Contrôle de la qualité des mitochondries et maladies neurodégénératives / Mitochondrial quality control and neurodegenerative diseases

Séminaire FSER organisé par Richard Youle (NINDS/NIH, Bethesda, USA) du 4 au 9 mai 2015

Participants

Baris Bingol, Olga Corti, Ivan Dikic, Michael Glickman, David Komander, Mondira Kundu, Renaud Legouis, Jean-Claude Martinou, Noriyuki Matsuda, Heidi McBride, Miratul Muqit, Alban Ordureau, Leo Pallanck, Christoph Potting, Felix Randow, Fulvio Reggiori, Katrin Rittinger, Anu Suomalainen Wartiovaara, Richard Youle

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Abstract

From May 5th to May 9th, 2015, the meeting entitled “Mitochondrial quality control and neurodegenerative diseases” was held at La Fondation des Treilles. Nineteen scientists from nine countries, including three junior scientists, presented talks and participated in intense discussions. The expertise of the meeting participants ranged from cell biology, genetics, biochemistry, and structural biology to medicine and included representatives from both academia and the pharmaceutical industry.

The scientific focus of this meeting was how mitochondrial damage, dysfunction and mitochondrial DNA mutation accumulation lead to cell death and neurodegenerative diseases, and the quality control pathways that mitigate these processes. A major driving force for the meeting was the relatively recent discovery that two genes mutated in heritable forms of Parkinson’s disease, PINK1 and Parkin, play key roles in the lysosomal degradation of damaged and dysfunctional mitochondria through a process termed mitophagy. Work on PINK1 and Parkin over the past several years has advanced to the point where collaborative contributions from scientists with diverse expertise now has the potential to lead to rapid progress in our understanding of mitochondrial quality control, and the development of therapeutics for mitochondrial disorders. Thus a major purpose of this meeting was to advance understanding in the field by bringing together experts in related areas who had never met and to introduce others in tangential disciplines to foster collaborations.

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Compte-rendu

The meeting “Mitochondrial quality control and neurodegenerative diseases,” held at La Fondation des Treilles, included 19 scientists from nine countries, all of whom presented talks and participated in prolonged discussions. Three junior scientists, two physician scientists and two scientists working in pharmaceutical companies were among the 19 speakers who considered how mitochondrial dysfunction is linked to neurodegenerative diseases, how endogenous mitochondrial quality control processes may mitigate neurodegenerative disease, and how quality control processes may be augmented to prevent or diminish neuron loss. The breadth of expertise among the speakers brought a wealth of insight and intense and critical discussion to bear on an important aspect of neurodegenerative disease.

The meeting was divided into four sessions, with each session comprising an entire day. The first session focused on autophagy, xenophagy, and ubiquitin-regulated pathways that either participate in mitochondrial quality control or yield insight into the process from parallel pathways in cells. Fulvio Reggiori showed how kinases regulate upstream autophagy machinery and described their role in anti-viral activity. Felix Randow presented exciting unpublished data on the mechanism of bacterial elimination by autophagy, and Ivan Dikic presented related results on how autophagosomes recognize their cargo, how endoplasmic reticulum can be recognized by autophagosomes, and how autophagy may be linked genetically to amyotrophic lateral sclerosis (ALS). Katrin Rittinger summarized insights from structural biology on how an E3 ubiquitin ligase functions in NF-kB activation and provided general guidance in discussion of later talks on how her work informs the mechanisms of the related E3 ligase Parkin. Renaud Legouis presented data from genetic studies in C. elegans that described some of the machinery involved in the degradation of paternal mitochondria following fertilization. This work was followed by a lively discussion on the logic of destroying paternal mitochondria, which appears to be an evolutionarily conserved process.

A second session on ubiquitin phosphorylation and deubiquitinases focused primarily on exciting new results regarding the mechanism by which PINK1 and Parkin promote mitophagy. Noriyuki Matsuda, Alban Ordureau and Miratul Muqit presented their latest unpublished results on PINK1 phosphorylation of ubiquitin and Parkin, and how these phosphorylation events lead to the mitochondrial recruitment and activation of Parkin. David Komander and Baris Bingol presented work relating to the mechanisms by which deubiquitinases remove ubiquitin from polyubiquitin chains and the types of substrates that they act upon. Of particular interest, Baris Bingol showed how particular deubiquitinases can counteract Parkin, thus highlighting the possibility that deubiquitinases may be good drug targets to promote mitochondrial quality control. Finally, Michael Glickman discussed the influence of ubiquitin phosphorylation on proteasomal degradation, and showed that oxidative stress leads to proteasome disassembly, thus raising the possibility that a defect in mitophagy could also trigger downstream proteasomal impairment.

A short session focusing on mitochondrial biology included a talk by Jean-Claude Martinou on mitochondrial metabolism, and in particular the regulation of pyruvate metabolism by the mitochondrial pyruvate transporter. Christoph Potting discussed his graduate work on the mechanism of cardiolipin synthesis in mitochondria, and his more recent postdoctoral studies aimed at the characterization of factors derived from a screen to identify new mitophagy regulators. Mondira Kundu presented new results on how upstream kinases regulate mitophagy and function in neurons and hematopoietic cells. Of particular interest, Dr. Kundu reported that there is cross-talk between autophagy and the constitutive secretory pathway.

The last session of the meeting focused on neurodegeneration models and a new feature of mitochondrial quality control that appears to be regulated by PINK1 and Parkin. Anu Suomalainen reported on a mouse model that accumulates mitochondrial DNA deletions and on human IPS cells from patients with mitochondrial DNA mutations. Olga Corti described physical and functional interactions of PINK1 and Parkin with the mitochondrial outer membrane protein import complex and with a mitochondrial dehydrogenase. Finally, talks by Richard Youle, Leo Pallanck, and Heidi McBride contributed insights into a novel mitochondrial vesicle-mediated form of mitochondrial quality control. Dr. McBride, who first discovered this vesicle-mediated pathway, discussed the mechanisms by which these vesicles form, their composition, and the cellular locations to which they are targeted. In addition, Dr. Youle reported on a mouse model of mitochondrial DNA mutation accumulation and showed that loss of endogenous Parkin in these animals caused a Parkinson’s disease–like phenotype. Dr. Pallanck also showed data that indicates, curiously, that mitophagy contributes variably to the degradation of individual mitochondrial proteins.

The participants lauded the meeting format. Questions and comments came continuously during the lectures and the vibrant discussions following each talk included all the participants. Especially vigorous debate ensued on two models of Parkin mechanism that lead to feed-forward activation. At least two active collaborations have begun between participants because of this meeting. Especially valuable was the presence of scientists outside the field of neurodegeneration who weighed in from distinct perspectives and expertise. The consensus among participants was that this was the best meeting style they had ever experienced. Undoubtedly the meeting site also lifted the spirits and invigorated the group.