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                    BIOINFORMATICS COLLOQUIUM
               School of Computational Sciences
                    George Mason University
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             On the role of outer membrane channels in 
                 mitochondria-initiated apoptosis

                        Dr. Marco Colombini
                      University of Maryland


                 Tuesday, April 11, 2006
                             4:30 pm
           Verizon Auditorium, Prince William Campus
ABSTRACT 
In addition to its many critical metabolic functions, mitochondria also 
have the ability to cause the entire cell to undergo programmed cell 
death, apoptosis.  In many cell types, mitochondria somehow detect and 
integrate information about cellular metabolic state and decide whether 
to activate the cytosolic apoptotic system.  While many mechanisms are 
under investigation, there is general agreement that the signal to the 
cytosol is the release of a set of proteins from the intermembrane 
space of mitochondria.  In the cytosol these pro-apoptotic proteins 
initiate a cascade that leads to the execution phase of apoptosis.   
One event that leads to the release of these proteins is the closure of 
VDAC channels.  VDAC normally facilitates the flow of virtually all 
metabolites between mitochondria and cytosol and thus VDAC closure 
signals to the mitochondrion a serious alteration in cellular state. 
This condition is reversible up to the point of protein release.  VDAC 
closure occurs naturally upon removal of growth factors or can be 
induced by addition of specific artificial agents.  Both result in 
protein release.  The pathway for protein release is not VDAC.  One 
pathway with the right properties is a ceramide channel.   These 
highly-organized channels can form in the outer membrane as steady-
state levels of ceramide rise but their formation may be inhibited or 
reversed by other factors, including other sphingolipids.  Ceramide 
channels can form in phospholipid membranes in the total absence of 
proteins and can be visualized by electron microscopy.  Bcl-2 family 
protein, well known for controlling the initial phase of the apoptotic 
process from the cytosolic side, can act on VDAC and may influence the 
formation of ceramide channels.  Thus the regulation of VDAC gating and 
the formation of ceramide channels are likely to be critical to 
mitochondria-initiated apoptosis.  (supported by NIH grant  NS42025)  

BIOSKETCH
Dr. Colombini obtained a Ph.D. in Biochemistry (1974) from McGill 
University for his research on the energetics of Na+ -gradient driven 
active transport of amino acids in plasma membrane vesicles.  He 
discovered the VDAC channel in mitochondria and was the first to record 
its single-channel properties during his post-doctoral research with 
Dr. Alan Finkelstein at Albert Einstein Coll. of Med. (1974-76).  He 
was appointed Assistant Prof. of Neuroscience and Physiology at Albert 
Einstein Coll. of Med.  (1976-79).  He joined the Zoology (now Biology) 
Dept. at the University of Maryland in 1979 and is now a Full 
Professor.  His research has focused on the structure and gating 
properties of VDAC channels and their role in apoptosis.  More recently 
his lab discovered ceramide channels and proposed that these are the 
pathways for protein efflux from mitochondria that lead to end-stage 
apoptosis.  He teaches courses on “Membrane Biophysics” and “Physical 
Chemistry for Biologists”. He serves as chair of the Bioenergetics 
Subgroup of the Biophysical Society and is on the editorial board of 
Biochimica et Biophysica Acta.  


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