The autophagy process degrades and recycles malformed proteins or worn-out organelles using lysosomal machinery. In the past, autophagy has been shown to act only as an adaptive response to extreme physiologic conditions, such as nutrient deprivation. Then, in 2006, two teams of Japanese researchers published papers on autophagy in Nature - both Hot Papers this month - showing that autophagy is important not only in stressed cells, but also is essential to the health and development of normal cells.
Both teams of researchers, based at the Tokyo Metropolitan Institute of Medical Science, knocked out mouse genes that...
A pathway repurposed
That autophagy is crucial to the function and development of healthy cells, and not just a cellular response to stressful physiologic conditions, represented a major shake-up in the way that scientists understood the pathway, according to Klionsky. "We had not been sure if autophagy was important in the brain or not," Noboru Mizushima, now at the Tokyo Medical and Dental University and principal investigator on the second paper, writes in an e-mail. "Our answer was that very low levels of autophagy, even under detectable levels, can be critically important to constitutive turnover of cytosolic contents, which prevents accumulation of abnormal proteins. We ourselves were indeed excited." Since then, many researchers are investigating a potential link between autophagy and disease.
Last year, Eileen White of Rutgers University found that autophagy normally suppresses tumor progression in breast tissue, and that an essential genetic autophagy regulator is monoallelically deleted in some breast carcinomas.
Also in 2007, University of Texas Southwestern researcher Joseph Hill found that in enlarged cardiac cells (a common response to hypertension or other myocardial injury), autophagy kicks in and actually accelerates cardiac remodeling and the associated functional problems in an enlarged heart.
Other researchers are exploring ways to upregulate autophagy in cases where it prevents or slows the progression of diseases, as happens with cancer or neurodegeneration. Conversely, others hope to downregulate autophagy when it is maladaptive, as in cardiac hypertrophy.
David Rubensztein of the Cambridge Institute for Medical Research, for example, published results in 2007 suggesting that inducing autophagy in neurons may alleviate Huntington's disease in animal models by clearing out toxic protein aggregates that accumulate in diseased cells.
The amount of autophagy needed to maintain healthy cell processes is still under scrutiny. Michelle Swanson of the University of Michigan, who studies how the microbe Legionella pneumophilia triggers autophagy,
Swanson also says that researchers have just begun to grasp the pervasive physiologic role of autophagy. "It's just the tip of the iceberg," she says. "I'm not sure there's an area of biology that won't be touched by autophagy."