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Novel avenues in mitochondrial function and diabetes

English title Novel avenues in mitochondrial function and diabetes
Applicant Maechler Pierre
Number 147637
Funding scheme Sinergia
Research institution Département de physiologie cellulaire et métabolisme Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Physiology : other topics
Start/End 01.11.2013 - 30.04.2017
Approved amount 1'251'182.00
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All Disciplines (2)

Discipline
Physiology : other topics
Endocrinology

Keywords (5)

diabetes; beta-cell; mitochondria; liver; metabolism

Lay Summary (French)

Lead
Les mitochondries et le contrôle métabolique, spécificités fonctionnelles dans le foie et les cellules bêta-pancréatiques
Lay summary

Le contrôle métabolique de l’organisme tend vers le maintien d’un équilibre très délicat, continuellement perturbé par les dépenses et les apports énergétiques. Ces perturbations sont corrigées par des signaux hormonaux et cellulaires. Notre consortium s’intéresse en particulier au rôle de sous-unités cellulaires appelées mitochondries et ceci dans deux organes impliqués directement dans le contrôle métabolique. Il s’agit des cellules bêta-pancréatiques qui produisent l’insuline (signal hormonal d’abondance énergétique) et du foie, comme organe central dans la distribution des ressources énergétiques.

Le maintien de la concentration de sucre dans le sang (glycémie) dans des valeurs physiologiques est essentiellement assuré par l’action de l’hormone insuline sur ses principaux tissus cibles que sont le foie, les muscles squelettiques et le tissu adipeux. Toutefois, l’équilibre glycémique résulte avant tout d’un relâchement adéquat d’insuline dans la circulation sanguine par le pancréas endocrine. Cette sécrétion dépend totalement de la bonne fonctionnalité des cellules bêta-pancréatiques qui se situent dans les îlots de Langerhans, un déficit entraînant un diabète. La cellule bêta est donc un gluco-senseur couplé à un fournisseur d’insuline, analysant en temps réel toute modification du taux de glucose dans le sang et traduisant immédiatement ces changements en ajustant la sécrétion d’insuline. Entre les périodes de repas, le foie est chargé du maintien de la glycémie en produisant du glucose. On voit ainsi le lien étroit entre îlots de Langerhans et foie dans le contrôle métabolique. La question est de savoir par quels mécanismes une même machinerie cellulaire (les mitochondries) s’adapte de façon spécifique à son organe.

Direct link to Lay Summary Last update: 20.08.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way
Li Lingzi, Martin-Levilain Juliette, Jiménez-Sánchez Cecilia, Karaca Melis, Foti Michelangelo, Martinou Jean-Claude, Maechler Pierre (2019), In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way, in Journal of Biological Chemistry, 294(34), 12581-12598.
SUMOFLUX: A Generalized Method for Targeted 13C Metabolic Flux Ratio Analysis
Kogadeeva M (2016), SUMOFLUX: A Generalized Method for Targeted 13C Metabolic Flux Ratio Analysis, in PLoS Computational Biology, e1005109.
Beta-cell mitochondrial carriers and the diabetogenic stress response
Brun T, Maechler p (2016), Beta-cell mitochondrial carriers and the diabetogenic stress response, in Biochim Biophys Acta, 2540.
Channels and transporters in cell metabolism
Sonveaux P (2016), Channels and transporters in cell metabolism, in Biochim Biophys Acta, 2359.
Embryonic Lethality of Mitochondrial Pyruvate Carrier 1 Deficient Mouse Can Be Rescued by a Ketogenic Diet.
Vanderperre B (2016), Embryonic Lethality of Mitochondrial Pyruvate Carrier 1 Deficient Mouse Can Be Rescued by a Ketogenic Diet., in PLoS Genet, e1006056.
MPC1-like Is a Placental Mammal-specific Mitochondrial Pyruvate Carrier Subunit Expressed in Postmeiotic Male Germ Cells
Vanderperre B (2016), MPC1-like Is a Placental Mammal-specific Mitochondrial Pyruvate Carrier Subunit Expressed in Postmeiotic Male Germ Cells, in J Biol Chem, 16448.
The mitochondrial pyruvate carrier in health and disease: To carry or not to carry?
Bender T (2016), The mitochondrial pyruvate carrier in health and disease: To carry or not to carry?, in Biochim Biophys Acta, 2436.
Mitochondrial pyruvate import and its effects on homeostasis
Vanderperre B (2015), Mitochondrial pyruvate import and its effects on homeostasis, in Curr Opin Cell Biol, 35.
Monitoring Mitochondrial Pyruvate Carrier Activity in Real Time Using a BRET-Based Biosensor: Investigation of the Warburg Effect
Compan V (2015), Monitoring Mitochondrial Pyruvate Carrier Activity in Real Time Using a BRET-Based Biosensor: Investigation of the Warburg Effect, in Mol Cell, 491.
Monitoring Mitochondrial Pyruvate Carrier Activity in Real Time Using a BRET-Based Biosensor: Investigation of the Warburg Effect.
Compan V, Martinou JC (2015), Monitoring Mitochondrial Pyruvate Carrier Activity in Real Time Using a BRET-Based Biosensor: Investigation of the Warburg Effect., in Mol Cell, 59(3), 491-501.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EASD - Islet Study Group and the Beta Cell Workshop Poster Identification of circulating metabolic biomarkers for early beta-cell death in pre-diabetic mice 08.05.2017 Dresden, Germany Maechler Pierre; Krznar Petra; Li Lingzi; Martin-Levilain Juliette; Zamboni Nicola;
annual meeting of the European Association for the Study of Diabetes 2016 Poster Identification of circulating metabolic biomarkers for early beta cell death in pre-diabetic mice 14.09.2016 Munich, Germany Krznar Petra; Li Lingzi; Maechler Pierre; Zamboni Nicola; Martin-Levilain Juliette;
LS2 annual meeting 2016 Poster Identification of early metabolic biomarkers for β-cell death in pre-diabetic mice 11.02.2016 Lausanne, Switzerland Martin-Levilain Juliette; Zamboni Nicola; Li Lingzi; Krznar Petra; Maechler Pierre;
2015 annual meeting of the Swiss Endocrine & Diabetes Society Talk given at a conference Glucose homeostasis and the mitochondrial morpho-function in ß-cells and hepatocytes lacking Prohibitins. 20.11.2015 Bern, Switzerland Li Lingzi; Zamboni Nicola; Maechler Pierre; Krznar Petra; Martin-Levilain Juliette;
Symposium "Metabolism & Cancer" Talk given at a conference The mitochondrial pyruvate carrier: regulation of its activity in cancer cell metabolism 25.09.2014 Nice, France Martinou Jean Claude;
50th annual meeting of the European Association for the Study of Diabetes Poster Liver-specific deletion of mitochondrial prohibitin-2 alters glucose homeostasis associated with liver damage 15.09.2014 Vienna, Austria Martin-Levilain Juliette;
50th annual meeting of the European Association for the Study of Diabetes Talk given at a conference Mitochondria and metabolic signalling in ß-cells 15.09.2014 Vienna, Austria Maechler Pierre;
SwissMito Meeting 2014 Talk given at a conference From cell metabolism to physiology through mitochondria 02.09.2014 Kandersteg, Switzerland Maechler Pierre;
SwissMito Meeting 2014 Talk given at a conference Mitochondria and cell metabolism 02.09.2014 Kandersteg, Switzerland Martinou Jean Claude;
SwissMito Meeting 2014 Poster Mitochondrial function and morphology in prohibitin-2 deleted beta-cells 02.09.2014 Kandersteg, Switzerland Li Lingzi;
Sinergia – 1st meeting Individual talk Novel avenues in mitochondrial function and diabetes 04.12.2013 Geneva, Switzerland Li Lingzi; Maechler Pierre; Hörl Manuel; Martin-Levilain Juliette; Martinou Jean Claude; Krznar Petra; Zamboni Nicola;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Journée Diabète et Obésité Western Switzerland 2014

Associated projects

Number Title Start Funding scheme
164095 NMR 600MHz for metabolomics and biomarker identification for life sciences, chemical biology and medical projects at the University of Geneva 01.01.2016 R'EQUIP
156319 Metabolic types and heterogeneity in breast cancer cell lines 01.09.2015 Project funding (Div. I-III)

Abstract

In the context of diabetes, mitochondria are sensitive organelles that may play a central role in the development of the disease. Recent advances have placed the pancreatic ß-cell at the center of the picture, since dysfunction and/or loss of these insulin-secreting cells seem to be a prerequisite for any form of diabetes. The liver is another important organ that may adapt to pre-diabetic stage and also contribute to hyperglycemia once diabetes is established through unrepressed gluconeogenesis. How dysfunction of mitochondria in ß-cells and/or in hepatocytes would contribute to diabetes is still unclear. This calls for a better understanding of mitochondrial regulation in metabolically active tissues, in particular pancreatic ß-cells and liver hepatocytes. The present proposal aims at investigating the causality between mitochondrial defects and development of diabetes and will focus on two recently generated mouse models in which Prohibitin-2 and the Mitochondrial Pyruvate Carrier are deleted, targeting mitochondrial dynamics and metabolic activation, respectively.The consortium members will team up to investigate the causal interplay from multiple angles and with multiple approaches that build on the expertise of the partner labs. Specifically, two groups will focus on the mouse models to investigate the systemic response to specific mitochondrial perturbations. A third group will use cell culture systems to perform a thorough characterization in tissue cultures under controlled conditions that will deliver a more detailed description of cellular responses to mitochondrial insults. Numerous interactions between labs are cemented in the specific aims to promote synergistic interactions. The multidisciplinary team brings together all of the experimental and theoretical apparatus necessary to address these general aims, including murine models, appropriate cell lines, wet-lab facilities, biochemical assays, metabolomics, flux analysis with stable isotopes, and mathematical modeling. It should be pointed out that the present consortium brings together complementary expertise in mitochondrial research.As a result of this research, we will obtain a quantitative analysis of the metabolic activity in standard cell lines, MEFs from lethal mouse knockouts, and primary cells isolated from adult mice by metabolomics and 13C metabolic flux analysis. The functional analysis will be complemented with a biochemical analysis of mitochondrial integrity (e.g. respiratory chain, mtDNA content, ROS), with measurements of insulin secretion in isolated pancreatic islets, and with an assessment of gluconeogenesis in murine liver with a perturbed MPC and Phb2 status. These data will be complemented with in vivo measurements of glucose tolerance, insulin sensitivity, diet-induced obesity, and loss of beta-cell mass in mice.The present project should allow us to analyze the pathophysiological consequences of various aspects of mitochondrial dysfunction on the function of beta cells and hepatocytes and how these perturbations may lead to diabetes or obesity. We expect our results to have a major impact in the field of diabetes.
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