| Shengkan (Victor)
Jin
Associate Professor
UMDNJ
Department of Pharmacology
Room 549
683 Hoes Lane West
Piscataway. NJ 08854
(732) 235-4329/6197
FAX - 235-4073
jinsh@umdnj.edu
|
Autophagy in Cellular Maintenance: Implications in Aging,
Cancer, and Metabolic Diseases
Humans, as well as other mammals with long life spans, face a formidable
challenge: the accumulation of damages inside the cells over time. These
cellular damages, especially damage in mitochondria, if not resolved in a timely
manner, will lead to loss of functionality or even death of cells. After
reaching a threshold, loss of cellular functionality or cells would cause organ
malfunctions or failure, resulting in many aging related diseases, such as
neurodegenerative diseases, cancer, metabolic diseases.
Autophagy is care-taking process at the subcellular level that eliminates
cellular damages by removal of dysfunctional proteins and organelles. It is a
highly regulated membrane-trafficking process leading to lysosomal degradation.
During autophagy, cytoplasmic components, such as protein aggregates or
dysfunctional mitochondria, are first sequestered in double-membrane vesicles,
the autophagosomes. These vesicles then dock and fuse to lysosomes, where they
are further degraded. Autophagy is essential for the maintenance of a healthy
cell.
Studies from our laboratory have helped determine the role of autophagy in a
number of physiological processes and human diseases. We showed that mice with
monoallelic deletion of an essential autophagy gene, beclin1, have increased
cancer rates. Part of the laboratory is working on the mechanism by which
autophagy defect causes cancer and how autophagy modification in cancer cells
would affect cancer prognosis and cancer chemotherapy.
White adipocyte has a unique cellular structure in which almost the entire
cytoplasm consists of a single lipid droplet while other subcellular structures
including nucleus are pushed aside and occupy minimal space. Recently we
demonstrated that autophagy plays a critical role in cytoplasmic remodeling
during adipocyte differentiation, especially in removing mitochondria.
Remarkably, the mice with adipose-specific deletion of an essential autophagy
gene, atg7, exhibit a combination of “fitness” phenotypes. They are physically
lean and resistant to high-fat diet induced obesity. They are more sensitive to
insulin, have reduced cholesterol and triglyceride levels. Currently, the lab is
trying to elucidate the molecular mechanisms by which autophagy inactivation in
adipose tissue leads to enhance metabolic fitness.
Autophagy is probably the only process for removal of damaged mitochondria, an
important contributing factor for aging. It is not surprising that autophagy is
involved in aging control. Inactivation of the beclin1 gene or other autophagy
genes in C. elegans would reduce the life-spans of the worms. Part of the lab is
working on how autophagy specifically degrades damaged mitochondria, how
age-related deterioration of mitochondrial functions is correlated with
reduction of autophagy capacity, and whether autophagy reactivation can prevent
or delay many aging phenotypes in mice.
|
