and causes greater harm.

Since ROS do have a variety of roles in cellular metabolism, and are not just agents of harm, it matters greatly where in the cell ROS levels are altered. In this paper researchers explore localized increases in ROS levels in nematode cells by selectively deleting genes that encode varieties of superoxide dismutase antioxidant proteins. These antioxidants reside in various different compartments of the cell, and so reduced levels lead to increased ROS, but only in the areas of the cell where the antioxidant is normally present:

Reactive oxygen species (ROS) are highly reactive, oxygen-containing molecules that can cause molecular damage within the cell. While the accumulation of ROS-mediated damage is widely believed to be one of the main causes of aging, ROS also act in signaling pathways. Recent work indicates that low levels of ROS can be beneficial and promote longevity. In this paper, we use a long-lived mitochondrial mutant C. elegans strain clk-1 to further examine the relationship between ROS and lifespan. While it was originally believed that clk-1 mutants had increased lifespan as a result of decreased ROS production, ROS levels have been shown to be increased in clk-1 worms.

Increasing levels of superoxide, one form of ROS, through treatment with paraquat, results in increased lifespan. Interestingly, treatment with paraquat robustly increases the already long lifespan of the clk-1 mitochondrial mutant, but not other long-lived mitochondrial mutants such as isp-1 or nuo-6. To genetically dissect the subcellular compartment in which elevated ROS act to increase lifespan, we deleted individual superoxide dismutase (sod) genes in clk-1 mutants, which are sensitized to ROS. We find that only deletion of the primary mitochondrial sod gene, sod-2 results in increased lifespan in clk-1 worms. In contrast, deletion of either of the two cytoplasmic sod genes, sod-1 or sod-5, significantly decreases the lifespan of clk-1 worms.

Further, we show that increasing mitochondrial superoxide levels through deletion of sod-2 or treatment with paraquat can still increase lifespan in clk-1;sod-1 double mutants, which live shorter than clk-1 worms. The fact that mitochondrial superoxide can increase lifespan in worms with a detrimental level of cytoplasmic superoxide demonstrates that ROS have a compartment specific effect on lifespan - elevated ROS in the mitochondria acts to increase lifespan, while elevated ROS in the cytoplasm decreases lifespan. This work also suggests that both ROS-dependent and ROS-independent mechanisms contribute to the longevity of clk-1 worms.



That result seems to be the opposite of what you'd expect given that famous catalase-in-mitochondria-extends-mice-lifespan paper ( Disarming H2O2 in mitochondria is good, but disarming superoxide is bad?

Posted by: ale at February 13th, 2015 8:13 AM

Ah no, I see. SOD converts superoxide to H2O2, so it might just be that H2O2 is the villain.

Posted by: ale at February 13th, 2015 8:19 AM

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