Mitochondrial homeostasis anti-cellulite strategy

 It is now well known that mitochondrial DNA, due to its closeness to reactive oxygen species, and mainly H2O2, is continually subject to damages leading to mitochondrial malfunction. However H2O2 is a messenger of vital importance in a large number of metabolic reactions. Therefore it is necessary to ensure a mitochondrial in and out H2O2 balance: mitochondrial homoeostasis. Aquaporine 8 (AQP8) was discovered in keratinocytes in 2008 by Codif International and is now famous for its role in skin hydration. Recently, Biernet et al13 discovered a new function of AQP8 in transporting H2O2 from mitochondria to the cytosol. Carrying on this work, Codif International then localised AQP8 in adipocyte and fibroblast mitochondria and made the connection between AQP8, mitochondrial homeostasis and cellulite treatment. Mitochondria are usually described as the powerhouse unit of the cell, because they contain the molecular machinery that governs many distinct metabolic pathways by which chemical energy is converted into ATP.1 Two of the key mechanisms are usually targeted by contouring cosmetics: collagen synthesis processed by fibroblasts, and lipolysis processed by adipocytes (Fig. 1). It has been long known that a decrease in intracellular ATP in adipocytes induced by uncouplers of oxidative phosphorylation or inhibitors of the mitochondrial respiratory chain can inhibit the lipolysis stimulated by catecholamines.2 Furthermore, lipolysis is now accepted to be a metabolic pathway that depends on the energy status of adipocytes as the activation of AMPactivated protein kinase, a central intracellular molecular sensor of energetic stress, can decrease the lipolysis stimulated by agonists of alphaadrenoreceptors. 3 These data sets clearly show a direct link between lipolysis and the functional state of the mitochondrial system in adipocytes. Meanwhile, it is well established that the mitochondrial genome displays a very high mutation rate (10 to 20 times higher than nuclear genome) because of the proximity of sites of reactive oxygen species (ROS) production. ROS are generated in a number of key metabolic processes in cells like the electron transport chain in the inner mitochondrial membrane (Fig. 1).4 Cells have a number of ROS-scavenging systems that are able to remove these molecules and to maintain a relatively low and constant ROS concentration.5 However, ROS are also intermediates in various signal transduction pathways and have been shown to initiate responses to various stresses and disorders. We understand here the duality of H2O2, potentially toxic for the mitochondria, but useful in different signalling pathways. It is therefore indispensable for the cell to maintain a balance between intra-mitochondrial H2O2 concentration and cytosol H2O2 concentration. This balance is called mitochondrial homeostasis and implies the channelling of H2O2 from the mitochondrial matrix to the cytosol. The transport of larger, polar or charged molecules depends on transporters and channels to decrease the activation energy needed for passive diffusion. Expression of aquaporins in yeast secretory vesicles lowered the activation energy for diffusion of water from between 46 and 55 to 17 kJ mol_1.6 H2O2 has a permanent dipole moment very similar to that of water.7 Consequently simple passive diffusion of H2O2 across the lipid bilayer should be limited as for water. The striking chemical similarity between water and H2O2 points to aquaporins as likely candidates for H2O2 permeation. Aquaporins form a large family of membrane proteins with members in all kingdoms of life and are known as efficient water channels.8,9 H2O2 has almost the same size, dielectric properties, and capacity to form hydrogen bonds as water does. Exactly those properties are the main factors determining the diffusion through major intrinsic proteins including aquaporins. In mammals, AQP8 is present in the plasma membrane10 and has recently been localised to the inner mitochondrial membrane.11 AQP8 may have a function in releasing H2O2 from the mitochondrial matrix in situations when the electron transport chain is highly reduced, conditions known to generate ROS.12 In 2006, Bienert et al13 presented the first molecular genetic evidence for the the diffusion of H2O2 through specific members of the aquaporin family, including AQP8. These last considerations suggest the role of AQP8 in maintaining mitochondrial homeostasis in adipocytes and fibroblasts for a slimming application. In addition, Henzler and Steudle14 showed that mercury, an aquaporin blocker, repressed H2O2 accumulation in internodal cells of the algae Chara corallina. The authors therefore suggested that some aquaporins in Chara served as peroxiporins. It is here interesting to note that Chara is an algae belonging to the family of Corallinacea, like Jania rubens, an alga studied by the laboratory of Codif Recherche et Nature, who has been the first one to cultivate a macro-alga in photo-bioreactor. The aim of the work presented hereafter is to confirm the expression of mitochondrial AQP8 in human adipocytes and human fibroblasts, to study the potential effect of a Jania rubens extract on AQP8 synthesis and the consequences on collagen synthesis, lipolysis and cellulite grade.

Description of Jania rubens

 Jania comes from the Latin Janus, the two headed god of Roman mythology, guardian of the House of the Gods. Rubens means the colour red. The alga was given this name due to its dichotomous branching and its colour. Jania rubens is a calcified alga that grows from 15 to 40 mm in height. It is fairly rare and grows in well-lit areas, on underwater rocky surfaces and also on marine sandy floors and in marine zostera herbaria. To prevent removal of this rare resource from its natural habitat, our laboratory has been the first one to develop cultures in a photo-bioreactor with controlled temperature, light and culture media. The algae obtained using this method have the shape of a ‘pompon’ (Fig. 2), similar to that observed in its natural habitat, but without any epiphytes. The obtained extract: Actiporine 8G is guaranteed to be 100% natural and to have no traces of impurities.