Interferences with cellular bioenergetics, causes and consequences

After oxidation of substrates by metabolism (see introduction) the metabolic energy could be transformed in different forms: 1) hydrogen ions and electrons bound to redox intermediates (coenzymes) such as the redox couples NAD/NADH+H+, FAD/FADH2, FMN/FMNH2, Q/QH2. 2) ions gradients across biological membranes such as proton gradient across mitochondrial inner membrane or Na+/K+ imbalance between external medium and intracellular domain. 3) Phosphate rich energy link such as in the reaction couples: ATP/ADP+Pi or Phosphocreatin/Creatin.
All could be considered as “batteries” with different potentials and charge content. They are connected one to another: electrons and hydrogen ions are driven to oxygen in the mitochondrial respiratory chain, this electron transfer builds the proton gradient across the mitochondrial inner membrane, which is used by the mitochondrial ATP synthase to generate ATP. This ATP is hydrolyzed in ADP by the Na/K ATPase of the plasma membrane, the resulting ionic gradient (Na/K imbalance) drives neural transmission along axons… ATP is the most flexible battery: in addition to ionic transports (see above), it drives many syntheses (addition of one nucleotide to DNA or RNA needs one “ATP” and of one amino acid to a protein four) or movement (muscle contraction), etc … None of these batteries has a large charge capacity and they must be continuously re-charged by metabolic activity. Cellular ATP reserve covers seconds, at most minutes, of cellular activity. Poisoning cellular respiration, with cyanide for example, has dramatic consequences in the short time. The question arises then if alterations “mild poisoning” of cellular bioenergetics might explain some biological observations or pathologies.
Then our projects aim: a) to recognize and characterize effects of a given factor (a drug, modification in environment, aging, … ) on cellular bioenergetics ; b) to provoke known bioenergetic interference and to examine its consequences.


Pathologies, environment and cellular bioenergetics

Does cellular bioenergetics reflect/influence complex biological processes? This is the origin of numerous collaborations (Le Foll et al. 2021, Grauso et al. 2019, Roux et al. 2019, Lorenz et al. 2017, Wilson et al. 2017, Haidar et al. 2017).
A recurring issue is the effect of small molecules on mitochondrial bioenergetics, for example the influence of methylene blue in (collaboration with Dr Ph Haouzi Pennstate University USA, Haouzi et al. 2019, 2018). This applies to drugs and implies partnership with pharmaceutical companies in the past (Boutin et al. 2019) and presently: Post-Doctoral contract of N Hammad.
Chemicals are not the unique drivers of changes in cellular energy metabolism. For example, we have shown how variations in the external osmotic pressure impact on cellular bioenergetics (Hamraz et al. 2020) and this appears relevant to metabolic changes associated to inflammation.

With these examples we aim to highlight how the constraints imposed by cellular bioenergetics and oxidative metabolism could be relevant in biological models (Ransy et al. 2020, Bouillaud et al. 2021).

Legend: The ATP turnover rate was quantified in pmol/min/well in “Seahorse experiments” with cells (CHO) in their isosmotic medium or in a 2x hypertonic medium. When glucose is present, Hypertonic conditions decrease the contribution of mitochondrial respiration (OxPhos ATP) and promote lactic fermentation (Glycolytic ATP). In absence of glucose Only OxPhos ATP is obtained, cellular ATP turnover rate is reduced and hypertonic conditions reduces it further. Cells remain viable. Therefore, a significant reduction in the cellular energy expenditure (ATP turnover rate) is possible to survive in an environment adverse for cellular bioenergetics.

Cellular ATP turnover rate (adapted from Hamraz et al. 2020)
Decision chart for the Warburg effect (adapted from supplementary in Bouillaud et al. 2021)

Legend: Warburg effect is the persistence of the low yield lactic fermentation although oxygen is available to allow the high yield mitochondrial respiration (mitochondrial oxphos) to take place. This appears therefore as a metabolic bias and reasons for it should be understood. This chart proposes a scheme to decide whether or not a genuine Warburg effect “a preference for lactic fermentation” is taking place opposed to an obligatory adaptation to the impairment of mitochondrial oxphos because of insufficient oxygen supply or direct impairment (poisoning).

Aging process in Ants

This project is supported by a CNRS grant 80prime shared between F. Criscuolo (Institut plurisdisciplinaire Hubert Curien , CNRS UMR Strasbourg) and F Bouillaud (Cochin, Paris),

Maïly Kervella PhD project 2020-2023.

A theory states that aging is directly linked to the intensity of oxidative energy metabolism. To a large extent this is supported by the consideration of metabolic and aging rates in different animals. However, this implies large differences in genomes. Social insects offer a unique opportunity because in a same colony the individuals are genetically close but show different lifetime. For example, with the garden black ant (Lasius niger) under laboratory conditions the queen could live more than ten years while a worker would die within two/three years. In addition, the age of workers could be deduced from their role in the colony. This project compares therefore oxidative metabolism and mitochondrial activity in queens and workers of different age.


Frédéric Bouillaud

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