Researchers identify novel regulator

(HOUSTON) — Researchers at the Texas A&M Health Science Center Institute of Biosciences and Technology have identified a novel regulator of autophagy that presents a new drug target for major diseases.

Leyuan Liu, Ph.D., assistant professor in the Center for Cancer and Stem Cell Biology at the TAMHSC-Institute of Biosciences and Technology, led the series of studies. The most recent study will be in the April issue of Journal of Biological Chemistry and is now available online.

Autophagy, controlled self-digestion, is a cellular garbage disposal and recycling system for dysfunctional aggregated proteins and worn-out organelles essential to normal cellular functions. Mitochondria are the organelle that fuel cell functions but are highly toxic and cause cell death when damaged or worn out.

In an August 2009 issue of Cell Cycle, Dr. Liu and his colleagues showed that robust autophagy to remove worn out mitochondria, a process called mitophagy, is essential during all phases of the cell life cycle, including mitosis. They also found mitophagy during mitosis is specifically blocked when genetic error occurs to cause mitotic cell death.

Autophagy is also activated when cells are stressed out, particularly when cell nutrition is limited. It serves to break down cellular components to their basic building blocks and reshuffle them into essential components aimed at surviving the particular situation.

During autophagy, cells locate and package spent mitochondria and other waste in special packages called autophagosomes. Closing the autophagosomes and moving them for disposal and reuse in the cell’s recycling organelles called lysosomes require specialized elements of the microtubular system, Dr. Liu and his colleagues found and presented in the November 2010 issue of BMC Cell Biology.

The most recent discovery grew out of a finding several years ago of a completely novel interactive complex of factors that interacted with microtubules and mitochondria at the same time. The current study revealed one of the components in the complex, MAP1S, serves as the bridge between microtubules, mitochondria and autophagosomes (mitophagosomes when containing mitochondria). Combining biochemical approaches with a genetically engineered mouse model, the group demonstrated MAP1S integrates microtubules with mitochondrial fission-fusion and autophagy through a molecule, LC3, that sticks out in autophagosome membranes.

It is estimated that most diseases, particularly those age-related, may be aggravated by excess accumulation of cellular garbage in the form of protein aggregates and worn-out organelles. Properly functioning disposal and recycling of the garbage through autophagy is essential to cell health and longevity and dysfunction related to diseases such as cancers, neurodegenerative diseases and heart diseases. Advances in the field will help better understand these diseases and identify new drug targets for disease intervention.

Other TAMHSC-Institute of Biosciences and Technology contributors were Wallace McKeehan, Ph.D., executive associate director, J.S. Dunn Foundation Endowed Professor, Regents Professor, and director of the Center for Cancer and Stem Cell Biology; Fen Wang, Ph.D., professor; graduate student Rui Xie and technical staff Kerstin McKeehan, Susan Nguyen and Min Ye. Research support was provided by the U.S. Department of Defense, the National Cancer Institute, U.S. Public Health Service, the Susan Komen Foundation and the John S. Dunn Research Foundation.