Yesterday we learned that the most well-characterized mammalian sirtuin, SIRT1, is involved in the control of behavior in response to food availability. SIRT1 is just one of seven sirtuins in mammalian genomes, each of which has a characteristic expression pattern, subcellular localization, and physiological importance.
Today we’re going to talk about another member of the sirtuin family, SIRT3, which has been known for a while now to localize to the mitochondria. Now, Kim et al. have shown that the SIRT3 protein acts as a tumor suppressor:
SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress
The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3−/− mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3−/− MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3−/− MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3−/− mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor.
So, the absence of the SIRT3 gene disrupts mitochondrial function and destabilizes the mitochondrial genome, but the causal relationship is unclear: one can imagine a derangement of mitochondrial morphology or physiology causing the genomic instability, but one can also imagine a primary defect in DNA metabolism causing the physiological defects — and one could also imagine both, operating in a vicious cycle.
The significance of the “single oncogene” observation requires a bit of explanation: In a normal cell, simply turning on a single tumor-promoting gene isn’t sufficient to transform the cell, i.e., create a tumor — if a cell detects a hyperphysiological level of a growth factor or internally generated mitogenic signal, it will undergo senescence, a permanent cell cycle arrest that (among other things) prevents mutated cells from turning into cancers.
In the case of the SIRT3 knockout, however, a single oncogene is enough to transform an otherwise normal cell, i.e., the loss of SIRT3 function appears to potentiate the transformation process. Furthermore, this implies that the mitochondria are involved in the decision to undergo senescence. This is not to say that SIRT3 is directly involved in the senescence fate decision: the SIRT3 knockout has broadly deranged mitochondria, and it’s not clear which mitochondrial function is involved in senescence.
While this report does not fully elucidate the mechanism of SIRT3 action, it is clear that oxidation must be central to the issue: reactive oxygen species (ROS) levels are high in the SIRT3 knockout, but increasing the dose of an antioxidant enzyme prevents the single-oncogene transformation. We don’t yet know whether the ROS themselves are causing oncogenic mutations, or the loss of the mitochondrial function in senescence is allowing cells that would have arrested to progress further down the path to cancer. (Could be both, obviously, but it’s likely that one of the two is more important.)
These findings are consistent with what we already know about the connection between mitochondrial ROS, cellular damage and lifespan (ideas that are central to one strategy for developing longevity-enhancing drug compounds by targeting antioxidants to mitochondria), but they raise a question: how much of the “longevity regulation” we owe to antioxidant genes can be attributed to tumor suppression?
Kim, H., Patel, K., Muldoon-Jacobs, K., Bisht, K., Aykin-Burns, N., Pennington, J., van der Meer, R., Nguyen, P., Savage, J., & Owens, K. (2010). SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress Cancer Cell, 17 (1), 41-52 DOI: 10.1016/j.ccr.2009.11.023
There’s lots more about SIRT3 in a recent post at @ging.