Simon's working hypothesis is that ROS are released into the fluid portion of the cell's interior, where they inhibit enzymes called HIF hydroxylases that lead to HIF degradation when oxygen levels are normal. Thus, HIF builds up and then sets in motion the cell's hypoxic response—activating the myriad genes that lead to blood vessel development and cell motility, for example. Yale's Shadel comments, "Simon has uncovered how this oxygen sensing has consequences beyond respiration—mitochondria are not just sensing oxygen for their own need but are telling the cell that it's low in oxygen and that it needs to initiate a response."

Some other labs have reported findings that support the theory that HIF hydroxylases (the enzymes leading to HIF degradation) serve as oxygen sensors. Simon reconciles the data by suggesting that two separate pathways may operate, one under extreme hypoxia (0.1 percent oxygen) and the other under modest hypoxia (1-3 percent oxygen). Her results indicate that when oxygen is nearly absent, mitochondria cease to be the dominant player and HIF hydroxylases become the oxygen sensor. However, she adds, cells in the body are more likely to encounter the conditions of modest hypoxia that she studies.

Understanding how mitochondria are involved in sensing and signaling may ultimately lead to new models for many diseases and their treatments. Researchers now know that mitochondrial dysfunction could affect more than just the cell's ability to produce energy, says Simon. "Many metabolites produced in the mitochondria have an impact on the rest of the cell, and these will be really important to consider in disease." As Shadel puts it, "The role of mitochondria in the cell is grossly underestimated, as is their role in human disease."

Scientists have known for more than two decades that type 2 diabetes begins its development as "insulin resistance," in which tissues such as muscle respond poorly to the hormone insulin and, therefore, don't facilitate glucose transport out of the blood and into muscle cells where it is metabolized. It made sense to Gerald I. Shulman, an HHMI Investigator at Yale University School of Medicine, that insulin resistance might be linked to mitochondrial function. After all, mitochondria convert glucose and fatty acids into energy—by a process called oxidation—and people with diabetes have too much unburned glucose in their blood, and too much fat in their muscle and liver cells.

So his group developed a novel method to tell how well mitochondria are functioning, using NMR methods to noninvasively measure rates of oxidation and ATP production. In 2003, Shulman's team reported evidence in lean, healthy, elderly volunteers that an age-related decline in mitochondrial function may contribute to insulin resistance. They hypothesized that reduced mitochondrial function predisposed these older people to accumulate fat in muscle and liver cells, and that, in turn, led to defective insulin signaling and then insulin resistance.

In an interesting twist, however, Shulman's most recent study suggests that reduced mitochondrial function might also be caused by low overall numbers of mitochondria—at least in young, lean adults whose parents have type 2 diabetes. The researchers had previously studied this group and detected reduced rates of oxidation and ATP production in their muscle cells. Next, Shulman's team decided to take tissue samples and use an electron microscope to count the number of mitochondria. The samples—which already exhibited large amounts of intracellular fat, insulin resistance, and signs of impaired insulin signaling—had on average 38 percent fewer mitochondria than normal. The results of the study appear in the December 2005 issue of the Journal of Clinical Investigation. "Our data suggest that reduced mitochondrial function in this young group can be attributed to their low numbers of mitochondria," Shulman says. Now, the team is trying to determine whether intracellular fat accumulation might cause the low numbers, or vice versa. And how important are mitochondrial numbers? "Having more mitochondria might seem to be better, but it's probably not as simple as that," says Shulman.

Scientists still have much to learn about how the cell senses that it should make more mitochondria or has enough already, according to David A. Clayton, HHMI's vice president and chief scientific officer. "The Holy Grail in this field at every seminar is: How does the cell regulate the number of mitochondria? It's a challenging question." Researchers know that nuclear genes control the biogenesis of mitochondria (which have their own DNA), that tissues naturally have 100 to 10,000 mitochondria per cell, and that exercise increases the number of mitochondria in muscles. As scientists fill in the details, they expect to find many additional signaling pathways at the crossroads, Clayton notes.

—Karen F. Schmidt

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