Cells die less readily if they have mitochondrial mutations (black bars).

Many cancer cells resort to inefficient glycolysis for their energy but can nevertheless survive, even when competing with their more energy-efficient noncancerous neighbors. One explanation, say Pelicano et al. (page 913), is that the altered metabolism can turn on an Akt survival pathway.

Most cells rely primarily on the rich energy harvest that comes from oxidative phosphorylation. But a switch to glycolysis can be induced by hypoxia, the loss of the tumor suppressor p53, expression of tumor inducers such as Myc and Ras, or mutation of certain mitochondrial enzymes.

Mitochondrial mutation is particularly common in cancer cells, which are under metabolic stress that generates mutagenic oxidants. Mitochondrial DNA is a prime target for these mutations as these organelles lack many of the safegard mechanisms that prevent and repair damage of nuclear DNA.

Pelicano et al. mutated mitochondrial DNA. The resultant cells grew better under hypoxic conditions and were less sensitive to common anticancer drugs. The cells produce high levels of NADH, which is normally consumed by oxidative phosphorylation, and this altered redox environment inactivated the PTEN phosphatase. With PTEN out of action, its target, Akt, was activated. This kinase is known to increase cell survival. In hypoxic or toxic conditions, this survival pathway may be used in normal cells to keep the cells healthy, but cancer cells have used it to survive despite their unorthodox metabolism.

When cells with mitochondrial mutations were treated to prevent the Akt activation, they once more became sensitive to anticancer drugs. Inhibition of the Akt pathway may also be a promising approach in the clinic, although it is not yet clear which protein in the Akt pathway would make the best target, or which anticancer drugs would make the best follow-up treatment.