Assembly of Mitochondrial Membranes in Health and Disease
Séminaire FSER organisé par Mindong Ren (New York University, School of Medicine) et Michael Schlame (New York University, Langone Medical Center) du 8 au 13 mars 2010
Miglena Angelova, Chin Lih-Shin , Steven M. Claypool, Michael Duchen, Jose Antonio Enriquez, Miriam L. Greenberg, Kerwyn Casey Huang, Nada Khalifat, Thomas Langer, Jean-Claude Martinou, Andreas Reichert, Mindong Ren, Michael Schlame, Luca Scorrano, Orian Shirihai, Cristina Ugalde, Dennis R. Voelker, Nils Wiedemann, Shirley Yan
This meeting brought together 19 scientists from Europe and North America with an interest in mitochondria. The participants had diverse backgrounds ranging from medicine and genetics to physics and chemistry, which prompted a stimulating interdisciplinary exchange of ideas in line with the mission of the Foundation. The four-day scientific sessions were loosely structured around four main topics: (1) mitochondrial protein complexes, (2) mitochondrial lipids, (3) mitochondrial membrane dynamics, and (4) mitochondrial disease processes. The format included both lectures and chalkboard talks.
The opening lecture was given by Nils Wiedemann (University of Freiburg, Germany) who provided an overview of import and assembly of mitochondrial proteins and presented new evidence about protein complex formation in mitochondrial membranes. This was followed by a talk on cryo electron tomography of the ATP synthase given by Michael Schlame (New York University, USA). New evidence suggests that the phospholipid cardiolipin plays a role in the supramolecular organization of the ATP synthase. Next, Michael Duchen (University College London, UK) reported on the effect of the protein IF1 on the function of ATP synthase. Manipulation of the expression level of IF1 has profound consequences for mitochondrial ultrastructure and energy metabolism. Finally, José Antonio Enriquez (CNIC Madrid, Spain) spoke about functional and structural interdependence of respiratory supercomplexes. The session was followed by five chalkboard talks, in which specific, mostly speculative or controversial topics were discussed. Kerwyn C. Huang (Stanford University, USA) proposed a theoretical model of membrane protein interactions based on elastic properties; Jean-Claude Martinou (University of Geneva, Switzerland) discussed protein aggregation on membranes; Steven M. Claypool (John’s Hopkins University, USA) provided a critical analysis of the widely used alkali extraction assay to probe for hydrophobic membrane-protein interactions; Nils Wiedemann (University of Freiburg, Germany) discussed the relationship between protein and lipid assembly in mitochondrial biogenesis; and Michael Duchen (University College London, UK) explored the effect of IF1 on mitochondrial turnover and autophagy.
The second day was dedicated to mitochondrial lipids, primarily to cardiolipin. The opening lecture was given by Thomas Langer (University of Cologne, Germany), who provided an overview of mitochondrial phospholipid biosynthesis and trafficking. He also reported the identification in yeast of phosphatidylglycerophosphate phosphatase, the last missing enzyme of the cardiolipin pathway. Next, Dennis Voelker (National Jewish Health Denver, USA) spoke about lipid transport pathways involving mitochondria associated membranes. Miriam L. Greenberg (Wayne State University Detroit, USA) showed that the loss of the specific mitochondrial lipid cardiolipin can lead to longevity defects that are alleviated by alterations in stress response. Another function of cardiolipin was elaborated on by Kerwyn C. Huang (Stanford University, USA) who presented a mechanism by which cardiolipin can induce curvature-mediated domain formation in bacterial membranes. Finally, Steven M. Claypool (Johns Hopkins University, USA) analyzed the mechanism, by which tafazzin mutations cause cardiolipin deficiency. Again, the session continued with five chalkboard presentations. Michael Schlame (New York University, USA) discussed the mechanism of phospholipid transacylations by tafazzin, Miriam L. Greenberg (Wayne State University Detroit, USA) discussed novel functions of cardiolipin, Luca Scorrano (University of Geneva, Switzerland) discussed lateral diffusion in mitochondrial membranes, Andreas Reichert (Goethe University Frankfurt, Germany) discussed theoretical models of the formation of cristae and crista junctions, and José Antonio Enriquez (CNIC Madrid, Spain) discussed the compartmentalization of quinones.
The theme for the third day morning session was mitochondrial membrane dynamics. Andreas Reichert (Goethe University Frankfurt, Germany) presented his lab’s recent studies on the molecular basis of cristae and crista junction architecture in mitochondria and proposed a model in which formation of cristae and crista junctions depends on antagonism between a mitochondrial membrane protein Fcj1 and the F1FO-ATP synthase subunits Su e/g. Next, Miglena Angelova (Universite Pierre et Marie Curie-Paris 6, France) described the work of her lab using giant unilamellar vesicles to model mitochondrial inner membrane and cristae, and suggested a theoretical model for elucidating the physical basis of membrane tubule formation triggered by modulation of local pH. Jean-Claude Martinou (University of Geneva, Switzerland) then discussed the mechanisms of mitochondrial membrane permeabilization during apoptosis and presented his group’s latest findings on the subject. The morning session was concluded with a talk by Orian Shirihai (Boston University, USA) on the mitochondrial dynamics of brown adipocytes, showing mitochondrial fragmentation in brown adipocytes in tissue culture activated by norepinephrine and free fatty acids. Adhering to the Fondation’s tradition, the third day afternoon was for local excursions and free activities.
Mitochondrial disease processes were the main topics of day four. Cristina Ugalde (Hospital Universitario 12 de Octubre, Spain) characterized the cellular pathophysiological consequences of mutations in BCS1L, an assembly factor that facilitates the insertion of the catalytic Rieske Iron-Sulphur subunit into respiratory chain complex III, and provided new insights into the role of pathogenic BCS1L mutations in mitochondrial function and dynamics. Lih Chin (Emory University, USA) discussed the Parkinson disease (PD)-associated kinase PINK1 and mitochondrial signaling. He showed that PINK1 protects against oxidative stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate the mitochondrial molecular chaperone TRAP1. In addition, PINK1 phosphorylates parkin, an E3 ubiquitin-protein ligase mutated in early-onset familial PD. These findings suggest that PINK1 mediates a novel neuroprotective signaling pathway in which PINK1 phosphorylates downstream effectors TRAP1 and parkin to protect cells against environmental stress and apoptosis. In line with this notion, he provided evidence that this novel mitochondrial neuroprotective signaling pathway is impaired in both familial and sporadic PD. Shi Du Yan (Columbia University, USA) showed that amyloid beta and oxidative stress perturb mitochondrial function in ageing and Alzheimer’s disease, and blockade of mitochondrial Aβ accumulation or interception of interaction of Aβ with its partners, such as the amyloid binding protein ABAD or cyclophilin D, may have a therapeutic benefit for preventing and halting Alzheimer’s disease progression. Luca Scorrano (University of Geneva, Switzerland) provided evidence that mitochondrial elongation is required for survival of starving cells. He showed that induction of autophagy by nutrient deprivation, both in vitro and in vivo, leads to mitochondrial elongation that correlates with increased fusion rate and requires the core mitochondrial fusion proteins; starvation triggers a rise in cellular cAMP levels and the activation of protein kinase A, which blocks translocation of the pro-fission protein DRP1 to mitochondria; during starvation, elongated mitochondria are spared from mitophagy, possess more cristae, and are more efficient in ATP production, as a result of increased dimerization and activity of the ATP synthase; on the other hand, mitochondria unable to elongate are dysfunctional and consume ATP, leading to starvation-induced death. Finally, Mindong Ren (New York University, USA) described his group’s effort of using fruit fly as a model to elucidate the pathogenetic mechanism of Barth syndrome, a genetic disorder of cardiolipin metabolism caused by tafazzin deficiency. By screening for suppressors of tafazzin-deficiency phenotype in fruit fly, they have identified several potential targets for therapeutic intervention of Barth syndrome. After the formal presentations, the session was concluded with five chalkboard talks. Orian Shirihai (Boston University, USA) addressed the issue of how mitochondria choose their fusion mates. He observed that the probability for a fusion event is independent of contact duration and organelle dimensions, but is influenced by organelle motility. Furthermore, the history of a previous fusion event of the individual mitochondrion influenced both the likelihood for a subsequent fusion event as well as the site on the mitochondrion at which the fusion occurred. Cristina Ugalde (Hospital Universitario 12 de Octubre, Spain) described her studies on the effect of the mitochondrial DNA background on the assembly of the respiratory chain. Lih Chin (Emory University, USA) discussed alternative mechanisms of Parkin-mediated ubiquitin signaling in regulating clearance of damaged mitochondria by autophagy. Nada Khalifat (Universite Pierre et Marie Curie-Paris 6, France) showed data of using giant unilamellar vesicles to model the effect of amyloid beta on mitochondrial cristae. Shi Du Yan (Columbia University, USA) discussed the role of cyclophilin D in mitochondrial membrane permeability transition pore and synaptic function in Alzheimer’s disease.
The intimate setting of this conference elicited lively discussions among the participants on a variety of topics, scientific or otherwise, and also brought out many hidden talents rarely seen in scientific gatherings, ranging from the entertaining chalkboard talk on how mitochondria choose their fusion mates, delivered outdoor by Orian Shirihai (Boston University, USA), to the after-dinner impromptu piano recitals performed on the concert grand in the Grande Maison by Michael Duchen (University College London, UK), Jean-Claude Martinou (University of Geneva, Switzerland), and Miriam L. Greenberg (Wayne State University Detroit, USA), just to mention a few. For many participants, this meeting was an enriching experience at many levels.