Energy metabolism is the process of generating energy (ATP) from nutrients such as carohydrates, fat or proteins, through a series of interconnected biochemical pathways. Those processes can be altered in a large number of genetic diseases or as a consequence of toxic insults.

Therefore, in addition to the approximately 200 rare diseases with an alteration of energy metabolism (Koopman WJ, Willems PH, Smeitink JA. Monogenic mitochondrial disorders. N Engl J Med 2012;366(12):1132–41), a huge number of individuals suffering from chronic illnesses and age-related diseases also present various aspects of bioenergetic alterations and could benefit from adapted bioenergetic modulation therapy (BIOMET). For instance, dysfunction and deregulation of numerous mitochondrial and cellular bioenergetic pathways (glycolysis, Krebs cycle, β-oxidation, amino-acid-degradation, energy sensing..) were reported in type 2 diabetes and chronic kidney diseases (CKD), metabolic syndrome, acute coronary syndrome (ACS), common neurodegenerative diseases such as Alzheimer’s, Huntington’s and Parkinson’s diseases, autoimmune disorders, age-related macular degeneration, optical atrophies, bipolar disorder, infertility, fatigue and several types of human cancer.

Moreover, environmental insults can alter energy metabolism, as iatrogeny, water pollution, pesticides, viral or bacterial infections and lifestyle. The aging process itself is characterized by a reduction of energy metabolism in several tissues, so that the number of individuals that could benefit from adapted BIOMET is in fact dramatically important. For references please read: Energy metabolism disorders. (Rossignol R. Int J Biochem Cell Biol. 2015 Jan 14)

• We provide expert consultancy on your problematics around energy metabolism
• We evaluate energy metabolism activity and alterations in your disease or conditions of interest
• We characterize the underlying biochemical, signaling and genetic regulatory mechanisms
• We suggest adapted bioenergetic strategies for energetic recovery or inhibition
• We evaluate the effect of adapted bioenergetic modulation strategies in your context

Mitochondria are central organelles involved in energy transduction to produce adenosine triphosphate (ATP) as well as energy signaling and cellular adaptations to various types of metabolic stress. The regulation of energy metabolism is multisite and includes:

1. the direct modulation of respiratory chain kinetic parameters,
2. modulation of OXPHOS intrinsic efficiency by changes in the basal proton conductance or the induced proton conductance,
3. possible changes in the morphological state of the mitochondrial compartment,
4. modulation of mitochondrial biogenesis and degradation, and
5. in situ regulation of mitochondrial heterogeneity by the cellular and the mitochondrial microenvironment.

Therefore, mitochondrial physiology research is central to the study of energy metabolism, and the modulation of mitochondrial function is also a strategy of choice to restore energy metabolism homeostasis in a large array of diseases. Several inhibitors of the respiratory chain have been discovered so far, and used in a broad range of applications such as insecticide, piscicide, and pesticide.

However, only few activators have been discovered and few compounds are active on the mitochondrial membrane, organelle biogenesis and the F1F0-ATPsynthase activity. Mitochondrial biology includes a large number of specific features, as heteroplasmy, organelle dynamics, and the existence of a biochemical threshold effect which must be considered for the investigation of energy metabolism alterations and for the development of mitochondrial drugs.

In addition to their biological function as the cell powerhouse, mitochondria are now also considered as signaling platforms that control pathways involved in cell fate (the intrinsic pathway of apoptosis) and the immune response to pathogens and cell stress. These highly dynamic organelles host numerous innate immune signaling regulators, of which some are directly linked to the OXPHOS capacity and its control of oxidative stress. Therefore, mitochondrial bioenergetics is tightly connected to innate immunity and the extent of the immune response (Lartigue L, Faustin B; Int J Biochem Cell Biol. 2013 Sep;45(9):2052-6). Importantly, mitochondrial oxidative metabolism in T cells is instrumental to acquire their adaptive effector immune functions. Therefore, they emerge as promising therapeutic targets to improve T-cell mediated antitumor immune response, impair inflammation, or inhibit autoimmune processes (Anaplerotic metabolism of alloreactive T cells provides a metabolic approach to treat graft-versus-host disease. J Pharmacol Exp Ther. 2014 Nov;351(2):298-307).

• We investigate several aspects of mitochondrial function, structure, dynamics and composition
• We study mitochondrial signaling and interactions with cellular metabolism
• We can modulate mitochondrial structure and function
• We possess cell models with various types of mitochondrial injuries (toxic and genetic)
• We study mitochondria ex situ, in situ and in vivo

The biochemical pathways involved in cellular energy transduction can undergo profound reorganization in response to various metabolic stresses associated with changes in human physiology (eg. during embryogenesis or exercise training) but also in situation of diseases. This rewiring of the biochemical pathways along with the rerouting of several metabolites allows the organism to cope with high fat and high sugar intake in the metabolic syndrome.

In cancer cells, metabolic flexibility allows tumors to grow despite the lack of oxygen or glucose, by switching from one energy substrate to another. Metabolic remodeling involves nodal enzymes (as PDH regulated by PDK1 under the control of HIF1alpha) but also transcription factors and kinases (such as AMPK).

The application of metabolic remodeling to mitochondria was named ‘mitoplasticity’ (Mitoplasticity: adaptation biology of the mitochondrion to the cellular redox state in physiology and carcinogenesis. Jose C, Melser S, Benard G, Rossignol R. Antioxid Redox Signal. 2013 Mar 1;18(7):808-49)

Metabolic remodeling constitutes a target of choice to modulate energy metabolism and advances in the field demonstrate that energy transduction processes are tightly linked with epigenetic control, amino-acid and lipid biosyntheses, antioxydant production or cellular adhesion and migration processes (Emerging concepts in bioenergetics and cancer research: Metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy. Obre E, Rossignol R. Int J Biochem Cell Biol. 2015 Feb;59C:167-181.). Therefore, large-scale methods are required to characterize the extent of metabolic remodeling in the cell, and multi-parameter analyses must be proposed to describe a pathologic condition or the mechanism of action of a metabolic drug.

Importantly, the metabolic remodeling enables tumorigenesis and immune functions in tissue-based environmental constraints such as nutrient deprivation and lack of oxygen.

• We decipher metabolic remodeling in your disease or condition of interest
• We characterize the underlying biochemical, signaling and genetic mechanisms
• We suggest adapted strategies to block or stimulate metabolic remodeling
• We provide a cellular map of metabolic remodeling and overall adaptomics
• Using bioinformatics we can predict the effect of a drug on metabolic remodeling

The regulation of energy metabolism is multisite and the potential sites for bioenergetic modulation therapy (BIOMET) with health benefits could be numerous. Some therapeutic strategies aiming at the stimulation of energy metabolism were already tested at the preclinical stage, either through pharmacology or genetic means, and clinical trials are ongoing for some drug candidates.

Some BIOMET drugs already approved or in development are indicated in blue in the figure shown on the right. Nineteen intervention sites for BIOMET are illustrated on the mitochondrion, although other possibilities exist at the level of plasma membrane or other cellular organelles (not depicted here but summarized in N°14).

oenergetic modulation can be obtained by intervention on mitochondrial turnover including organelle biogenesis and degradation (N°1,4), mitochondrial DNA (N°5), mitochondrial overall and internal structure (N°2,6), respiratory chain activity and organization (N°10,11,17,15), mitochondrial protein import and translation (N°3,18), energy substrate delivery (N°9,7), mitochondrial membrane composition and properties (N°13,8), energy sensing, nutrient sensing and retrograde signaling (N°14) and mitochondrial cell death execution pathways (N°11,12).

• We decipher the MOA of your compound on energy metabolism
• We evaluate the toxicity of drugs on energy metabolism at different sites
• We analyze the effect of a bioactive drugs on 19 points of bioenergetic regulation
• We use various models of genetic or induced bioenergetic alteration to evaluate the therapeutic potential of your drugs