Remodeling of Mitochondrial Flashes in Muscular Development and Dystrophy in Zebrafish

Zhang, Meiling; Sun, Tao; Jian, Chongshu; Lei, Lei; Han, Peidong; Lv, Quanlong; Yang, Ran; Zhou, Xiaohai; Xu, Jiejia; Hu, Yingchun; Men, Yongfeng; Huang, Yanyi; Zhang, Chuanmao; Zhu, Xiaojun; Wang, Xianhua; Cheng, Heping; Xiong, Jing-Wei

doi:10.1371/journal.pone.0132567

Cited by 21 publications

(25 citation statements)

References 36 publications

(48 reference statements)

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“…SS-31 attenuates the excessive mitochondrial flash (mitoflash) activity of aged cardiomyocytes, while normalizing membrane potential and ROS. The mitoflash Hou et al, 2014;Shen et al, 2014;Wang et al, 2008;Wang et al, 2016b;Zhang et al, 2015), is triggered by nanodomain proton influx into the mitochondrial matrix (Wang et al, 2016c). Thus, we wondered whether the increased proton leak in the old cells triggered excessive mitoflash activity.…”

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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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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“…mSOF are metabolically linked, depending on the activity of the ETC, ATP synthase, adenine nucleotide transporter, and substrate availability . The probe has also been used in vivo in C. elegans and zebra fish , as well as in mice , to examine flashes in various disease models. Future studies will enable us to understand the composite nature of mitochondrial flash activity and will encourage the generation of new indicators to better measure these phenomena.…”

Section: Fluorophores Novel Biosensors and Imaging Approachesmentioning

confidence: 99%

Reactive Oxygen Species and Oxidative Stress in Obesity—Recent Findings and Empirical Approaches

McMurray

Patten

Harper

2016

Obesity

210

143

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Objective: High levels of reactive oxygen species (ROS) are intricately linked to obesity and associated pathologies, notably insulin resistance and type 2 diabetes. However, ROS are also thought to be important in intracellular signaling, which may paradoxically be required for insulin sensitivity. Many theories have been developed to explain this apparent paradox, which have broadened our understanding of these important small molecules. While many sites for intracellular ROS production have been described, mitochondrial generated ROS remain a major contributor in most cell types. Mitochondrial ROS generation is controlled by a number of factors described in this review. Moreover, these studies have established both a demand for novel sensitive approaches to measure ROS, as well as a need to standardize and review their suitability for different applications. Methods: To properly assess levels of ROS and mitochondrial ROS in the development of obesity and its complications, a growing number of tools have been developed. This paper reviews many of the common methods for the investigation of ROS in mitochondria, cell, animal, and human models. Results: Available approaches can be generally divided into those that measure ROS-induced damage (e.g., DNA, lipid, and protein damage); those that measure antioxidant levels and redox ratios; and those that use novel biosensors and probes for a more direct measure of different forms of ROS (e.g., 2 0 ,7 0 -dichlorofluorescein (DCF), dihydroethidium (DHE) and its mitochondrial targeted form (MitoSOX), Amplex Red, roGFP, HyPer, mt-cpYFP, ratiometric H 2 O 2 probes, and their derivatives). Moreover, this review provides caveats and strengths for the use of these techniques in different models. Conclusions: Advances in these techniques will undoubtedly advance the understanding of ROS in obesity and may help resolve unanswered questions in the field.

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“…Individual mitoflashes consist of bursting superoxide production [2][3][4], transient matrix alkalinization [5][6][7], and oscillation of the inner membrane potential (ΔΨ m ) at the single-mitochondrion level [2,7,8]. They are widely found in different types of cells and tissues across species from worms to humans, indicating that mitoflashes are highly conserved activity of the organelle [2,3,[9][10][11][12][13][14][15][16]. As expected for their roles in signaling, the rate of mitoflash occurrence is richly modulated by factors including metabolic state, oxidative stress, developmental stage, and aging [3,9,[11][12][13][14][15][16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Identification of EFHD1 as a novel Ca2+ sensor for mitoflash activation

Hou

Jian

et al. 2016

Cell Calcium

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Mitochondrial flashes (mitoflashes) represent stochastic and discrete mitochondrial events that each comprises a burst of superoxide production accompanied by transient depolarization and matrix alkalinization in a respiratory mitochondrion. While mitochondrial Ca(2+) is shown to be an important regulator of mitoflash activity, little is known about its specific mechanism of action. Here we sought to determine possible molecular players that mediate the Ca(2+) regulation of mitoflashes by screening mitochondrial proteins containing the Ca(2+)-binding motifs. In silico analysis and targeted siRNA screening identified four mitoflash activators (MICU1, EFHD1, SLC25A23, SLC25A25) and one mitoflash inhibitor (LETM1) in terms of their ability to modulate mitoflash response to hyperosmotic stress. In particular, overexpression or down-regulation of EFHD1 enhanced or depressed mitoflash activation, respectively, under various conditions of mitochondrial Ca(2+) elevations. Yet, it did not alter mitochondrial Ca(2+) handling, mitochondrial respiration, or ROS-induced mitoflash production. Further, disruption of the two EF-hand motifs of EFHD1 abolished its potentiating effect on the mitoflash responses. These results indicate that EFHD1 functions as a novel mitochondrial Ca(2+) sensor underlying Ca(2+)-dependent activation of mitoflashes.

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Remodeling of Mitochondrial Flashes in Muscular Development and Dystrophy in Zebrafish

Cited by 21 publications

References 36 publications

Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte

Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte

Reactive Oxygen Species and Oxidative Stress in Obesity—Recent Findings and Empirical Approaches

Identification of EFHD1 as a novel Ca2+ sensor for mitoflash activation

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