MITODYN · Role of calcium fluxes in mitochondrial dynamics

Role of calcium fluxes in mitochondrial dynamics

The MBU mitochondria Biology Unit (MBU) is an Institute dedicated to the study of mitochondria, a crucial organelle in the cell responsible for energy production. The MBU is composed of 8 different research groups exploring different aspects of mitochondria physiology. Numerous mutations in human mitochondrial DNA (mtDNA) have been identified and assigned to various deficiencies of the respiratory chain leading to severe diseases. Moreover, mitochondria house hundreds of biochemical reactions involved in processes critical for the survival and homeostatic adaptation of the cell. They are highly dynamic organelles, which adapt their shape and network depending on the cellular needs. As mitochondria play a central and unique role in metabolism, our understanding of the complex network of interrelations between mitochondria and other organelles has crucially changed our view on the cell biology of mitochondria and a new biology and pathophysiology of this organelle are emerging. Our research team is specialized in that aspect of mitochondria that is called mitochondrial dynamics. Mitochondria are in dynamic contact with the endoplasmic reticulum (ER) and this specialized contact is essential for a number of relevant processes, including mitochondrial dynamics, lipid exchange, calcium homeostasis and the programmed cell death (apoptosis). The Mitochondrial Calcium Uniporter (MCU) and its regulators subunits (MICU1-2-3, EMRE) have recently been identified as forming the key complex regulating mitochondrial calcium uptake after calcium release form the ER. The amount of calcium in the mitochondrial matrix is tightly regulated as it controls the activities of three dehydrogenases of the Krebs cycle allowing the respiratory chain to function properly. In contrast, an excess of calcium can lead to mitochondria swelling and induce cell death. Thus, mitochondrial calcium uptake and energy production are directly connected and our goal is to understand how the MCU complex interacts with other proteins or protein complexes in the inner membrane to drive its functions. Mitochondrial diseases are one of the most common groups of genetic diseases with a minimum prevalence of greater than 1 in 5000 in adults. They are characterized most of the time by severe neurological manifestation. Recently mutations in MICU-1, the major regulator of MCU, have been identified in patients suffering either from proximal myopathy associated to learning difficulties or general fatigue and lethargy associated and difficulties to adapt to effort, confirming the importance of mitochondrial calcium homeostasis in human pathology. By shedding lights on MCU complex function, we hope to contribute to the understanding of mitochondrial calcium related diseases and more broadly to all the mitochondrial diseases characterized by energy production deficiencies. The overall objective of this project is to define the complete interactome of the Mitochondrial Calcium Uptake Machinery (MCUM) in different physiological conditions and to characterize the functions associated to this complex. To address these goals, an unbiased proteomic analysis has been performed, both in cellulo (human cells) and in vivo (zebrafish), to identify the interactors of the MCUM at steady state and under different cellular stresses using the BioID technic. The mechanisms involved in the regulation of mitochondrial dynamics, apoptosis and cell migration have been studied using molecular and cell biology experiments coupled with the most recent advances in microscopic analysis. Finally, we have explored the relevance of these findings in the physiopathology associated to mitochondrial diseases using cell lines derived from patients harbouring a MCUM dysfunction.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз