Pub Date : 2025-04-01Epub Date: 2025-01-17DOI: 10.1016/j.bbabio.2025.149539
Michèle J.C. de Kok , Alexander F.M. Schaapherder , Jonna R. Bloeme - ter Horst , Maria Letizia Lo Faro , Dorottya K. de Vries , Rutger J. Ploeg , Jaap A. Bakker , Jan H.N. Lindeman
Ischemia-reperfusion (IR) injury remains a major contributor to organ dysfunction following transient ischemic insults. Although numerous interventions have been found effective to reduce IR injury in preclinical models, none of these therapies have been successfully translated to the clinical setting. In the context of the persistent translational gap, we systematically investigated the mechanisms implicated in IR injury using kidney donation and transplantation as a clinical model of IR. Whilst our results do not implicate traditional culprits such as reactive oxygen species, complement activation or inflammation as triggers of IR injury, they reveal a clear metabolic signature for renal IR injury. This discriminatory signature of IR injury is consistent with a post-reperfusion metabolic paralysis and involves high-energy phosphate depletion, tricarboxylic acid cycle defects, and a compensatory activation of catabolic routes. Against this background, the picture emerges that clinical IR injury is driven by reductive stress. In this article, we therefore wish to elaborate on the processes contributing to reductive stress in the context of clinical IR injury and provide a better insight in potential clinical therapeutic strategies that might be helpful in restoring the redox balance.
{"title":"Clinical ischemia-reperfusion injury: Driven by reductive rather than oxidative stress? A narrative review","authors":"Michèle J.C. de Kok , Alexander F.M. Schaapherder , Jonna R. Bloeme - ter Horst , Maria Letizia Lo Faro , Dorottya K. de Vries , Rutger J. Ploeg , Jaap A. Bakker , Jan H.N. Lindeman","doi":"10.1016/j.bbabio.2025.149539","DOIUrl":"10.1016/j.bbabio.2025.149539","url":null,"abstract":"<div><div>Ischemia-reperfusion (IR) injury remains a major contributor to organ dysfunction following transient ischemic insults. Although numerous interventions have been found effective to reduce IR injury in preclinical models, none of these therapies have been successfully translated to the clinical setting. In the context of the persistent translational gap, we systematically investigated the mechanisms implicated in IR injury using kidney donation and transplantation as a clinical model of IR. Whilst our results do not implicate traditional culprits such as reactive oxygen species, complement activation or inflammation as triggers of IR injury, they reveal a clear metabolic signature for renal IR injury. This discriminatory signature of IR injury is consistent with a post-reperfusion metabolic paralysis and involves high-energy phosphate depletion, tricarboxylic acid cycle defects, and a compensatory activation of catabolic routes. Against this background, the picture emerges that clinical IR injury is driven by reductive stress. In this article, we therefore wish to elaborate on the processes contributing to reductive stress in the context of clinical IR injury and provide a better insight in potential clinical therapeutic strategies that might be helpful in restoring the redox balance.</div></div>","PeriodicalId":50731,"journal":{"name":"Biochimica et Biophysica Acta-Bioenergetics","volume":"1866 2","pages":"Article 149539"},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01Epub Date: 2025-01-17DOI: 10.1016/j.bbabio.2025.149541
David G. Nicholls
To professional bioenergeticists, the thermodynamic and kinetic constraints on mitochondrial function are self-evident. It is therefore profoundly concerning that high-profile cell biology papers continue to appear containing fundamental bioenergetic errors that appear to have evaded the scrutiny of the principal investigator, co-authors, editors and, apparently, at least some of the referees. The problem is not new, and seems to stem from a perception that bioenergetics is a ‘difficult’ subject, both at undergraduate level, if it is taught in any depth, and in research, where cell biologists are faced with biophysical concepts such as protonmotive force, ion flux, redox potential and Gibbs free energy.
{"title":"Commentary: Why do many cell biology papers contain fundamental bioenergetic errors?","authors":"David G. Nicholls","doi":"10.1016/j.bbabio.2025.149541","DOIUrl":"10.1016/j.bbabio.2025.149541","url":null,"abstract":"<div><div>To professional bioenergeticists, the thermodynamic and kinetic constraints on mitochondrial function are self-evident. It is therefore profoundly concerning that high-profile cell biology papers continue to appear containing fundamental bioenergetic errors that appear to have evaded the scrutiny of the principal investigator, co-authors, editors and, apparently, at least some of the referees. The problem is not new, and seems to stem from a perception that bioenergetics is a ‘difficult’ subject, both at undergraduate level, if it is taught in any depth, and in research, where cell biologists are faced with biophysical concepts such as protonmotive force, ion flux, redox potential and Gibbs free energy.</div></div>","PeriodicalId":50731,"journal":{"name":"Biochimica et Biophysica Acta-Bioenergetics","volume":"1866 2","pages":"Article 149541"},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01Epub Date: 2025-02-09DOI: 10.1016/j.bbabio.2025.149545
Yi-Hao Yan , Yu-Qian Li , Mei-Juan Zou , Long-Jiang Yu , Jian-Ping Zhang
The light-harvesting complex 1-reaction center (LH1-RC) photosystem of the thermophilic purple sulfur bacterium Thermochromatium (Tch.) tepidum exhibits a near-infrared LH1-Qy absorption band at 915 nm as regulated by binding calcium ions (Ca2+). To further explore the possible involvement of the C-terminal lysine residues of the LH1 α-polypeptide, we have genetically engineered a Rhodospirillum rubrum mutant strain to yield the site-directed modifications of the terminal α-Lys60 and α-Lys61 residues of Tch. tepidum LH1 α-polypeptide. Four of the LH1 mutants exhibit a subtle blue shift of 3 nm upon deletion or substitution of the lysine residues, however, they display over 40 nm blue shifts upon Ca2+ removal by ethylene diamine tetraacetic acid (EDTA) treatment. Spectral properties of native Tch. tepidum LH1-RC, the LH1-only, and the mutant LH1-only complexes are compared on a structural basis, which allows us to conclude that the C-terminal lysine residues and the Ca2+ binding synergistically affect the structural integrity and the LH1-Qy spectral shift. This work demonstrates a methodology for the genetic manipulation of photosynthetic proteins lacking mutagenesis information, and may shed light on understanding the detailed structural factors involved in tuning the LH1-Qy absorption.
{"title":"Structural integrity and near-infrared absorption of the LH1 complex of Thermochromatium tepidum: Influence from the C-terminal lysine residues of LH1 α-polypeptide","authors":"Yi-Hao Yan , Yu-Qian Li , Mei-Juan Zou , Long-Jiang Yu , Jian-Ping Zhang","doi":"10.1016/j.bbabio.2025.149545","DOIUrl":"10.1016/j.bbabio.2025.149545","url":null,"abstract":"<div><div>The light-harvesting complex 1-reaction center (LH1-RC) photosystem of the thermophilic purple sulfur bacterium <em>Thermochromatium</em> (<em>Tch</em>.) <em>tepidum</em> exhibits a near-infrared LH1-Q<sub>y</sub> absorption band at 915 nm as regulated by binding calcium ions (Ca<sup>2+</sup>). To further explore the possible involvement of the C-terminal lysine residues of the LH1 α-polypeptide, we have genetically engineered a <em>Rhodospirillum rubrum</em> mutant strain to yield the site-directed modifications of the terminal α-Lys60 and α-Lys61 residues of <em>Tch</em>. <em>tepidum</em> LH1 α-polypeptide. Four of the LH1 mutants exhibit a subtle blue shift of 3 nm upon deletion or substitution of the lysine residues, however, they display over 40 nm blue shifts upon Ca<sup>2+</sup> removal by ethylene diamine tetraacetic acid (EDTA) treatment. Spectral properties of native <em>Tch</em>. <em>tepidum</em> LH1-RC, the LH1-only, and the mutant LH1-only complexes are compared on a structural basis, which allows us to conclude that the C-terminal lysine residues and the Ca<sup>2+</sup> binding <em>synergistically</em> affect the structural integrity and the LH1-Q<sub>y</sub> spectral shift. This work demonstrates a methodology for the genetic manipulation of photosynthetic proteins lacking mutagenesis information, and may shed light on understanding the detailed structural factors involved in tuning the LH1-Q<sub>y</sub> absorption.</div></div>","PeriodicalId":50731,"journal":{"name":"Biochimica et Biophysica Acta-Bioenergetics","volume":"1866 2","pages":"Article 149545"},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143378758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01Epub Date: 2025-01-06DOI: 10.1016/j.bbabio.2025.149537
Raaif Siddeeque , Lucia Heger , Jan Kägi , Thorsten Friedrich , Frédéric Melin , Petra Hellwig
The reduction of oxygen to water is crucial to life under aerobic conditions. Cytochrome bd oxidases perform this reaction with a very high oxygen affinity. Members of this protein family are solely found in prokaryotes and some archaea playing an important role in bacterial virulence and antibiotic resistance. Here, we combine mutagenesis, electrocatalysis, nitric oxide binding and release experiments as well as FTIR spectroscopy to demonstrate that proton delivery to the active site is essentially rate limiting in Cyt bd-I electrocatalysis. D58 and D105 of subunit CydB are crucial residues in this proton path and communicate via a hydrogen bond network. Oxygen reduction depends on proton delivery to the active site, which also influences NO release.
{"title":"Interplay of acidic residues in the proton channel of E. coli cytochrome bd-I oxidase to promote oxygen reduction and NO release","authors":"Raaif Siddeeque , Lucia Heger , Jan Kägi , Thorsten Friedrich , Frédéric Melin , Petra Hellwig","doi":"10.1016/j.bbabio.2025.149537","DOIUrl":"10.1016/j.bbabio.2025.149537","url":null,"abstract":"<div><div>The reduction of oxygen to water is crucial to life under aerobic conditions. Cytochrome <em>bd</em> oxidases perform this reaction with a very high oxygen affinity. Members of this protein family are solely found in prokaryotes and some archaea playing an important role in bacterial virulence and antibiotic resistance. Here, we combine mutagenesis, electrocatalysis, nitric oxide binding and release experiments as well as FTIR spectroscopy to demonstrate that proton delivery to the active site is essentially rate limiting in Cyt <em>bd-</em>I electrocatalysis. D58 and D105 of subunit CydB are crucial residues in this proton path and communicate via a hydrogen bond network. Oxygen reduction depends on proton delivery to the active site, which also influences NO release.</div></div>","PeriodicalId":50731,"journal":{"name":"Biochimica et Biophysica Acta-Bioenergetics","volume":"1866 2","pages":"Article 149537"},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01Epub Date: 2025-01-07DOI: 10.1016/j.bbabio.2025.149535
José Teixeira , Sofia Benfeito , Rodrigo Carreira , André Barbosa , Ricardo Amorim , Ludgero C. Tavares , John G. Jones , Nuno Raimundo , Fernando Cagide , Catarina Oliveira , Fernanda Borges , Werner J.H. Koopman , Paulo J. Oliveira
Mitochondrial dysfunction and increased reactive oxygen species (ROS) generation play an import role in different human pathologies. In this context, mitochondrial targeting of potentially protective antioxidants by their coupling to the lipophilic triphenylphosphonium cation (TPP) is widely applied. Employing a six‑carbon (C6) linker, we recently demonstrated that mitochondria-targeted phenolic antioxidants derived from gallic acid (AntiOxBEN2) and caffeic acid (AntiOxCIN4) counterbalance oxidative stress in primary human skin fibroblasts by activating ROS-protective mechanisms. Here we demonstrate that C6-TPP (but not AntiOxBEN2 and AntiOxCIN4) induce cell death in human skin fibroblasts. This indicates that C6-TPP cytoxocity is counterbalanced by the antioxidant moieties of AntiOxBEN2 and AntiOxCIN4. Remarkably, C6-TPP and AntiOxBEN2 (but not AntiOxCIN4) induced a glycolytic switch, as exemplified by a reduced cellular oxygen consumption rate (OCR), increased extracellular acidification rate (ECAR), elevated extracellular lactate levels, and higher protein levels of glucose transporter 1 (GLUT-1). This switch involved activation of AMP-activated protein kinase (AMPK) and fully compensated for the loss in mitochondrial ATP production by sustaining cellular ATP content. When glycolytic switch induction was prevented (i.e. by using a glucose-free, galactose-containing medium), AntiOxBEN2 induced cell death whereas AntiOxCIN4 did not. We conclude that, despite their similar chemical structure and antioxidant capacity, AntiOxBEN2 and AntiOxCIN4 display both common (redox-adaptive) and specific (bioenergetic-adaptive) effects.
{"title":"The mitochondriotropic antioxidants AntiOxBEN2 and AntiOxCIN4 are structurally-similar but differentially alter energy homeostasis in human skin fibroblasts","authors":"José Teixeira , Sofia Benfeito , Rodrigo Carreira , André Barbosa , Ricardo Amorim , Ludgero C. Tavares , John G. Jones , Nuno Raimundo , Fernando Cagide , Catarina Oliveira , Fernanda Borges , Werner J.H. Koopman , Paulo J. Oliveira","doi":"10.1016/j.bbabio.2025.149535","DOIUrl":"10.1016/j.bbabio.2025.149535","url":null,"abstract":"<div><div>Mitochondrial dysfunction and increased reactive oxygen species (ROS) generation play an import role in different human pathologies. In this context, mitochondrial targeting of potentially protective antioxidants by their coupling to the lipophilic triphenylphosphonium cation (TPP) is widely applied. Employing a six‑carbon (C<sub>6</sub>) linker, we recently demonstrated that mitochondria-targeted phenolic antioxidants derived from gallic acid (AntiOxBEN<sub>2</sub>) and caffeic acid (AntiOxCIN<sub>4</sub>) counterbalance oxidative stress in primary human skin fibroblasts by activating ROS-protective mechanisms. Here we demonstrate that C<sub>6</sub>-TPP (but not AntiOxBEN<sub>2</sub> and AntiOxCIN<sub>4</sub>) induce cell death in human skin fibroblasts. This indicates that C<sub>6</sub>-TPP cytoxocity is counterbalanced by the antioxidant moieties of AntiOxBEN<sub>2</sub> and AntiOxCIN<sub>4</sub>. Remarkably, C<sub>6</sub>-TPP and AntiOxBEN<sub>2</sub> (but not AntiOxCIN<sub>4</sub>) induced a glycolytic switch, as exemplified by a reduced cellular oxygen consumption rate (OCR), increased extracellular acidification rate (ECAR), elevated extracellular lactate levels, and higher protein levels of glucose transporter 1 (GLUT-1). This switch involved activation of AMP-activated protein kinase (AMPK) and fully compensated for the loss in mitochondrial ATP production by sustaining cellular ATP content. When glycolytic switch induction was prevented (<em>i.e.</em> by using a glucose-free, galactose-containing medium), AntiOxBEN<sub>2</sub> induced cell death whereas AntiOxCIN<sub>4</sub> did not. We conclude that, despite their similar chemical structure and antioxidant capacity, AntiOxBEN<sub>2</sub> and AntiOxCIN<sub>4</sub> display both common (redox-adaptive) and specific (bioenergetic-adaptive) effects.</div></div>","PeriodicalId":50731,"journal":{"name":"Biochimica et Biophysica Acta-Bioenergetics","volume":"1866 2","pages":"Article 149535"},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01Epub Date: 2025-02-18DOI: 10.1016/j.bbabio.2025.149547
Lada E. Petrovskaya , Vadim A. Bolshakov , Evgeniy P. Lukashev , Elena A. Kryukova , Eugene G. Maksimov , Andrei B. Rubin , Dmitriy A. Dolgikh , Sergei P. Balashov , Mikhail P. Kirpichnikov
Solubilization in detergents is a widely used technique for the isolation of membrane proteins and the study of their properties. Unfortunately, protein stability in detergent micelles can sometimes be compromised. We encountered this issue with xanthorhodopsin (XR) from Salinibacter ruber, which had been previously engineered for expression in Escherichia coli cells. To explore the factors affecting stability and to enhance thermal stability of recombinant XR preparations following solubilization of membranes using n-dodecyl-β-D-maltopyranoside and nickel-affinity chromatography, we developed a series of hybrid proteins based on the homology between XR and a stable rhodopsin from Gloeobacter violaceus (GR). Functional studies of these hybrids and measurements of their melting temperatures revealed the structural elements of XR that account for its notable difference in stability compared to GR, despite their high overall homology of approximately 50 % identical residues.
In particular, XR variants with an engineered loop between transmembrane helices D and E, similar to that in GR, demonstrated enhanced stability. However, we found that replacing the DE loop affects carotenoid binding. Additionally, two hybrid proteins containing the C and D helices from GR exhibited increased stability as well as improved photocycle and proton transport rates. In conclusion, we have demonstrated that optimizing the amino acid sequence of xanthorhodopsin from S. ruber based on its homology with Gloeobacter rhodopsin is an effective approach to enhance its thermal stability in vitro and improve its potential for optogenetic applications.
洗涤剂中的增溶是一种广泛应用于膜蛋白分离及其性质研究的技术。不幸的是，洗涤剂胶束中的蛋白质稳定性有时会受到损害。我们在使用来自橡胶盐碱杆菌的XR时遇到了这个问题，XR先前被设计用于在大肠杆菌细胞中表达。为了探索影响XR稳定性的因素，并利用n-十二烷基-β- d -麦芽吡喃苷和镍亲和层析法提高膜增溶后重组XR制剂的热稳定性，我们基于XR与Gloeobacter violaceus （GR）中稳定的紫红质的同源性，开发了一系列杂交蛋白。对这些杂合体的功能研究和熔融温度的测量揭示了XR的结构元素，这些结构元素解释了XR与GR相比稳定性的显著差异，尽管它们的总体同源性约为50%相同的残基。特别是，在跨膜螺旋D和E之间带有工程环的XR变异，与GR相似，表现出更高的稳定性。然而，我们发现替换DE环会影响类胡萝卜素的结合。此外，含有GR的C和D螺旋的两种杂交蛋白表现出更高的稳定性，并改善了光循环和质子运输速率。综上所述，基于与Gloeobacter rhodopsin的同源性，优化橡胶树黄紫质的氨基酸序列是提高其体外热稳定性和光遗传学应用潜力的有效途径。
{"title":"Engineering of thermal stability in the recombinant xanthorhodopsin from Salinibacter ruber","authors":"Lada E. Petrovskaya , Vadim A. Bolshakov , Evgeniy P. Lukashev , Elena A. Kryukova , Eugene G. Maksimov , Andrei B. Rubin , Dmitriy A. Dolgikh , Sergei P. Balashov , Mikhail P. Kirpichnikov","doi":"10.1016/j.bbabio.2025.149547","DOIUrl":"10.1016/j.bbabio.2025.149547","url":null,"abstract":"<div><div>Solubilization in detergents is a widely used technique for the isolation of membrane proteins and the study of their properties. Unfortunately, protein stability in detergent micelles can sometimes be compromised. We encountered this issue with xanthorhodopsin (XR) from <em>Salinibacter ruber</em>, which had been previously engineered for expression in <em>Escherichia coli</em> cells. To explore the factors affecting stability and to enhance thermal stability of recombinant XR preparations following solubilization of membranes using n-dodecyl-β-D-maltopyranoside and nickel-affinity chromatography, we developed a series of hybrid proteins based on the homology between XR and a stable rhodopsin from <em>Gloeobacter violaceus</em> (GR). Functional studies of these hybrids and measurements of their melting temperatures revealed the structural elements of XR that account for its notable difference in stability compared to GR, despite their high overall homology of approximately 50 % identical residues.</div><div>In particular, XR variants with an engineered loop between transmembrane helices D and E, similar to that in GR, demonstrated enhanced stability. However, we found that replacing the DE loop affects carotenoid binding. Additionally, two hybrid proteins containing the C and D helices from GR exhibited increased stability as well as improved photocycle and proton transport rates. In conclusion, we have demonstrated that optimizing the amino acid sequence of xanthorhodopsin from <em>S. ruber</em> based on its homology with <em>Gloeobacter</em> rhodopsin is an effective approach to enhance its thermal stability in vitro and improve its potential for optogenetic applications.</div></div>","PeriodicalId":50731,"journal":{"name":"Biochimica et Biophysica Acta-Bioenergetics","volume":"1866 2","pages":"Article 149547"},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01Epub Date: 2024-12-20DOI: 10.1016/j.bbabio.2024.149533
Howard T. Jacobs , Anthony L. Moore
{"title":"There is often – but not always – an alternative!","authors":"Howard T. Jacobs , Anthony L. Moore","doi":"10.1016/j.bbabio.2024.149533","DOIUrl":"10.1016/j.bbabio.2024.149533","url":null,"abstract":"","PeriodicalId":50731,"journal":{"name":"Biochimica et Biophysica Acta-Bioenergetics","volume":"1866 2","pages":"Article 149533"},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01Epub Date: 2024-12-02DOI: 10.1016/j.bbabio.2024.149530
Kateryna Gaertner , Mügen Terzioglu , Craig Michell , Riikka Tapanainen , Jaakko Pohjoismäki , Eric Dufour , Sina Saari
The temperate climate-adapted brown hare (Lepus europaeus) and the cold-adapted mountain hare (Lepus timidus) are closely related and interfertile species. However, their skin fibroblasts display distinct gene expression profiles related to fundamental cellular processes. This indicates important metabolic divergence between the two species. Through targeted metabolomics and metabolite tracing, we identified species-specific variations in glycerol 3-phosphate (G3P) metabolism. G3P is a key metabolite of the G3P shuttle, which transfers reducing equivalents from cytosolic NADH to the mitochondrial electron transport chain (ETC), consequently regulating glycolysis, lipid metabolism, and mitochondrial bioenergetics. Alterations in G3P metabolism have been implicated in multiple human pathologies including cancer and diabetes. We observed that mountain hare mitochondria exhibit elevated G3P shuttle activity, alongside increased membrane potential and decreased mitochondrial temperature. Silencing mitochondrial G3P dehydrogenase (GPD2), which couples the conversion of G3P to the ETC, uncovered its species-specific role in controlling mitochondrial membrane potential and highlighted its involvement in skin fibroblast thermogenesis. Unexpectedly, GPD2 silencing enhanced wound healing and cell proliferation rates in a species-specific manner. Our study underscores the pivotal role of the G3P shuttle in mediating physiological, bioenergetic, and metabolic divergence between these hare species.
{"title":"Species differences in glycerol-3-phosphate metabolism reveals trade-offs between metabolic adaptations and cell proliferation","authors":"Kateryna Gaertner , Mügen Terzioglu , Craig Michell , Riikka Tapanainen , Jaakko Pohjoismäki , Eric Dufour , Sina Saari","doi":"10.1016/j.bbabio.2024.149530","DOIUrl":"10.1016/j.bbabio.2024.149530","url":null,"abstract":"<div><div>The temperate climate-adapted brown hare (<em>Lepus europaeus</em>) and the cold-adapted mountain hare (<em>Lepus timidus</em>) are closely related and interfertile species. However, their skin fibroblasts display distinct gene expression profiles related to fundamental cellular processes. This indicates important metabolic divergence between the two species. Through targeted metabolomics and metabolite tracing, we identified species-specific variations in glycerol 3-phosphate (G3P) metabolism. G3P is a key metabolite of the G3P shuttle, which transfers reducing equivalents from cytosolic NADH to the mitochondrial electron transport chain (ETC), consequently regulating glycolysis, lipid metabolism, and mitochondrial bioenergetics. Alterations in G3P metabolism have been implicated in multiple human pathologies including cancer and diabetes. We observed that mountain hare mitochondria exhibit elevated G3P shuttle activity, alongside increased membrane potential and decreased mitochondrial temperature. Silencing mitochondrial G3P dehydrogenase (GPD2), which couples the conversion of G3P to the ETC, uncovered its species-specific role in controlling mitochondrial membrane potential and highlighted its involvement in skin fibroblast thermogenesis. Unexpectedly, GPD2 silencing enhanced wound healing and cell proliferation rates in a species-specific manner. Our study underscores the pivotal role of the G3P shuttle in mediating physiological, bioenergetic, and metabolic divergence between these hare species.</div></div>","PeriodicalId":50731,"journal":{"name":"Biochimica et Biophysica Acta-Bioenergetics","volume":"1866 2","pages":"Article 149530"},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Circadian rhythms driven by biological clocks regulate physiological processes in all living organisms by anticipating daily geophysical changes, thus enhancing environmental adaptation. Time-resolved serial multi-omic analyses in vivo, ex vivo, and in synchronized cell cultures have revealed rhythmic changes in the transcriptome, proteome, and metabolome, involving up to 50 % of the mammalian genome. Mitochondrial oxidative metabolism is central to cellular bioenergetics, and many nuclear genes encoding mitochondrial proteins exhibit both circadian and ultradian oscillatory expression. However, studies on mitochondrial DNA (mtDNA) gene expression remain incomplete. Using a well-established in vitro synchronization protocol, we investigated the time-resolved expression of mtDNA genes coding for respiratory chain complex subunits, revealing a rhythmic profile dependent on BMAL1, the master circadian clock transcription factor. Additionally, the expression of genes coding for key mitochondrial biogenesis transcription factors, PGC1a, NRF1, and TFAM, showed BMAL1-dependent circadian oscillations. Notably, LC3-II, involved in mitophagy, displayed a similar in-phase circadian expression, thereby maintaining stable respiratory chain complex levels. Moreover, we found that simultaneous mitochondrial biogenesis and degradation occur in a coordinated manner with cycles in organelle dynamics, leading to rhythmic changes in mitochondrial fission and fusion. This study provides new insights into circadian clock regulation of mitochondrial turnover, emphasizing the importance of temporal regulation in cellular metabolism. Understanding these mechanisms opens potential therapeutic avenues for targeting mitochondrial dysfunctions and related metabolic disorders.
{"title":"Circadian clockwork controls the balance between mitochondrial turnover and dynamics: What is life … without time marking?","authors":"Olga Cela , Rosella Scrima , Michela Rosiello , Consiglia Pacelli , Claudia Piccoli , Mirko Tamma , Francesca Agriesti , Gianluigi Mazzoccoli , Nazzareno Capitanio","doi":"10.1016/j.bbabio.2025.149542","DOIUrl":"10.1016/j.bbabio.2025.149542","url":null,"abstract":"<div><div>Circadian rhythms driven by biological clocks regulate physiological processes in all living organisms by anticipating daily geophysical changes, thus enhancing environmental adaptation. Time-resolved serial multi-omic analyses in vivo, ex vivo, and in synchronized cell cultures have revealed rhythmic changes in the transcriptome, proteome, and metabolome, involving up to 50 % of the mammalian genome. Mitochondrial oxidative metabolism is central to cellular bioenergetics, and many nuclear genes encoding mitochondrial proteins exhibit both circadian and ultradian oscillatory expression. However, studies on mitochondrial DNA (mtDNA) gene expression remain incomplete. Using a well-established in vitro synchronization protocol, we investigated the time-resolved expression of mtDNA genes coding for respiratory chain complex subunits, revealing a rhythmic profile dependent on BMAL1, the master circadian clock transcription factor. Additionally, the expression of genes coding for key mitochondrial biogenesis transcription factors, PGC1a, NRF1, and TFAM, showed BMAL1-dependent circadian oscillations. Notably, LC3-II, involved in mitophagy, displayed a similar in-phase circadian expression, thereby maintaining stable respiratory chain complex levels. Moreover, we found that simultaneous mitochondrial biogenesis and degradation occur in a coordinated manner with cycles in organelle dynamics, leading to rhythmic changes in mitochondrial fission and fusion. This study provides new insights into circadian clock regulation of mitochondrial turnover, emphasizing the importance of temporal regulation in cellular metabolism. Understanding these mechanisms opens potential therapeutic avenues for targeting mitochondrial dysfunctions and related metabolic disorders.</div></div>","PeriodicalId":50731,"journal":{"name":"Biochimica et Biophysica Acta-Bioenergetics","volume":"1866 2","pages":"Article 149542"},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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