Marco Gallo
Friday,
July 9, 2010, 12:30 pm. Room 200, Graduate Student Centre
“misc-1/OGC is a
New Stress Response Gene and Regulator of Apoptosis, Germline Stem Cell
Proliferation and Insulin Secretion”
EXAMINING
COMMITTEE
Chair: TBA
Supervisory
Committee: Dr. Donald Riddle, Research Supervisor (Medical Genetics)
& Dr. Angela Brooks-Wilson (Medical Genetics)
University
Examiners: Dr. Douglas Allan (Cellular and Physiological Sciences)
& Dr. Donald Moerman (Zoology)
External
Examiner: TBA
SUPERVISORY
COMMITTEE
Dr. Donald L. Riddle, Research Supervisor (Medical Genetics), Dr. David L. Baillie (Molecular Biology and Biochemistry, Simon Fraser University), Dr. Angela R. Brooks-Wilson (Medical Genetics) & Dr. Marco A. Marra (Medical Genetics)
ABSTRACT
The present work produced new insights on the function of an
ascaroside molecule and a gene that affect formation of dauer larvae, a
diapause stage in Caenorhabditis elegans.
Our results indicate that the ascaroside daumone, although a
component of the dauer pheromone, does not act through signalling pathways
active in the cilia. Furthermore,
daumone has toxic effects if the animals are exposed to dauer-inducing
concentrations of the compound.
This ascaroside is not able, by itself, to recapitulate the full
spectrum of events that occur during dauer formation.
We identified misc-1 (MItochondrial Solute Carrier) as a
novel suppressor of the dauer phenotype of daf-2/IGF1R mutants. We provide evidence that MISC-1 is the
putative orthologue of mammalian OGC (2-OxoGlutarate Carrier), a metabolic
carrier of the inner mitochondrial membrane. We show that a misc-1 null allele suppresses the dauer
phenotype of daf-2 mutants by increasing insulin secretion. Consistent with this result, misc-1
mutants have increased proliferation of germline stem cells. Furthermore, we show that MISC-1 and
OGC are involved in a phylogenetically conserved apoptosis pathway. Reduced levels of MISC-1 in C. elegans
and OGC in human cells result in mitochondrial fragmentation. MISC-1 and human OGC physically
interact with the anti-apoptotic Bcl-2-family members CED-9 and Bcl-xL,
respectively, and are novel components of the mitochondrial permeability
transition pore. Decreased levels
of MISC-1 and OGC induce apoptosis in C. elegans and mouse cells. Finally, our experiments confirm that
MISC-1/OGC has Reactive Oxygen Species (ROS)-detoxifying functions in
vivo. We use misc-1 mutants to
show that increased levels of ROS do not have negative effects on life span,
contrary to current theories of aging.
Using misc-1 mutants as a model, we show that extended life span of some
C. elegans mitochondrial mutants is dependent on upregulation of
extra-mitochondrial pathways of energy production. In conclusion, we show that the metabolic protein MISC-1/OGC
affects insulin secretion, mitochondrial dynamics, apoptosis and ROS
detoxification. We propose that
MISC-1/OGC integrates metabolic and cell survival decisions by its physical
interaction with the apoptotic machinery.
PUBLICATIONS
Gallo, M., Mah,
A.K., Johnsen, R.C., Rose, A.M., Baillie, D.L. (2006) Caenorhabditis elegans dpy-14: An Essential Collagen Gene with
Unique Expression Profile and Physiological Roles in Early Development. Mol.
Gen. Genomics 275: 527-539.
Jensen, V.L.,* Gallo,
M.,* Riddle, D.L. (2006) Targets of DAF-16 Involved in C. elegans Adult Longevity and Dauer Formation. Exp. Gerontol. 41:
922-927.
Gallo, M., Riddle,
D.L. (2009) Effects of a Caenorhabditis
elegans dauer pheromone ascaroside on physiology and signal transduction
pathways. J. Chem. Ecol. 35: 272-279.
Gallo, M., Riddle,
D.L. (2010) Regulation of metabolism in C.
elegans longevity. J. Biol. 9: 7-9.
SELECTED
PRESENTATIONS
2004 West Coast Worm Meeting, University of California at
Santa Barbara, CA, USA, “Molecular Characterization of C. elegans dpy-14, a
Collagen Gene with Homology to the Human Collagen III Gene COL3A1” (Poster, 2004).
15th International C.
elegans Meeting, University of California at Los Angeles, CA, USA, “The
DPY-14 Paradox: an Essential Collagen Expressed by Both Hypoderm and Ciliated
Neurons” (Poster, 2005).
Michael Smith Laboratories Colloquium (UBC), “Identifying
new longevity genes & the dauer pheromone receptor” (Talk, 2006).
16th International C.
elegans Meeting, University of California, Los Angeles, CA, USA, “Effects
of daumone on C. elegans physiology
and signal transduction pathways” (Poster, 2007).
International Meeting of the Canadian Proteomics Initiative
(Burnaby, BC, Canada), “Mitochondrial proteomics in Caenorhabditis elegans” (Talk, 2008).
International Meeting of the Canadian Proteomics Initiative,
Burnaby, BC “Mitochondrial proteomics in C.
elegans” (Poster, 2008).
C. elegans Aging
Meeting, University of Wisconsin, Madison, WI, USA, “The novel non-essential
longevity gene misc-1 controls
mitochondrial morphology and apoptosis” (Poster, 2008).
HUPO 2008 7th World Congress, Amsterdam, The Netherlands,
“Mitochondrial proteomics in C. elegans” (Poster,
2008).
2nd Canadian Human Genetics Conference, Harrison Hot
Springs, BC, “The longevity gene misc-1/OGC
modulates apoptosis and mitochondrial morphology in C. elegans and human cells” (Poster, 2009).
17th International C.
elegans Meeting, University of California at Los Angeles, CA, USA, “The
longevity gene misc-1 modulates
apoptosis in C. elegans and human
cell lines” (Poster, 2009).
VanWoRM (Vancouver Worm Research Meeting), Simon Fraser
University (Burnaby, BC, Canada), “misc-1/OGC
modulates apoptosis in C. elegans and
human cells” (Talk, 2009).
Center for Molecular Medicine and Therapeutics, The
University of British Columbia (Vancouver, BC, Canada), “The mitochondrial
carrier MISC-1/OGC mediates apoptosis & insulin secretion” (Talk, 2009).
Diabetes Research Group, The University of British Columbia
(Vancouver, BC, Canada), “A new role for an old gene: Involvement of misc-1/OGC in apoptosis & insulin
secretion” (Talk, 2009).
Michael Smith Laboratories Colloquium (UBC), “The
mitochondrial carrier MISC-1/OGC controls oxidative stress response,
mitochondrial fission and insulin secretion” (Talk, 2010).
BIOGRAPHICAL
NOTES
Born: March,
13th, 1982, Bra, Piemônt/Italy
Academic
Studies: B. Sc. (1st Class Hon.), Simon Fraser University, 2005
GRADUATE
STUDIES
Field of
Study: Mitochondria and apoptosis, Department of Medical Genetics
Courses:
MEDG 505: Genome Analysis, Dr. S. Jones
MEDG 520: Advanced Human Molecular Genetics, Dr. C. Brown
MEDG 530: Human Genetics, Dr. L. Clarke
MEDG 540: Stem Cells, Dr. F. Rossi
MEDG 545: Current Topics in Medical Genetics Research, Dr.
A. Brooks-Wilson
MEDG 548: Directed Studies, Dr. D. Riddle
AWARDS
Graduate Entrance Scholarship (2005)
University Graduate Fellowship (2006)
William and Dorothy Gilbert Graduate Scholarship in
Bio-Medical Sciences (2008)
MSFHR SGS (2008)
Izaak Walton Killam Memorial Pre-Doctoral Fellowship (2008)
Senior Poster Prize, Medical Genetics (2008)
NSERC CGS (2009)
Genetics Society of America Poster Award (2009)
UBC FYF (2009)
Marco Gallo- PhD Programme (pdf)