The complete lack of attenuation in the telomere-driven degenerative phenotypes in the setting of Ink4a/Arf deficiency was somewhat at odds with the reported role of the Bmi1–Ink4a/Arf axis in stem-cell maintenance30, as Ink4a/Arf deficiency has been shown to rescue the HSC–NSC depletion phenotype of Bmi1 deficiency and specific loss of p16INK4A through targeted mutation of Ink4a can enhance the regenerative potential of ageing HSCs, NSCs, lymphocytes and islet β-cells30. That said, the stem-cell depletion phenotype of Bmi1 deficiency has been linked not only to upregulated Ink4a/Arf expression (BMI1 is a repressor of the Ink4a/Arf locus) but also to increased mitochondrial dysfunction that results in increased ROS concentrations and subsequent activation of the DNA damage response pathway32. Thus, it is tempting to speculate that these increased ROS concentrations in the setting of Bmi1 deficiency may further drive telomere damage and erosion, and the consequent enhanced p53 activation, thereby overriding any ameliorative impact of Ink4a/Arf deficiency on the stem-cell and progenitor-cell compartments of late-generation Terc−/− Ink4a/Arf−/− mice. The molecular basis of how Bmi1–Ink4a/Arf regulates mitochondrial biology remains an important area for continued investigation.
