Autophagy Revisited

Autophagy in action. This artist's rendition of autophagy shows the formation of autophagosomes (center) and the fusion of these transport vesicles with vacuoles (bottom right), where misshapen proteins and obsolete organelles are degraded.

Reproduced from The Journal of Cell Biology, 175(6), 2006; issue cover image. © 2006 The Rockefeller University Press

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. ¹

Both teams of researchers, based at the Tokyo Metropolitan Institute of Medical Science, knocked out mouse genes that code for enzymes central to autophagy in neurons. They studied the effects of short-circuiting autophagy in otherwise healthy mice and found similar results: Healthy mice deprived of autophagy in neurons suffer progressive neurodegeneration, marked by the accumulation of abnormal, or misfolded, proteins inside nerve cells. ²

"These were two of the most exciting papers that I have ever read," says Daniel Klionsky, a University of Michigan autophagy researcher, and founder and editor-in-chief of the journal Autophagy. "They were elegantly done, and the points that they made I considered to be paradigm shifts for the field."

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. ³ "Normal cells or tumor cells need to take care of their damaged proteins," she says. "If they fail to do so, that can lead to the accumulation of damaged cells, neurodegeneration, or cancer."

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. ⁴ Hill says that the precise mechanism behind autophagy's role in exacerbating cardiac hypertrophy remains unclear, but that in this case the autophagy appears to be maladaptive, and that disrupting the pathway is a potential target for therapy.

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. ⁵ Ralph Nixon, of the New York University School of Medicine, has studied how autophagy failure in neurons can be a precursor to the onset of Alzheimer's disease and how inducing autophagy may be a way to clear effective proteins from diseased neurons. ⁶ "The autophagy pathway has been a completely overlooked aspect of [Alzheimer's]," says Nixon.

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, ⁷ warns that autophagy seems to function best while maintaining a subtle balance: Too much autophagy can incite cell death, while too little can result in problems related to the accumulation of misfolded proteins. "It's very enticing to think about manipulating autophagy for a variety of different diseases," she says, "but how you're going to avoid cell death is a big challenge."

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."