Korsmeyer: The remodeling of the inner mitochondrial membrane is dramatic and was not anticipated within the biologic process of apoptosis. The fusion of the cristae coupled with the opening of the cristae junctions results in the mobilization of cytochrome C stores which can now be released from the mitochondrion to drive cell death.

Scorrano: Our results provide a mechanistic explanation for the complete release of cytochrome c which occurs during apoptosis.

Korsmeyer: This indicated that the intra-mitochondrial portion of apoptotic cell death will also be defined into distinct steps by using this combination of genetics, biochemistry, and tomographic reconstructions of mitochondria.

Scorrano: The notion of remodelling of the mitochondrial inner membrane during apoptosis is a novel concept that is now deeply investigated in several laboratories.

Korsmeyer: The death of cells exploits two pathways that operate at the mitochondrion, the power house of the cell.  One path makes the mitochondrion leaky and the second remodels it so that proteins critical for cell death can be released.

Korsmeyer: We had been pursuing the mechanism of cytochrome C release from the mitochondrion. We realized that in addition to our genetic models, biochemistry, and physiologic measurements; we also required a 3-dimensional image of the mitochondrion during apoptosis to better understand this process. Teaming up with our colleagues Carmen Mannella and Karolyn Buttle at the NCRR Resource for the Visualization of Biologic Complexity at the Wadsworth Center, who performed the highly instructive high-voltage electron microscopic (HVEM) tomography of apoptotic mitochondria, was the key.

Scorrano: During my postdoc in Stan Korsmeyer’s lab, I was investigating the mechanism of cytochrome c release combining the genetic tools Stan made available to me and the knowledge on mitochondrial physiology and biochemistry that came from my doctoral studies. Soon we realized that a one-step, outer membrane limited permeabilization process was inadequate to explain all the events that occur at the mitochondrion during apoptosis. Our biochemical, physiological, and morphological data indicated that something was happening at the level of the inner membrane: to understand this inner membrane process, we teamed up with Carmen Mannella and Karolyn Buttle, who performed the electron tomography and 3D reconstruction that proved essential to our work.

Stanley J. Korsmeyer, M.D., Ph.D.
Harvard University School of Medicine
Dana Farber Cancer Institute
Boston, MA, USA

Luca Scorrano, M.D., Ph.D.
Group Leader, Venetian Institute of Molecular Medicine
University of Padova, Italy
Assistant Scientist, Dulbecco-Telethon Institute

	Korsmeyer & Scorrano's fast moving front paper (above) is also featured in the Research Front Map in the field of Molecular Biology & Genetics.