bims-midhyp 2023-06-25 papers

bims-midhyp

Biomed News

on Mitochondrial dysfunction and hypoxia

Issue of 2023–06–25
fourteen papers selected by
Alia Ablieh, Universität Heidelberg

Two-Step Tag-Free Isolation of Mitochondria for Improved Protein Discovery and Quantification.
MFN2-mediated mitochondrial fusion facilitates acute hypobaric hypoxia-induced cardiac dysfunction by increasing glucose catabolism and ROS production.
Invasive and noninvasive markers of human skeletal muscle mitochondrial function.
Myocardial capacity of mitochondrial oxidative phosphorylation in response to prolonged electromagnetic stress.
Loss of functional peroxisomes leads to increased mitochondrial biogenesis and reduced autophagy that preserve mitochondrial function.
A DEFECT IN MITOCHONDRIAL COMPLEX III BUT NOT IN COMPLEXES I OR IV CAUSES EARLY BETA CELL DYSFUNCTION AND HYPERGLYCEMIA IN MICE.
The impacts of the mitochondrial myopathy-associated G58R mutation on the dynamic structural properties of CHCHD10.
Chemical biology approaches to uncovering nuclear ROS control.
Inflation using hydrogen improves donor lung quality by regulating mitochondrial function during cold ischemia phase.
How soluble misfolded proteins bypass chaperones at the molecular level.
OP2113, a new drug for chronic hypoxia-induced pulmonary hypertension treatment in rat.
Patch-clamp technique to study mitochondrial membrane biophysics.
Transcriptional landscape of mitochondrial electron transport chain inhibition in renal cells.
Proton leak through the UCPs and ANT carriers and beyond: A breath for the electron transport chain.

J Vis Exp. 2023 Jun 02.

Two-Step Tag-Free Isolation of Mitochondria for Improved Protein Discovery and Quantification.

Joan Blanco-Fernandez, Alexis A Jourdain.

Most physiological and disease processes, from central metabolism to immune response to neurodegeneration, involve mitochondria. The mitochondrial proteome is composed of more than 1,000 proteins, and the abundance of each can vary dynamically in response to external stimuli or during disease progression. Here, we describe a protocol for isolating high-quality mitochondria from primary cells and tissues. The two-step procedure comprises (1) mechanical homogenization and differential centrifugation to isolate crude mitochondria, and (2) tag-free immune capture of mitochondria to isolate pure organelles and eliminate contaminants. Mitochondrial proteins from each purification stage are analyzed by quantitative mass spectrometry, and enrichment yields are calculated, allowing the discovery of novel mitochondrial proteins by subtractive proteomics. Our protocol provides a sensitive and comprehensive approach to studying mitochondrial content in cell lines, primary cells, and tissues.

DOI: https://doi.org/10.3791/65252
Biochim Biophys Acta Gen Subj. 2023 Jun 16. pii: S0304-4165(23)00111-3. [Epub ahead of print] 130413

MFN2-mediated mitochondrial fusion facilitates acute hypobaric hypoxia-induced cardiac dysfunction by increasing glucose catabolism and ROS production.

Ailin Yang, Lifei Guo, Yanfang Zhang, Chenjin Qiao, Yijin Wang, Jiaying Li, Min Wang, Jinliang Xing, Fei Li, Lele Ji, Haitao Guo, Ru Zhang.

   BACKGROUND: Rapid ascent to high-altitude environment which is characterized by acute hypobaric hypoxia (HH) may increase the risk of cardiac dysfunction. However, the potential regulatory mechanisms and prevention strategies for acute HH-induced cardiac dysfunction have not been fully clarified. Mitofusin 2 (MFN2) is highly expressed in the heart and is involved in the regulation of mitochondrial fusion and cell metabolism. To date, however, the significance of MFN2 in the heart under acute HH has not been investigated.
METHODS AND RESULTS: Our study revealed that MFN2 upregulation in hearts of mice during acute HH led to cardiac dysfunction. In vitro experiments showed that the decrease in oxygen concentration induced upregulation of MFN2, impairing cardiomyocyte contractility and increasing the risk of QT prolongation. Additionally, acute HH-induced MFN2 upregulation promoted glucose catabolism and led to excessive mitochondrial reactive oxygen species (ROS) production in cardiomyocytes, ultimately resulting in decreased mitochondrial function. Furthermore, co-immunoprecipitation (co-IP) and mass spectrometry analyses indicated that MFN2 interacted with the NADH-ubiquinone oxidoreductase 23 kDa subunit (NDUFS8). Specifically, acute HH-induced MFN2 upregulation increased NDUFS8-dependent complex I activity.
CONCLUSIONS: Taken together, our studies provide the first direct evidence that MFN2 upregulation exacerbates acute HH-induced cardiac dysfunction by increasing glucose catabolism and ROS production.
GENERAL SIGNIFICANCE: Our studies indicate that MFN2 may be a promising therapeutic target for cardiac dysfunction under acute HH.

Keywords:  Acute hypobaric hypoxia; Cardiac function; Glucose catabolism; MFN2; Mitochondrial fusion; ROS production

DOI:  https://doi.org/10.1016/j.bbagen.2023.130413
Physiol Rep. 2023 06;11(12): e15734

Invasive and noninvasive markers of human skeletal muscle mitochondrial function.

Rodrigo Mancilla, Diego Pava-Mejia, Nynke van Polanen, Vera de Wit, Maaike Bergman, Lotte Grevendonk, Johanna Jorgensen, Esther Kornips, Joris Hoeks, Matthijs K C Hesselink, Vera B Schrauwen-Hinderling.

  Mitochondria are organelles that fuel cellular energy requirements by ATP formation via aerobic metabolism. Given the wide variety of methods to assess skeletal muscle mitochondrial capacity, we tested how well different invasive and noninvasive markers of skeletal muscle mitochondrial capacity reflect mitochondrial respiration in permeabilized muscle fibers. Nineteen young men (mean age: 24 ± 4 years) were recruited, and a muscle biopsy was collected to determine mitochondrial respiration from permeabilized muscle fibers and to quantify markers of mitochondrial capacity, content such as citrate synthase (CS) activity, mitochondrial DNA copy number, TOMM20, VDAC, and protein content for complex I-V of the oxidative phosphorylation (OXPHOS) system. Additionally, all participants underwent noninvasive assessments of mitochondrial capacity: PCr recovery postexercise (by 31 P-MRS), maximal aerobic capacity, and gross exercise efficiency by cycling exercise. From the invasive markers, Complex V protein content and CS activity showed the strongest concordance (Rc = 0.50 to 0.72) with ADP-stimulated coupled mitochondrial respiration, fueled by various substrates. Complex V protein content showed the strongest concordance (Rc = 0.72) with maximally uncoupled mitochondrial respiration. From the noninvasive markers, gross exercise efficiency, VO2max , and PCr recovery exhibited concordance values between 0.50 and 0.77 with ADP-stimulated coupled mitochondrial respiration. Gross exercise efficiency showed the strongest concordance with maximally uncoupled mitochondrial respiration (Rc = 0.67). From the invasive markers, Complex V protein content and CS activity are surrogates that best reflect skeletal muscle mitochondrial respiratory capacity. From the noninvasive markers, exercise efficiency and PCr recovery postexercise most closely reflect skeletal muscle mitochondrial respiratory capacity.

Keywords:  human skeletal muscle; mitochondrial function; skeletal muscle mitochondrial respiration

DOI:  https://doi.org/10.14814/phy2.15734
Front Cardiovasc Med. 2023 ;10 1205893

Myocardial capacity of mitochondrial oxidative phosphorylation in response to prolonged electromagnetic stress.

Lesia Savchenko, Ilenia Martinelli, Dimitri Marsal, Vyacheslav Zhdan, Junwu Tao, Oksana Kunduzova.

   Introduction: Mitochondria are central energy generators for the heart, producing adenosine triphosphate (ATP) through the oxidative phosphorylation (OXPHOS) system. However, mitochondria also guide critical cell decisions and responses to the environmental stressors.
Methods: This study evaluated whether prolonged electromagnetic stress affects the mitochondrial OXPHOS system and structural modifications of the myocardium. To induce prolonged electromagnetic stress, mice were exposed to 915 MHz electromagnetic fields (EMFs) for 28 days.
Results: Analysis of mitochondrial OXPHOS capacity in EMF-exposed mice pointed to a significant increase in cardiac protein expression of the Complex I, II, III and IV subunits, while expression level of α-subunit of ATP synthase (Complex V) was stable among groups. Furthermore, measurement of respiratory function in isolated cardiac mitochondria using the Seahorse XF24 analyzer demonstrated that prolonged electromagnetic stress modifies the mitochondrial respiratory capacity. However, the plasma level of malondialdehyde, an indicator of oxidative stress, and myocardial expression of mitochondria-resident antioxidant enzyme superoxide dismutase 2 remained unchanged in EMF-exposed mice as compared to controls. At the structural and functional state of left ventricles, no abnormalities were identified in the heart of mice subjected to electromagnetic stress.
Discussion: Taken together, these data suggest that prolonged exposure to EMFs could affect mitochondrial oxidative metabolism through modulating cardiac OXPHOS system.

Keywords:  electromagnetic stress; heart; metabolism; oxidative phosphorylation; superoxide dismutase

DOI:  https://doi.org/10.3389/fcvm.2023.1205893
Cell Mol Life Sci. 2023 Jun 20. 80(7): 183

Loss of functional peroxisomes leads to increased mitochondrial biogenesis and reduced autophagy that preserve mitochondrial function.

Lijun Chi, Dorothy Lee, Sharon Leung, Guanlan Hu, Bijun Wen, Paul Delgado-Olguin, Miluska Vissa, Ren Li, John H Brumell, Peter K Kim, Robert H J Bandsma.

  Peroxisomes are essential for mitochondrial health, as the absence of peroxisomes leads to altered mitochondria. However, it is unclear whether the changes in mitochondria are a function of preserving cellular function or a response to cellular damage caused by the absence of peroxisomes. To address this, we developed conditional hepatocyte-specific Pex16 deficient (Pex16 KO) mice that develop peroxisome loss and subjected them to a low-protein diet to induce metabolic stress. Loss of PEX16 in hepatocytes led to increased biogenesis of small mitochondria and reduced autophagy flux but with preserved capacity for respiration and ATP capacity. Metabolic stress induced by low protein feeding led to mitochondrial dysfunction in Pex16 KO mice and impaired biogenesis. Activation of PPARα partially corrected these mitochondrial disturbances, despite the absence of peroxisomes. The findings of this study demonstrate that the absence of peroxisomes in hepatocytes results in a concerted effort to preserve mitochondrial function, including increased mitochondrial biogenesis, altered morphology, and modified autophagy activity. Our study underscores the relationship between peroxisomes and mitochondria in regulating the hepatic metabolic responses to nutritional stressors.

Keywords:  Fenofibrate; Malnutrition; Metabolism; Mitophagy; Nuclear hormone receptor; mTOR

DOI:  https://doi.org/10.1007/s00018-023-04827-3
Diabetes. 2023 Jun 21. pii: db220728. [Epub ahead of print]

A DEFECT IN MITOCHONDRIAL COMPLEX III BUT NOT IN COMPLEXES I OR IV CAUSES EARLY BETA CELL DYSFUNCTION AND HYPERGLYCEMIA IN MICE.

Anna L Lang, Nadee Nissanka, Ruy A Louzada, Alejandro Tamayo, Elizabeth Pereira, Carlos T Moraes, Alejandro Caicedo.

Mitochondrial metabolism and oxidative respiration are crucial for pancreatic beta cell function and stimulus secretion coupling. Oxidative phosphorylation (OxPhos) produces ATP and other metabolites that potentiate insulin secretion. However, the contribution of individual OxPhos complexes to beta cell function is unknown. We generated beta cell specific, inducible OxPhos complex KO mouse models to investigate the effects of disrupting Complex I, Complex III, or Complex IV on beta cell function. Although all KO models had similar mitochondrial respiratory defects, Complex III caused early hyperglycemia, glucose intolerance, and loss of glucose-stimulated insulin secretion in vivo. However, ex vivo insulin secretion did not change. Complex I and IV KO models showed diabetic phenotypes much later. Mitochondrial Ca2+ responses to glucose stimulation 3 weeks after gene deletion ranged from not affected to severely disrupted depending on the complex targeted, supporting the unique roles of each complex in beta cell signaling. Mitochondrial antioxidant enzyme immunostaining increased in islets from Complex III KO, but not from Complex I or IV KO mice, indicating that severe diabetic phenotype in the Complex III deficient mice is causing alterations in cellular redox status. The current study highlights that defects in individual OxPhos complexes lead to different pathogenic outcomes.

DOI: https://doi.org/10.2337/db22-0728
J Biomol Struct Dyn. 2023 Jun 22. 1-10

The impacts of the mitochondrial myopathy-associated G58R mutation on the dynamic structural properties of CHCHD10.

Hakan Alici, Vladimir N Uversky, David E Kang, Junga Alexa Woo, Orkid Coskuner-Weber.

  The mitochondria are responsible for producing energy within the cell, and in mitochondrial myopathy, there is a defect in the energy production process. The CHCHD10 gene codes for a protein called coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10), which is found in the mitochondria and is involved in the regulation of mitochondrial function. G58R mutation has been shown to disrupt the normal function of CHCHD10, leading to mitochondrial dysfunction and ultimately to the development of mitochondrial myopathy. The structures of G58R mutant CHCHD10 and how G58R mutation impacts the wild-type CHCHD10 protein at the monomeric level are unknown. To address this problem, we conducted homology modeling, multiple run molecular dynamics simulations and bioinformatics calculations. We represent herein the structural ensemble properties of the G58R mutant CHCHD10 (CHCHD10G58R) in aqueous solution. Moreover, we describe the impacts of G58R mutation on the structural ensembles of wild-type CHCHD10 (CHCHD10WT) in aqueous solution. The dynamics properties as well as structural properties of CHCHD10WT are impacted by the mitochondrial myopathy-related G58R mutation. Specifically, the secondary and tertiary structure properties, root mean square fluctuations, Ramachandran diagrams and results from principal component analysis demonstrate that the CHCHD10WT and CHCHD10G58R proteins possess different structural ensemble characteristics and describe the impacts of G58R mutation on CHCHD10WT. These findings may be helpful for designing new treatments for mitochondrial myopathy.Communicated by Ramaswamy H. Sarma.

Keywords:  CHCHD10; G58R mutation; genetics; mitochondrial myopathy

DOI:  https://doi.org/10.1080/07391102.2023.2227713
Curr Opin Chem Biol. 2023 Jun 21. pii: S1367-5931(23)00090-X. [Epub ahead of print]76 102352

Chemical biology approaches to uncovering nuclear ROS control.

Junbing Zhang, Liron Bar-Peled.

Heightened concentrations of reactive metabolites, including reactive oxygen species (ROS), can damage all macromolecules leading to the erosion of cellular fidelity. In this regard, the control of ROS in the nuclues is essential for cellular homeostasis, and dysregulation of nuclear ROS has been attributed to multiple pathologies and the mechanism of action of certain chemotherapies. How nuclear ROS is generated, detoxified and sensed is poorly understood, and stems in part, from a historical lack of tools that allow for its precise generation and detection. Here, we summarize the latest advances in chemical biology inspired approaches that have been developed to study nuclear ROS and highlight how these tools have led to major breakthroughs in understanding its regulation. The continued development and application of chemical biology approaches to understand nuclear ROS promises to unlock fundamental insights into human physiology and disease.

DOI: https://doi.org/10.1016/j.cbpa.2023.102352
BMC Pulm Med. 2023 Jun 17. 23(1): 213

Inflation using hydrogen improves donor lung quality by regulating mitochondrial function during cold ischemia phase.

Le Duan, Lini Quan, Bin Zheng, Zhe Li, Guangchao Zhang, Mengdi Zhang, Huacheng Zhou.

   BACKGROUND: Mitochondrial dysfunction results in poor organ quality, negatively affecting the outcomes of lung transplantation. Whether hydrogen benefits mitochondrial function in cold-preserved donors remain unclear. The present study assessed the effect of hydrogen on mitochondrial dysfunction in donor lung injury during cold ischemia phase (CIP) and explored the underlying regulatory mechanism.
METHODS: Left donor lungs were inflated using 40% oxygen + 60% nitrogen (O group), or 3% hydrogen + 40% oxygen + 57% nitrogen (H group). Donor lungs were deflated in the control group and were harvested immediately after perfusion in the sham group (n = 10). Inflammation, oxidative stress, apoptosis, histological changes, mitochondrial energy metabolism, and mitochondrial structure and function were assessed. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were also analyzed.
RESULTS: Compared with the sham group, inflammatory response, oxidative stress, histopathological changes, and mitochondrial damage were severe in the other three groups. However, these injury indexes were remarkably decreased in O and H groups, with increased Nrf2 and HO-1 levels, elevated mitochondrial biosynthesis, inhibition of anaerobic glycolysis and restored mitochondrial structure and function compared with the control group. Moreover, inflation using hydrogen contributed to stronger protection against mitochondrial dysfunction and higher levels of Nrf2 and HO-1 when comparing with O group.
CONCLUSIONS: Lung inflation using hydrogen during CIP may improve donor lung quality by mitigating mitochondrial structural anomalies, enhancing mitochondrial function, and alleviating oxidative stress, inflammation, and apoptosis, which may be achieved through activation of the Nrf2/HO-1 pathway.

Keywords:  Cold ischemia; Donor lung quality; Hydrogen; Inflammation; Lung transplantation; Mitochondrial function

DOI:  https://doi.org/10.1186/s12890-023-02504-6
Nat Commun. 2023 Jun 21. 14(1): 3689

How soluble misfolded proteins bypass chaperones at the molecular level.

Ritaban Halder, Daniel A Nissley, Ian Sitarik, Yang Jiang, Yiyun Rao, Quyen V Vu, Mai Suan Li, Justin Pritchard, Edward P O'Brien.

Subpopulations of soluble, misfolded proteins can bypass chaperones within cells. The extent of this phenomenon and how it happens at the molecular level are unknown. Through a meta-analysis of the experimental literature we find that in all quantitative protein refolding studies there is always a subpopulation of soluble but misfolded protein that does not fold in the presence of one or more chaperones, and can take days or longer to do so. Thus, some misfolded subpopulations commonly bypass chaperones. Using multi-scale simulation models we observe that the misfolded structures that bypass various chaperones can do so because their structures are highly native like, leading to a situation where chaperones do not distinguish between the folded and near-native-misfolded states. More broadly, these results provide a mechanism by which long-time scale changes in protein structure and function can persist in cells because some misfolded states can bypass components of the proteostasis machinery.

DOI: https://doi.org/10.1038/s41467-023-38962-z
Br J Pharmacol. 2023 Jun 23.

OP2113, a new drug for chronic hypoxia-induced pulmonary hypertension treatment in rat.

Lukas Roubenne, Margaux Laisné, David Benoist, Marilyne Campagnac, Bénédicte Prunet, Philippe Pasdois, Guillaume Cardouat, Thomas Ducret, Jean-François Quignard, Pierre Vacher, Isabelle Baudrimont, Roger Marthan, Patrick Berger, Bruno Le Grand, Véronique Freund-Michel, Christelle Guibert.

   BACKGROUND AND PURPOSE: Pulmonary hypertension (PH) is a cardiovascular disease characterised by an increase in pulmonary arterial (PA) resistance leading to right ventricular (RV) failure. Reactive oxygen species (ROS) play a major role in PH. OP2113 is a drug with beneficial effects on cardiac injuries that targets mitochondrial ROS. The aim of the study was to address the in vivo therapeutic effect of OP2113 in PH.
EXPERIMENTAL APPROACH: PH was induced by 3 weeks of hypoxia (CH-PH) in rats treated with OP2113 or its vehicle via subcutaneous osmotic mini-pumps. Hemodynamic parameters and both PA and heart remodelling were assessed. Reactivity was quantified in PA rings and in RV or left ventricular (LV) cardiomyocytes. Oxidative stress was detected by electron paramagnetic resonance and Western blotting. Mitochondrial mass and respiration were measured by Western blotting and oxygraphy, respectively.
KEY RESULTS: In CH-PH rats, OP2113 reduced the mean PA pressure, PA remodelling, PA hyperreactivity in response to 5-HT, the contraction slowdown in RV and LV and increased the mitochondrial mass in RV. Interestingly, OP2113 had no effect on hemodynamic parameters, both PA and RV wall thickness and PA reactivity in control rats. Whereas oxidative stress was evidenced by an increase in protein carbonylation in CH-PH, it was not affected by OP2113.
CONCLUSION AND IMPLICATIONS: Our study provides evidence for a selective protective effect of OP2113 in vivo on alterations in both PA and RV from CH-PH rats without side effects in control rats.

Keywords:  Pulmonary hypertension; oxidative stress; pulmonary circulation; right ventricle

DOI:  https://doi.org/10.1111/bph.16174
J Gen Physiol. 2023 Aug 07. pii: e202313347. [Epub ahead of print]155(8):

Patch-clamp technique to study mitochondrial membrane biophysics.

Anshu Kumari, Dung M Nguyen, Vivek Garg.

Mitochondria are double-membrane organelles crucial for oxidative phosphorylation, enabling efficient ATP synthesis by eukaryotic cells. Both of the membranes, the highly selective inner mitochondrial membrane (IMM) and a relatively porous outer membrane (OMM), harbor a number of integral membrane proteins that help in the transport of biological molecules. These transporters are especially enriched in the IMM, where they help maintain transmembrane gradients for H+, K+, Ca2+, PO43-, and metabolites like ADP/ATP, citrate, etc. Impaired activity of these transporters can affect the efficiency of energy-transducing processes and can alter cellular redox state, leading to activation of cell-death pathways or metabolic syndromes in vivo. Although several methodologies are available to study ion flux through membrane proteins, the patch-clamp technique remains the gold standard for quantitatively analyzing electrogenic ion exchange across membranes. Direct patch-clamp recordings of mitoplasts (mitochondria devoid of outer membrane) in different modes, such as whole-mitoplast or excised-patch mode, allow researchers the opportunity to study the biophysics of mitochondrial transporters in the native membrane, in real time, in isolation from other fluxes or confounding factors due to changes in ion gradients, pH, or mitochondrial potential (ΔΨ). Here, we summarize the use of patch clamp to investigate several membrane proteins of mitochondria. We demonstrate how this technique can be reliably applied to record whole-mitoplast Ca2+ currents mediated via mitochondrial calcium uniporter or H+ currents mediated by uncoupling protein 1 and discuss critical considerations while recording currents from these small vesicles of the IMM (mitoplast diameter = 2-5 µm).

DOI: https://doi.org/10.1085/jgp.202313347
Cell Biol Toxicol. 2023 Jun 23.

Transcriptional landscape of mitochondrial electron transport chain inhibition in renal cells.

Giada Carta, Wanda van der Stel, Emma W J Scuric, Liliana Capinha, Johannes Delp, Susanne Hougaard Bennekou, Anna Forsby, Paul Walker, Marcel Leist, Bob van de Water, Paul Jennings.

  Analysis of the transcriptomic alterations upon chemical challenge, provides in depth mechanistic information on the compound's toxic mode of action, by revealing specific pathway activation and other transcriptional modulations. Mapping changes in cellular behaviour to chemical insult, facilitates the characterisation of chemical hazard. In this study, we assessed the transcriptional landscape of mitochondrial impairment through the inhibition of the electron transport chain (ETC) in a human renal proximal tubular cell line (RPTEC/TERT1). We identified the unfolded protein response pathway (UPR), particularly the PERK/ATF4 branch as a common cellular response across ETC I, II and III inhibitions. This finding and the specific genes elaborated may aid the identification of mitochondrial liabilities of chemicals in both legacy data and prospective transcriptomic studies.

Keywords:  In vitro; Mitochondria; Renal; Stress pathway; Transcriptomic

DOI:  https://doi.org/10.1007/s10565-023-09816-7
Biochimie. 2023 Jun 17. pii: S0300-9084(23)00146-3. [Epub ahead of print]214(Pt B): 77-85

Proton leak through the UCPs and ANT carriers and beyond: A breath for the electron transport chain.

Salvatore Nesci.

  Mitochondria produce heat as a result of an ineffective H+ cycling of mitochondria respiration across the inner mitochondrial membrane (IMM). This event present in all mitochondria, known as proton leak, can decrease protonmotive force (Δp) and restore mitochondrial respiration by partially uncoupling the substrate oxidation from the ADP phosphorylation. During impaired conditions of ATP generation with F1FO-ATPase, the Δp increases and IMM is hyperpolarized. In this bioenergetic state, the respiratory complexes support H+ transport until the membrane potential stops the H+ pump activity. Consequently, the electron transfer is stalled and the reduced form of electron carriers of the respiratory chain can generate O2∙¯ triggering the cascade of ROS formation and oxidative stress. The physiological function to attenuate the production of O2∙¯ by Δp dissipation can be attributed to the proton leak supported by the translocases of IMM.

Keywords:  Electron transport chain; Mitochondria; Proton conductance; Proton leak; Proton-motive force; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.biochi.2023.06.008