The overall goal of this research project is to highlight the molecular and biochemical mechanisms by which some mtDNA polymorphisms could change the mitochondrial metabolism.
Mitochondria are the powerhouses of eukaryotic cells, being the main source of the cellular energy (ATP). Besides, these cell organelles are involved in many other essential processes like Ca2+ signaling, apoptosis, production of heat and reactive oxygen species, as well as biosynthesis of amino acids, nucleotides and fatty acids.
Mitochondria have their own maternally inherited DNA (mtDNA), which does not recombine and accumulates mutations much faster than nuclear DNA (nDNA). These properties are used for understanding the remote origins of the human race, for tracing population movements, and for matching people who belong to the same female line (characterized by their haplogroup). Indeed, mitochondrial haplogroups are defined by a distinctive set of neutral mutations of the mtDNA, socalled polymorphisms that have occurred during human evolution and migration.
Several recent studies have demonstrated associations between haplogroups and specific geographic repartitions or diseases (neurodegenerative or multifactorial diseases), suggesting that haplogroups, and therefore some of the polymorphisms defining them, are able to have an effect on mitochondrial functions. Thus haplogroups can be considered as a protector or risk factors for several pathologies and mitochondrial diseases.
The experimental approach will be perform on yeast cells that offer a unique possibility in that mutants exhibiting complete or very severe respiratory deficiencies can grow by fermentative metabolism on glucose and are therefore amenable to molecular functional studies.
The analysis of a wide set of parameters (physiologic, bioenergetic,etc.), will allow highlighting variations in the mitochondrial metabolism due to different mitochondria belonging to different yeast laboratory strains.
Recently, mitochondrial replacement therapy has been proposed as an innovative technology for assisted in vitro fertilization for women being affected by a hereditary mitochondrial disorder, and preclinical trials are actually performed (Hyslop et al. 2016, Zhang et al. 2016). Here, after being fertilized by the father sperm, the pronuclei of a mother oocyte from women being affected by a hereditary mitochondrial disorder are transferred in an fertilized enucleated donor oocyte (containing functional mitochondria) (Hyslop et al. 2016).
This new method reinforces the debate on the impact of mtDNA variations on energetic metabolism, raising additionally the question of an eventual mitochondrial-nucleus incompatibility (Rishishwar and Jordan 2017, Levin et al. 2014, Meiklejohn et al. 2013) and thus of the safety of this new approach and the consequences of the offspring; highlighting the necessity of a more profound understanding of mtDNA variants influence on the interaction of nucleus and mitochondria. Our research project is to propose a pluridisplinary and multisystemic approach in order to have an integrate view of this phenomenon.