FAT GENE AND MITOCHONDRIA : CELLULAR CONNECTION
Researchers led by Dr.
Helen McNeill at the Lunenfeld-Tanenbaum Research Institute have revealed an
unusual biochemical connection. Their discovery has implications for diseases
linked to mitochondria, which are the primary sources of energy production within
our cells
Dr. McNeill's team has
an international reputation for their work in understanding how cells become
organized into tissues and how growth is regulated during development. The
group focuses on mutations in the fat (ft) gene. The
protein product of this gene, called 'Fat', acts at the cell membrane to
promote adhesion and communication between cells. Mutations in ft can
cause cells to overgrow and become tumours. This occurs partially through the
Hippo pathway, a pathway that is frequently activated in cancers such as liver,
breast, ovarian and sarcomas.
Fat proteins are
typically thought to work at the cell surface, but the team's paper, published
in the journalCell, uncovers for the first time that a piece of the Fat
protein is actually processed and delivered into the mitochondria where it
influences the energy status of the cell. Importantly, when this particular
component is missing, the energy generating pipeline inside mitochondria become
destabilized, leading to loss of energy production.
"We were amazed
to find that Fat proteins interact directly with mitochondria in a cell,
regulating the cell's metabolism" says Dr. McNeill, a Senior Investigator
at the Lunenfeld-Tanenbaum Research Institute and a Professor in the Department
of Molecular Genetics at the University of Toronto. "We still want to know
how a cell knows when to release the Fat protein into mitochondria, but for
now, this new linkage opens up a whole new way of thinking about how cellular
energy is controlled as well as new ideas about how to shut down cancer cell
growth."
When mitochondria stop
working properly, cells no longer have an efficient energy source. Instead,
cells will switch to glycolysis to produce the energy they require, known as
the Warburg effect. Similarly, tumour cells have glycolytic rates up to 200
times higher compared to normal cells. Since the mitochondria is responsible
for producing energy for essential cellular functions, problems with
mitochondria can also lead to illnesses such as Type 2 diabetes, Parkinson's
disease, heart disease, stroke, and Alzheimer's disease.
The research team has
been evaluating their unique discovery in fruit flies, since they serve as a
powerful model for human mitochondria. Their next steps are to test these
findings on human cells.
"This new finding
that links the cell membrane to mitochondrial function is important since it
defines a totally new mechanism of cellular regulation," says Yonit Tsatskis,
a Research Associate in Dr. McNeill's lab.
Her co-author Anson
Sing adds, "When I started this project I had expected to learn a bit
about eye development in fruit flies, but I had no idea that it would lead me
to work on mitochondrial and metabolic defects in tumour cells. That's what's
great about working in research, making new discoveries and connections. It's
exciting to be a part of that scientific process." Sing is a Ph.D.
candidate at the University of Toronto's Faculty of Medicine and a researcher
in Dr. McNeill's lab.
Dr. McNeill and her
research team are investigating the specific role the ft gene
plays with the hope of identifying new treatment targets for cancer and other
diseases related to Fat malfunction.
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