The conundrum of hot mitochondria

Macherel, David; Haraux, Francis; Guillou, Hervé; Bourgeois, Olivier

doi:10.1016/j.bbabio.2020.148348

Cited by 40 publications

(57 citation statements)

References 93 publications

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“…It has been demonstrated that the optimum temperature of PfMQO is 37 • C. Surprisingly, our analysis showed that TgMQO displayed an optimum temperature for its activity at 50 • C (Figure 2a). This may suggest that under physiological conditions, T. gondii mitochondria are maintained at 50 • C, as recently suggested for respiratory complex enzymes (complex III, II-III, IV, and V) in mitochondria of human cells [73,74], or is the result of adaptation to mitochondrial recruitment after invasion [75][76][77][78].…”

Section: Discussionmentioning

confidence: 79%

Biochemical Studies of Mitochondrial Malate: Quinone Oxidoreductase from Toxoplasma gondii

Acharjee

Talaam

Hartuti

et al. 2021

IJMS

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Toxoplasma gondii is a protozoan parasite that causes toxoplasmosis and infects almost one-third of the global human population. A lack of effective drugs and vaccines and the emergence of drug resistant parasites highlight the need for the development of new drugs. The mitochondrial electron transport chain (ETC) is an essential pathway for energy metabolism and the survival of T. gondii. In apicomplexan parasites, malate:quinone oxidoreductase (MQO) is a monotopic membrane protein belonging to the ETC and a key member of the tricarboxylic acid cycle, and has recently been suggested to play a role in the fumarate cycle, which is required for the cytosolic purine salvage pathway. In T. gondii, a putative MQO (TgMQO) is expressed in tachyzoite and bradyzoite stages and is considered to be a potential drug target since its orthologue is not conserved in mammalian hosts. As a first step towards the evaluation of TgMQO as a drug target candidate, in this study, we developed a new expression system for TgMQO in FN102(DE3)TAO, a strain deficient in respiratory cytochromes and dependent on an alternative oxidase. This system allowed, for the first time, the expression and purification of a mitochondrial MQO family enzyme, which was used for steady-state kinetics and substrate specificity analyses. Ferulenol, the only known MQO inhibitor, also inhibited TgMQO at IC50 of 0.822 μM, and displayed different inhibition kinetics compared to Plasmodium falciparum MQO. Furthermore, our analysis indicated the presence of a third binding site for ferulenol that is distinct from the ubiquinone and malate sites.

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Section: Discussionmentioning

confidence: 79%

Biochemical Studies of Mitochondrial Malate: Quinone Oxidoreductase from Toxoplasma gondii

Acharjee

Talaam

Hartuti

et al. 2021

IJMS

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“…A recent review summarizing empirical and theoretical findings surrounding the debate of accurate in vivo mitochondrial temperatures identifies 10 studies that report an increase in temperature with mitochondrial respiratory uncoupling, and 5 of those studies are reported to identify temperature heterogeneity in the organelle when using fluorescent thermosensors to study mitochondrial heating and temperature (see Table 1 in reference). 96 Of these studies, Chretien et al (2018) notably provided seminal evidence to suggest that several components of the electron transport system function optimally at temperatures reaching over 50°C, or ~10°C higher than the encompassing cell when studying HEK 293 cells and primary skin fibroblasts. 82 These findings have since been verified in HeLa cell lines.…”

Section: Aim 3a: Temperature Correcting Standardized Hrr Measures Wmentioning

confidence: 99%

“…83 Several issues have been raised in opposition of these findings, such as: (i) methodological concerns specific to research utilizing fluorescent probes for determination of cellular temperatures that includes possibly confounding influence(s) of the surrounding environment (ie pH, reactive oxygen species, membrane potential, viscosity and ionic strength); (ii) thermodynamic modelling of the cell describing the so-called "10 −5 gap" theory that renders intracellular temperature gradients as all but impossible and (iii) biological improbabilities of such high in vivo temperatures that would challenge human biological function as we understand it. [96][97][98] Thus, considerations for appropriate temperature corrections range from a minimum that reflects the cellular temperature specific to the tissue being analysed when taking into account the metabolic state also being measures (ie basal vs maximal metabolic states) to a maximum of 10°C above that minimum value. As noted previously, temperature corrections used to reflect the temperature of the exercising muscle (eg 38°C) are still lower than in vivo methodologies identify.…”

Section: Aim 3a: Temperature Correcting Standardized Hrr Measures Wmentioning

confidence: 99%

Contextualizing the biological relevance of standardized high‐resolution respirometry to assess mitochondrial function in permeabilized human skeletal muscle

Jacobs

Lundby

2021

Acta Physiologica

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Aim This study sought to provide a statistically robust reference for measures of mitochondrial function from standardized high‐resolution respirometry with permeabilized human skeletal muscle (ex vivo), compare analogous values obtained via indirect calorimetry, arterial‐venous O2 differences and 31P magnetic resonance spectroscopy (in vivo) and attempt to resolve differences across complementary methodologies as necessary. Methods Data derived from 831 study participants across research published throughout March 2009 to November 2019 were amassed to examine the biological relevance of ex vivo assessments under standard conditions, ie physiological temperatures of 37°C and respiratory chamber oxygen concentrations of ~250 to 500 μmol/L. Results Standard ex vivo‐derived measures are lower (Z ≥ 3.01, P ≤ .0258) en masse than corresponding in vivo‐derived values. Correcting respiratory values to account for mitochondrial temperatures 10°C higher than skeletal muscle temperatures at maximal exercise (~50°C): (i) transforms data to resemble (Z ≤ 0.8, P > .9999) analogous yet context‐specific in vivo measures, eg data collected during maximal 1‐leg knee extension exercise; and (ii) supports the position that maximal skeletal muscle respiratory rates exceed (Z ≥ 13.2, P < .0001) those achieved during maximal whole‐body exercise, e.g. maximal cycling efforts. Conclusion This study outlines and demonstrates necessary considerations when actualizing the biological relevance of human skeletal muscle respiratory control, metabolic flexibility and bioenergetics from standard ex vivo‐derived assessments using permeabilized human muscle. These findings detail how cross‐procedural comparisons of human skeletal muscle mitochondrial function may be collectively scrutinized in their relationship to human health and lifespan.

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“…The new nano-thermometric instrument presented in this work opens up unique opportunities to answer the urgent paradigm-shifting questions of cell physiology thermodynamics, such as: Can open ionic channels be really very hot (tens of degrees °C) in densely packed clusters 29 ? Can separate mitochondria be warmer than the surrounding cytoplasm (conundrum of hot mitochondria) 30 ? Can the local intracellular temperature be really high (“10 5 gap issue”) 31 , 32 ?…”

Section: Discussionmentioning

confidence: 99%

“…Can separate mitochondria be warmer than the surrounding cytoplasm (conundrum of hot mitochondria) 30 ?…”

Section: Discussionmentioning

confidence: 99%

A new approach to precise mapping of local temperature fields in submicrometer aqueous volumes

Romshin

Zeeb

Martyanov

et al. 2021

Sci Rep

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Nanodiamonds hosting temperature-sensing centers constitute a closed thermodynamic system. Such a system prevents direct contact of the temperature sensors with the environment making it an ideal environmental insensitive nanosized thermometer. A new design of a nanodiamond thermometer, based on a 500-nm luminescent nanodiamond embedded into the inner channel of a glass submicron pipette is reported. All-optical detection of temperature, based on spectral changes of the emission of “silicon-vacancy” centers with temperature, is used. We demonstrate the applicability of the thermometric tool to the study of temperature distribution near a local heater, placed in an aqueous medium. The calculated and experimental values of temperatures are shown to coincide within measurement error at gradients up to 20 °C/μm. Until now, temperature measurements on the submicron scale at such high gradients have not been performed. The new thermometric tool opens up unique opportunities to answer the urgent paradigm-shifting questions of cell physiology thermodynamics.

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The conundrum of hot mitochondria

Cited by 40 publications

References 93 publications

Biochemical Studies of Mitochondrial Malate: Quinone Oxidoreductase from Toxoplasma gondii

Biochemical Studies of Mitochondrial Malate: Quinone Oxidoreductase from Toxoplasma gondii

Contextualizing the biological relevance of standardized high‐resolution respirometry to assess mitochondrial function in permeabilized human skeletal muscle

A new approach to precise mapping of local temperature fields in submicrometer aqueous volumes

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