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EQUIPE 2

 

Team 2 - Bioenergetics and metabolism (leader: Eric Fontaine, PUPH)

Team 2 has two main fields of interest in bioenergetics, namely: (i) mitochondrial physiology and cell death, and (ii) energy metabolism, exercise and nutrition. The former has been one of the strong points of the unit, yielding several important publications (Cell Death Dis, JBC), and being supported by public, association and industry funding, including ANR (CADMIDIA), AGIR à dom, and POXEL (Lyon, France). However, several aspects of our original project were affected by the premature death of Prof. Xavier Leverve (PUPH) in 2010, former director of our unit, and to lesser degree by the retirement of Dr Christiane Chauvin (CR INSERM) and the relocation of Dr Luc Demaison (CR INRA) for private reasons to Clermont-Ferrand in 2012. New recruitments at UJF have been impossible so far due to UJF budget restrictions.

The mitochondrial permeability transition pore (PTP) is a mitochondrial inner membrane channel involved in cell death induced by oxidative stress. Even if its molecular nature is still an issue of controversy, its regulation has been studied in quite some detail in hepatic tissue, with the implicit assumption that it is identical in all other tissues. Although a technique for measuring PTP opening in isolated mitochondria has been known for long, its direct visualization in intact cells remained a challenge for a long time, only solved in 1999. However, this initial technique (the so-called calcein-cobalt-method) was unable to differentiate between a transient and persistent PTP opening, with only the latter triggering cell death. This led to inconsistencies between the number of cells where PTP was (or had been) in an open state, and the number of cells undergoing apoptosis. In this context, we have been at the origin of two major advances:

  • First, we have established a novel PTP detection technique based on the simultaneous measurement of mitochondrial membrane potential and cellular repartition of NADH. It is capable to differentiate between transient and permanent PTP opening (Dumas et al 2009 J Biol Chem). This technique is now routinely used in our laboratory and allowed to demonstrate that PTP opening is involved in glucose, fructose (Lablanche et al 2011 Cell Death Dis), and alcohol toxicity (Lamarche et al 2013 Chem Res Toxicol) and ischemia-reperfusion (Lablanche et al in revision).
  • Second, we demonstrated that regulation of PTP is partially tissue-dependent. This makes the study of PTP even more complex and suggests that its molecular nature is considerably different, depending on the tissue considered. In turn, this discovery allowed us to develop a strategy to induce cell death selectively in certain cancerous cells but preserving the healthy parental cells (Devun et al 2010 PLoS One). Back ten years ago, we have been at the origin of the observation that inhibitors of respiratory complex I also inhibit PTP opening, but only in certain tissues. In the present contracting, we have up-dated the molecular mechanism at the origin of this observation (Li et al 2012 BBA Bioenergetics).

Mitochondria and the adaptation to the metabolic environment, in particular in liver, has been another topic in mitochondrial physiology that has been pursued despite the premature death of the scientific leader.

  • Exposure to high fat diet, a key feature of contemporary western diet, affects regulation of oxidative phosphorylation in a rat model by (i) lowering the mitochondrial quinone pool, (ii) increasing its degree of reduction, (iii) affecting lipid composition of mitochondrial membranes, and (iv) increasing production of reactive oxygen species (Vial et al 2011 J Hepatol).
  • Preclinical tests of a novel oral antidiabetic drug (Imeglimin, Poxel) have been under embargo until recently and will be published shortly.

We are very much interested to continue this topic for which we acquired a recognized expertise, among others by industry contracts. Nevertheless, in the context of our limited human resources, this topic requires to be reinforced by the appointment of a competent scientist in this domain.

Effects of exercise and nutrition on energy metabolism

  • The study of polyphenols of nutritional origin is another important topic of the team. It is at the origin of numerous scientific collaborations and industry contracts. During the past 5-year period, have shown that cinnamon extract modifies the liver metabolism of glycogen (Couturier et al 2011, Metabolism) and prevents the deleterious effects of a high fat/high fructose diet in the brain (Anderson et al 2013, PLoS One). More recently, we have been interested in the effects of aleurone and we could show that this polyphenol modifies the composition of omega-3 fatty acids within membrane phospholipids (2014, Food and Nutrition Research, in press).
  • The importance of physical exercise and nutrition on muscle metabolism, but also on other tissues, is an emerging topic of our team. This topic has not yet yielded publications coming from our team, but very promising results have been obtained in our laboratory that motivate us to develop this subject. For this reason, C Moinard (MCF Univ. Paris Descartes), an expert in this field, has joined us in 2013 in the frame of a “delegation universitaire”, with the explicit ambition to recruit him on a PR position. A summary of his research during the last 5 years is given below.