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The multiple facets of mitochondrial regulations controlling cellular thermogenesis

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Abstract

Understanding temperature production and regulation in endotherm organisms becomes a crucial challenge facing the increased frequency and intensity of heat strokes related to global warming. Mitochondria, located at the crossroad of metabolism, respiration, Ca2+ homeostasis, and apoptosis, were recently proposed to further act as cellular radiators, with an estimated inner temperature reaching 50 °C in common cell lines. This inner thermogenesis might be further exacerbated in organs devoted to produce consistent efforts as muscles, or heat as brown adipose tissue, in response to acute solicitations. Consequently, pathways promoting respiratory chain uncoupling and mitochondrial activity, such as Ca2+ fluxes, uncoupling proteins, futile cycling, and substrate supplies, provide the main processes controlling heat production and cell temperature. The mitochondrial thermogenesis might be further amplified by cytoplasmic mechanisms promoting the over-consumption of ATP pools. Considering these new thermic paradigms, we discuss here all conventional wisdoms linking mitochondrial functions to cellular thermogenesis in different physiological conditions.

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Acknowledgements

The authors wish to warmly thank the french Direction Générale pour l'Armement and the Région Pays de la Loire for supporting this project.

Funding

This study was funded by ANR (ANR-ASTRID TEMPO-MITO Project N° ANR-21-ASTR-0010) and DGA/MinDef. FB is supported by a PhD. fellowship from DGA/Région Pays de la Loire.

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  1. Univ Angers, MitoLab, Unité MITOVASC, UMR CNRS 6015, INSERM U1083, SFR ICAT, Angers, France

    Florian Beignon, Naig Gueguen & Guy Lenaers

  2. Service de Biochimie et Biologie Moléculaire, CHU d’Angers, Angers, France

    Naig Gueguen

  3. Univ Angers, CarMe, Unité MITOVASC, UMR CNRS 6015, INSERM U1083, SFR ICAT, Angers, France

    Hélène Tricoire-Leignel & César Mattei

  4. Service de Neurologie, CHU d’Angers, Angers, France

    Guy Lenaers

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Glossary

Adenine nucleotide translocase (ANT)

Mitochondrial ADP/ATP carrier that exchanges ATP with ADP across the inner mitochondrial membrane, also called AAC for ADP/ATP carrier protein

Adenosine triphosphate (ATP) / Adenosine diphosphate (ADP)

Key molecules in the management of cellular energy. The hydrolysis of ATP to ADP provides energy to drive most chemical reactions involved in all cellular processes

Brown adipose tissue (BAT)

Adipose tissue subtype which main function is to ensure thermogenesis, through lipolysis of adipocytes, in mammals

Calcium (Ca2+)

Ions that participate in many signaling pathways, as a second messenger regulating biological functions, such as muscle contraction, nerve conduction, and metabolism

Exertional Heat Stroke (EHS)

Severe pathological life-threatening reaction characterized by a drastic increase in body temperature during a physical exertion, high external temperatures, or both

Endoplasmic reticulum (ER)/Sarcoplasmic reticulum (SR)

Organelles involved in protein synthesis and folding, and lipid synthesis, which also constitute the main intracellular Ca2+ store, essential for muscular cell contraction

Electron-transferring flavoprotein (ETF)

Flavoprotein that functions as an electron acceptor for dehydrogenases

Heat shock protein (HSP)

Family of proteins involved in cellular stress response, such as un-physiological heat, cold, UV light, or tissue damages

Inositol triphosphate receptor 3 (IP3R)

Membrane glycoprotein complex localized in ER/SR that acts as a Ca2+ channel activated by inositol trisphosphate (IP3)

Malignant Hyperthermia (MHT)

Severe reaction in response to volatile anesthetic agents whose symptoms result in pathological muscle rigidity, fever, and heart rate

Mitochondrial calcium uniporter (MCU)

Mitochondrial transmembrane protein described as the main actor in mitochondrial Ca2+ uptake

Nicotinamide adenine dinucleotide (NADH/NAD+)

Reduced and oxidized form of a coenzyme involved in redox reactions that carry electrons from one reaction to another

Non-shivering thermogenesis (NST)

Process related to an increase in metabolic heat production that is not associated with muscle activity

Oxidative phosphorylation (OXPHOS)

An aerobic metabolic pathway where NADH and FADH2 are oxidized by a series of protein complexes within the mitochondria to produce ATP

P/O

Defines the stoichiometric efficiency of OXPHOS, which is the amount of inorganic phosphate (Pi) incorporated into ATP per amount of consumed oxygen

Mechanistic P/O is the maximal P/O ratio, in the absence of proton leak or other uncoupling reactions, and is equivalent to the combination of the H+/O and ATP/O ratios

Effective P/O is the ratio of mitochondrial ATP synthesis to oxygen consumed in tissue or cells, in different metabolic conditions. It differs from the mechanistic P/O mainly according to mitochondrial proton leak or other uncoupling reactions, and by the energetic demand corresponding to the mitochondrial ATP synthesis rate

Proton gradient (Δp)

Gradient associated to the higher H+ concentration in the intra-membrane space than in the matrix, which results from the respiratory chain activity and serving as the driving force for ATP synthesis by the mitochondrial ATP synthase

Reactive oxygen species (ROS)

Reactive chemicals formed from O2, such as O2•−, that play a role in cell signaling and homeostasis, in addition to causing cellular damages by altering DNA, proteins, or lipids, when over-produced

Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)

A Ca2+ ATPase that transports Ca2+ from the cytosol into the ER/SR lumen by hydrolyzing ATP

Sarcolipin (Sln)

Small peptide regulating SERCA activity

Sirtuin 3 (SIRT3)

A NAD-dependent deacetylase localized in mitochondria regulating many metabolic functions

Tricarboxylic acid cycle (TCA cycle)

A series of chemical reactions occurring in the mitochondrial matrix where the oxidation of acetyl-CoA, derived from carbohydrates, lipids, and proteins, provides reduced cofactors to feed the OXPHOS

Uncoupling proteins (UCPs)

Mitochondrial inner membrane proteins acting as transporters to dissipate H+ gradient and generate heat, leading to mitochondrial stimulation

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Beignon, F., Gueguen, N., Tricoire-Leignel, H. et al. The multiple facets of mitochondrial regulations controlling cellular thermogenesis. Cell. Mol. Life Sci. 79, 525 (2022). https://doi.org/10.1007/s00018-022-04523-8

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  • DOI: https://doi.org/10.1007/s00018-022-04523-8

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