DS0403 -

An unexpected link between mitochondrial dynamics and the mevalonate pathway: a new pathophysiological mechanism in mitochondrial disease – DynaMitoQ10

Submission summary

Mitochondria hold a central role in cell metabolism as they produce the bulk part of the energy currency ATP through the oxidative phosphorylation system. Beside their role in energy transduction, mitochondria are also involved in some intermediary metabolism pathways, Calcium homeostasis, cell behavior, and apoptosis. Mitochondrial dysfunction is a common cause of disease in both children and adults. Within the cell mitochondria form a dynamic network as a result of balanced fusion and fission. Mammalian mitofusin 1 (MFN1) and mitofusin 2 (MFN2) belong to the GTPase family of proteins and are required for mitochondrial outer membrane fusion. Despite their high similarity and their common role in mitochondrial fusion through their physical interaction, MFN1 and MFN2 seem to functionally differ. Mutations in the Mfn2 gene were recently identified in patients affected with Charcot-Marie-Tooth neuropathy type 2A. Remarkably, no Mfn1 related diseases have been reported so far. Due to the poor understanding of the pathophysiological mechanisms underpinning this neuropathy, there is currently no effective treatment to reverse or slow the underlying disease process. My recent investigation of heart tissue specific Mfn2 mouse knockouts unravelled that loss of MFN2 causes depletion of mitochondrial coenzyme Q, which in turn, leads to respiratory chain dysfunction. The coenzyme Q depletion originates from a global reduction in the mevalonate synthesis pathway, which produces the isoprenoid precursor of coenzyme Q. The mevalonate synthesis pathway is of great medical interest as inhibition of this pathway by statins is commonly used to treat hypercholesterolemia. Beyond its role in cholesterol synthesis, the mevalonate pathway also produces essential precursors for the Coenzyme Q10 de novo synthesis and for the prenylation of proteins. In vivo studies of independent mouse models have previously shown that MFN2 is required to maintain mitochondrial function and morphology, steroidogenesis activity, and autophagy. Interestingly, The discovery of the role of MFN2 in maintaining the activity of the mevalonate pathway could help to address the great diversity of phenotypes related to the loss of MFN2 through a common metabolic origin. Indeed, defects in steroidogenesis, coenzyme Q and autophagy previously associated with loss of MFN2 are also known to rely on precursors produced by the mevalonate biosynthetic pathway. The discovery of an unexpected link between mitochondrial fusion and the mevalonate pathway shed a new light on the metabolic role of mitochondrial dynamics and opens up innovative therapeutic perspectives.

My working hypothesis is that the mevalonate biosynthetic pathway plays a major role in the pathophysiology of neuropathy associated to defective mitochondrial dynamics. The use of new cell lines, cultured and analyzed in near physiological conditions combined to the analysis of new transgenic mouse models will help our laboratory to further decipher the molecular link between the mevalonate biosynthetic pathway and mitochondrial dynamics. In addition, the DynaMitoQ10 research project aims to develop and evaluate the potential of new therapeutic approaches to prevent adverse side effects related to the impairment of the mevalonate pathway. Obtaining ANR JCJC 2016 is an indispensable financial support that will allow me to establish my independent research aiming to decipher the importance of organelles morphology and inter-organelles interactions in maintaining the energy homeostasis of the cell.

Project coordinator

Monsieur Arnaud Mourier (Institut de Biochimie et de Genetique Cellulaire)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IBGC - UMR5095 Institut de Biochimie et de Genetique Cellulaire

Help of the ANR 359,866 euros
Beginning and duration of the scientific project: December 2016 - 48 Months

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