Mitochondria on the MARCH

No way to treat a tumor O n page 93, Yuneva et al. provide bittersweet news for efforts to turn cancer cells’ big appetite against them. Contrary to previous work, the study shows that a sugar shortage snuffs out normal cells as well as cancer cells. But the results bolster another nutritional target: the amino acid glutamine. The idea that cancer cells hunger for glucose is more than 50 years old. In the 1990s, researchers showed that glucose depletion kills rodent cells that carry an overactive form of the cancer-promoting gene MYC. Nontransformed cells survived. Tumors also need plenty of glutamine, and two drugs that disrupt metabolism of the amino acid reached clinical trials but have since proved toxic. Some scientists question whether scarcity of either nutrient is lethal to human tumors: cancer cells synthesize their own glutamine, and some tumors switch to alternative food sources if glucose runs out. Yuneva et al. wanted to nail down whether the nutrients are essential for cells with overactive MYC. To their surprise, the researchers found that, unlike rodent cells, human cells were killed by glucose deprivation whether or not extra MYC was present. By contrast, shutting off the glutamine supply had a stronger effect on MYC-overproducing cells. The results suggest that glutamine deprivation as a cancer treatment—which researchers have abandoned—deserves a second look. The fi ndings don’t show that glucose deprivation is a bust, the authors caution. Instead, they say, scientists need to carefully compare the intricacies of metabolism in normal and cancer cells before they can predict whether such treatments will work. Mitochondria on the MARCH B reaking up isn’t hard to do for mitochondria, which are continually separating and merging. On page 71, Karbowski et al. pinpoint a protein that prods the organelles to go their own way. Cells carefully control mitochondrial fusion and fi ssion, and an imbalance between the processes can be disastrous. For example, a faulty fusion-promoting protein triggers dominant optic atrophy, the leading cause of inherited blindness. Researchers know more about the regulation of fusion and fi ssion in yeast than in mammals. But they do know that one of the mammalian proteins essential for mitochondrial breakup is Drp1. Karbowski et al. pinpointed another, called MARCH5, which colocalizes with Drp1. Although two studies published last year suggested that MARCH5 promoted mitochondrial fusion, the scientists now fi nd the opposite. When they altered cells to produce a defective version of the protein, mitochondria stuck together to form extra-long networks instead of breaking apart. The researchers also observed this abnormal elongation when they added RNAi against MARCH5. The protein normally spreads out around the mitochondrial membrane, but the mutant MARCH5 clumped. These clusters trapped Drp1. These fi ndings suggest that MARCH5 spurs mitochondrial splitting by helping to direct Drp1 to the future separation site. MARCH5 is a ubiquitin ligase that works by attaching a ubiquitin molecule to its target. The researchers’ next move is to track down that target. p53 hits the brakes C rawling cells shift into high gear after they lose the tumor suppressor protein p53, as Gadea et al. report on page 23. The work reveals that the same fl aw that allows cancer cells to divide uncontrollably also increases their mobility. Most cancer cells sport faulty versions of p53, which normally halts the cell cycle or triggers apoptosis in response to DNA damage. The researchers and other groups had previously shown that deleting p53 gets cells moving in two-dimensional cultures. Gadea et al. tested for the same effect in more realistic, three-dimensional cultures. The researchers found that crawling mouse embryonic fi broblasts came in two varieties. If they carried working p53, the cells were elongated and sluggish. But if p53 was absent, they were rounder and slithered six times faster. This speedier movement required RhoA GTPase and its downstream enforcer, ROCK. Inactivating p53 in melanoma cells that normally carry a functional version of the protein increases their invasiveness, confi rming that p53 loss can accelerate the dispersion of cancer cells. The results suggest that cancer treatments that restore p53 activity bring an added benefi t by reining in the rogue cells. Mitochondria (red) are stickier in cells that make faulty MARCH5 (green).