New results suggest that escape from the cell cycle is hooked to mitochondrial performance, say Vijay Sankaran, Stuart Orkin, and Carl Walkley (Harvard Medical School, Boston, MA). The group finds that both escape and performance are controlled by Rb in differentiating red blood cells.

The precursors to red blood cells, like many cell types, must stop proliferating before they can differentiate. Previous work showed that the precursors of red blood cells must also boost mitochondrial activity, perhaps to generate enough ATP for the impending onslaught of globin synthesis. In the new work, the authors reveal that Rb-mediated exit from the cell cycle allows differentiation by providing this mitochondrial boost.

In several cell types, Rb is necessary for the transition from G1 to S phase. But reports on its function in red blood cell development were conflicting. Sankaran et al. eliminated some of the complications that afflicted previous studies by knocking out Rb activity only in the cell lineage that produces red blood cells in mice.

The mutant precursors failed at a late stage of differentiation, when exit from the cell cycle is needed. Gene expression patterns revealed that S phase genes were maintained at high levels in the mutants. Several of these genes were targets of the E2F transcription factor—a known substrate of Rb's inhibitory powers. As a result, whereas normal precursors escaped proliferation at this G1 stage, the mutants pushed forward into another S phase.

Loss of Rb also impaired mitochondrial biogenesis, electron transport, and oxidative phosphorylation. These pathways were up-regulated just before differentiation in normal precursors but remained flat in the mutants.

One transcription factor that promotes mitochondrial biogenesis in muscle and fat, called PGC, was reduced in the Rb mutants. The authors imagine that PGC levels are kept low by the mutant cells' high levels of S phase cyclin-dependent kinases, one of which has been shown to block PGC function.


Sankaran, V., et al.
Genes Dev.