Sci. Aging Knowl. Environ., 17 November 2004
Solving the Energy Crisis
Signaling molecule spurs cells to generate mitochondria
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/46/nf101
Finding enough gas to fill ravenous SUVs isn't the world's only energy crisis. As people age, they lose mitochondria, the cell's power producers. Now, researchers have pegged a signaling molecule that prompts cells to make more of the organelles. The finding could lead researchers to ways of augmenting mitochondrial supplies in the elderly and in people with diseases such as diabetes.
Like any machine, human bodies need fuel to operate. Mitochondria provide it by converting food molecules into ATP, the cell's energy currency. Damage that subverts enzymes involved in this process might promote tissue deterioration or foster disease, but disappearing mitochondria could also contribute. For instance, numbers of these organelles often plunge in older folks and individuals with diabetes. To devise new methods for fighting aging and disease, researchers want to understand the pathways that encourage cells to craft new mitochondria.
While studying whether nitric oxide (NO), a cellular signaling molecule that relaxes blood vessels and increases blood flow, goads mammalian cells to reproduce, cellular pharmacologist Emilio Clementi of the San Raffaele Institute in Milan, Italy, and colleagues discovered instead that the molecule enhances mitochondrial production. In the new work, the researchers investigated whether the extra organelles operate normally. NO can directly block enzymes that manufacture ATP, so the researchers sought to plug into the mitochondrial-duplication pathway downstream of NO to avoid potential data-interpretation problems. Previous studies suggested that this pathway involves another signaling molecule called cyclic GMP (cGMP). The team treated cells with a compound similar to cGMP but that doesn't break down as quickly. This chemical expanded mitochondrial numbers: It roused PGC-1, a gene that spurs the formation of mitochondria, and increased the amount of mitochondrial DNA.
Cells doused with the cGMP mimic burned more oxygen than did untreated cells, a sign of increased metabolic activity. Moreover, the cells carried more ATP than did controls. Further studies confirmed that treated cells ramp up the oxygen-dependent mitochondrial ATP assembly line rather than glycolysis, a system that makes ATP without oxygen. To determine whether NO hikes mitochondrial numbers in animals, the team analyzed mice that lack eNOS, an enzyme that synthesizes NO. The animals' liver, heart, muscle, and brain tissue produced less ATP and used less oxygen than did tissues from normal rodents. These animals also carried unusually few mitochondria. Together, the results suggest that by bolstering mitochondrial stores, NO augments metabolism and increases energy production.
"It's very exciting," says biochemist Guy Brown of Cambridge University in the U.K. "There's very little known about mitochondrial formation." The observation that NO increases mitochondrial quantities was important, and the new work reveals that they're functional, he adds. Next, researchers should hunt for the molecules that orchestrate mitochondrial formation because "cyclic GMP controls many genes" in addition to PGC-1, Brown says. Doctors already prescribe drugs that strengthen the NO-cGMP pathway, such as Viagra and nitroglycerin, which might also incite manufacture of mitochondria in people. Strong muscles and nimble neurons need mitochondria, so an extra dose of the organelles could help bedridden patients maintain muscle tone or keep the elderly mentally sharp and physically strong, he adds. If it pans out, the approach could keep cellular gas tanks topped off.
November 17, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150