Mitochondrial Flashes: Dump Superoxide and Dance with Protons Now

Demaurex, Nicolas; Schwarzländer, Markus

doi:10.1089/ars.2016.6819

Cited by 11 publications

(9 citation statements)

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“…For example, shifts in intracellular pH can be significant in plants where dynamic changes in photosynthesis and vacuolar transport rely on changes in pH gradients (Raven & Smith, ; Felle, ). Particularly strong and sudden pH changes can occur in the matrix of individual mitochondria (Schwarzländer et al ., ; Santo‐Domingo et al ., ), which have led to confusion over the usage of different pH‐sensitive biosensors (Demaurex & Schwarzländer, ). RoGFP2‐Orp1 will rule out pH‐related ambiguities in interpretation of H 2 O 2 sensing data in future studies.…”

Section: Discussionmentioning

confidence: 99%

The fluorescent protein sensor roGFP2‐Orp1 monitors in vivo H₂O₂ and thiol redox integration and elucidates intracellular H₂O₂ dynamics during elicitor‐induced oxidative burst in Arabidopsis

et al. 2018

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Hydrogen peroxide (H 2 O 2 ) is ubiquitous in cells and at the centre of developmental programmes and environmental responses. Its chemistry in cells makes H 2 O 2 notoriously hard to detect dynamically, specifically and at high resolution. Genetically encoded sensors overcome persistent shortcomings, but pH sensitivity, silencing of expression and a limited concept of sensor behaviour in vivo have hampered any meaningful H 2 O 2 sensing in living plants.We established H 2 O 2 monitoring in the cytosol and the mitochondria of Arabidopsis with the fusion protein roGFP2-Orp1 using confocal microscopy and multiwell fluorimetry.We confirmed sensor oxidation by H 2 O 2 , show insensitivity to physiological pH changes, and demonstrated that glutathione dominates sensor reduction in vivo. We showed the responsiveness of the sensor to exogenous H 2 O 2 , pharmacologically-induced H 2 O 2 release, and genetic interference with the antioxidant machinery in living Arabidopsis tissues. Monitoring intracellular H 2 O 2 dynamics in response to elicitor exposure reveals the late and prolonged impact of the oxidative burst in the cytosol that is modified in redox mutants.We provided a well defined toolkit for H 2 O 2 monitoring in planta and showed that intracellular H 2 O 2 measurements only carry meaning in the context of the endogenous thiol redox systems. This opens new possibilities to dissect plant H 2 O 2 dynamics and redox regulation, including intracellular NADPH oxidase-mediated ROS signalling.

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Section: Discussionmentioning

confidence: 99%

The fluorescent protein sensor roGFP2‐Orp1 monitors in vivo H₂O₂ and thiol redox integration and elucidates intracellular H₂O₂ dynamics during elicitor‐induced oxidative burst in Arabidopsis

et al. 2018

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“…The evaluation of mitochondrial proton leak by Seahorse Assay is indirect, as it is based on the oxygen consumption rate. Thus, to directly investigate the reduction of mitochondrial proton leak in old cardiomyocytes by SS-31, we expressed the protein mt-cpYFP, a mitochondrial matrixtargeted pH indicator (Demaurex and Schwarzlander, 2016;Schwarzlander et al, 2012;Wang et al, 2016a;Wei-LaPierre et al, 2013) in the rat cardiomyocytes ( Fig. S3).…”

Section: Ss-31 Alleviates the Excessive Mitochondrial Proton Leak In mentioning

confidence: 99%

Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte

Zhang

Alder

Wang

et al. 2020

Preprint

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17Aging-associated diseases, including cardiac dysfunction, are increasingly common in the 18population. However, the mechanisms of physiologic aging in general, and cardiac aging in 19 particular, remain poorly understood. While effective medical interventions are available for 20 some kinds of heart failure, one age-related impairment, diastolic dysfunction in Heart Failure 21with Preserved Ejection Fraction (HFpEF) is lacking a clinically effective treatment. Using the 22 model of naturally aging mice and rats, we show direct evidence of increased proton leak in the 23 aged heart mitochondria. Moreover, we identified ANT1 as mediating the increased proton 24 permeability of old cardiomyocytes. Most importantly, the tetra-peptide drug SS-31 25(elamipretide) prevents age-related excess proton entry, decreases the mitochondrial flash 26 activity and mitochondrial permeability transition pore (mPTP) opening and rejuvenates 27 mitochondrial function by direct association with ANT1 and the mitochondrial ATP synthasome. 28Our results uncover a novel mechanism of age-related cardiac dysfunction and elucidate how 29 SS-31 is able to reverse this clinically important complication of cardiac aging. 30 31 Significance 32Aging is the greatest risk factor for cardiac dysfunction, including Heart Failure with Preserved 33Ejection Fraction (HFpEF). Unfortunately, the mechanisms of cardiac aging remain elusive, and 34there are no effective pharmacologic therapies for HFpEF. Here, we show direct evidence of 35 increased proton leak in aged cardiac mitochondria and have identified ANT1 as mediating the 36 increased proton permeability of old cardiomyocytes. Moreover, the mitochondrial-targeted 37 tetra-peptide SS-31 (elamipretide) prevents the age-related excess proton entry and 38 rejuvenates mitochondrial function by direct association with ANT1 and the mitochondrial ATP 39 synthasome, resulting in alleviation of diastolic dysfunction in old mice. Our results unmask a 40 novel mechanism of cardiac aging and elucidate how SS-31 reverses this clinically important 41 complication of aging. 42

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“…The authors proposed that both hormones act as mitochondrial signals through ROS formation. Those conclusions will require future reassessment because the employed ROS-detection methodology based on the cpYFP sensor protein has since proven inappropriate (Schwarzländer et al, 2014;Demaurex and Schwarzländer, 2016). A potential link between mitochondrial ROS and auxin is independently supported by Arabidopsis plants lacking the mitochondrial FTSH4 AAA-protease that is required for the assembly and/or stability of complex I and, even more, complex V. Similar to abo6 mutants, auxin accumulation or responsiveness was reduced in these plants, and external application of auxin could revert the phenotypic symptoms of ftsh4 mutant plants .…”

Section: Auxinmentioning

confidence: 99%

Mitochondrial Energy Signaling and Its Role in the Low-Oxygen Stress Response of Plants

et al. 2018

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ORCID IDs: 0000-0001-5369-7911 (S.W.); 0000-0003-4024-968X (O.V.A.); 0000-0003-0796-8308 (M.S.).Cells of complex organisms typically rely on mitochondria for energy provision. The amount of energy required to sustain cellular activity can vary strongly depending on external conditions. Vice versa, constraints on respiratory activity due to metabolic status or stress insult require mitochondrial signaling to coordinate cellular physiology with the function of the organelle. In this update, we review recent insights into plant mitochondrial energy signaling in the light of their significance to stress acclimation. First, we focus on the characteristic adjustments of the nuclear transcriptome that occur after pharmacological inhibition of the mitochondrial electron transport chain as the output of mitochondrial retrograde signaling. Second, we discuss the proteins that have recently been identified as regulators of the transcript responses and the emerging picture of their action as a signaling network. We then pose the question of how well our current models of inducing mitochondrial dysfunction relate to conditions that plants face naturally. We reason that low-oxygen stress shows striking similarities with electron transport inhibitors with respect to their impact on mitochondrial energy physiology upstream, as well as the cellular transcriptomic response. Finally, we highlight and discuss changes in mitochondrial physiology that are common to both stimuli as candidates for upstream signals. The aim of this update is to better define the physiological context in which mitochondrial signaling operates to provide new directions for future research. RESPONSES TO MITOCHONDRIAL ENERGY SIGNALING AT THE TRANSCRIPT LEVEL

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Mitochondrial Flashes: Dump Superoxide and Dance with Protons Now

Cited by 11 publications

References 4 publications

The fluorescent protein sensor roGFP2‐Orp1 monitors in vivo H₂O₂ and thiol redox integration and elucidates intracellular H₂O₂ dynamics during elicitor‐induced oxidative burst in Arabidopsis

The fluorescent protein sensor roGFP2‐Orp1 monitors in vivo H₂O₂ and thiol redox integration and elucidates intracellular H₂O₂ dynamics during elicitor‐induced oxidative burst in Arabidopsis

Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte

Mitochondrial Energy Signaling and Its Role in the Low-Oxygen Stress Response of Plants

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Mitochondrial Flashes: Dump Superoxide and Dance with Protons Now

Cited by 11 publications

References 4 publications

The fluorescent protein sensor roGFP2‐Orp1 monitors in vivo H2O2 and thiol redox integration and elucidates intracellular H2O2 dynamics during elicitor‐induced oxidative burst in Arabidopsis

The fluorescent protein sensor roGFP2‐Orp1 monitors in vivo H2O2 and thiol redox integration and elucidates intracellular H2O2 dynamics during elicitor‐induced oxidative burst in Arabidopsis

Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte

Mitochondrial Energy Signaling and Its Role in the Low-Oxygen Stress Response of Plants

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The fluorescent protein sensor roGFP2‐Orp1 monitors in vivo H₂O₂ and thiol redox integration and elucidates intracellular H₂O₂ dynamics during elicitor‐induced oxidative burst in Arabidopsis

The fluorescent protein sensor roGFP2‐Orp1 monitors in vivo H₂O₂ and thiol redox integration and elucidates intracellular H₂O₂ dynamics during elicitor‐induced oxidative burst in Arabidopsis