Mitochondrial Dysfunction and Lipid Accumulation in the Human Diaphragm during Mechanical Ventilation

Picard, Martin; Jung, Boris; Liang, Feng; Azuelos, Ilan; Hussain, Sabah N. A.; Goldberg, Peter; Godin, Richard; Danialou, Gawiyou; Chaturvedi, Rakesh; Rygiel, Karolina A.; Matecki, Stéfan; Jaber, Samir; Rosiers, Christine Des; Karpati, George; Ferri, Lorenzo; Burelle, Yan; Turnbull, Doug M.; Taivassalo, Tanja; Petrof, Basil J.

doi:10.1164/rccm.201206-0982oc

Cited by 189 publications

(186 citation statements)

References 62 publications

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“…In vivo, administration of a mitochondria-targeted antioxidant molecule (SS-31) reduced mitochondrial ROSemitting potential by 50% in rat muscle cells (3) and consequently prevented dietary glucose-induced cellular oxidation of GSH into GSSG and inhibited the development of insulin resistance in a model of high-fat diet (3). Likewise, abolishing mitochondrial ROS release with SS-31 also prevented the activation of the muscle ubiquitin-proteasome atrophy pathway in a rat model of diaphragm disuse (119); similar results were obtained by overexpression of the endogenous mitochondrial antioxidant enzyme peroxiredoxin 3 (PRX3) in mice (114). Furthermore, hypertriglyceridemia-induced mitochondrial ROS production in the hypothalamus was found to alter cellular oxidative stress and signal satiety, such that blocking this mitochondrial signal with antioxidants prevented satiety in rats and increased calorie intake (9).…”

Section: R399 Mitochondrial Morphology and Functionmentioning

confidence: 73%

Mitochondrial morphology transitions and functions: implications for retrograde signaling?

Picard

Shirihai

Gentil

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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268

193

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In response to cellular and environmental stresses, mitochondria undergo morphology transitions regulated by dynamic processes of membrane fusion and fission. These events of mitochondrial dynamics are central regulators of cellular activity, but the mechanisms linking mitochondrial shape to cell function remain unclear. One possibility evaluated in this review is that mitochondrial morphological transitions (from elongated to fragmented, and vice-versa) directly modify canonical aspects of the organelle's function, including susceptibility to mitochondrial permeability transition, respiratory properties of the electron transport chain, and reactive oxygen species production. Because outputs derived from mitochondrial metabolism are linked to defined cellular signaling pathways, fusion/fission morphology transitions could regulate mitochondrial function and retrograde signaling. This is hypothesized to provide a dynamic interface between the cell, its genome, and the fluctuating metabolic environment. mitochondrial dynamics; morphology; fusion and fission; bioenergetics; retrograde signaling MITOCHONDRIA are crucial organelles involved in cellular energy production and in the regulation of numerous aspects of cellular activity, including, but not limited to, apoptosis, Ca 2ϩ signaling, and redox homeostasis (41). Over the last decade, mitochondria have moved to the forefront of cell biology research for their ability to undergo regulated events of membrane fusion and fission, which remodel the architecture of the mitochondrial network within the cytoplasm (43,36,146). Processes of mitochondrial fusion and fission are collectively termed mitochondrial dynamics. Importantly, abnormal mitochondrial dynamics cause bioenergetic defects (26), induce embryonic lethality in transgenic animal models (27), and underly a heterogenous group of human diseases (164), attesting to the pivotal role of these processes in physiopathology (25,50,91). In addition, experimental work has shown that mitochondrial dynamics are involved in regulating cellular activity and that mitochondria participate in important cellular signaling pathways (136,158).Mitochondrial retrograde signaling is defined as the transfer of information from mitochondria to the cytoplasm and nucleus. Retrograde signaling pathways have been established to occur in response to metabolic perturbations, with the aim to trigger adaptive cellular responses orchestrated by coordinated changes in gene expression (reviewed in Refs. 21 and 93). Among the retrograde signals produced by mitochondria that are known to regulate different aspects of cellular activity, the most studied include reactive oxygen species (ROS), pro-apoptotic molecules, ATP/ADP/AMP, metabolic intermediates (NAD ϩ /NADH), and Ca 2ϩ (20,39,58). From recent discoveries revealing that mitochondrial dynamics regulate cellular activity in response to various stressors, it is hypothesized that changes in mitochondrial morphology regulate, either directly or indirectly, various aspects of mitochondrial funct...

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Section: R399 Mitochondrial Morphology and Functionmentioning

confidence: 73%

Mitochondrial morphology transitions and functions: implications for retrograde signaling?

Picard

Shirihai

Gentil

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

268

193

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“…Moreover, the activities of the electron transport chain complexes II, III, and IV are depressed in mitochondria isolated from diaphragms of rats exposed to only 12 h of MV and prolonged MV in rats also promotes diaphragmatic mitochondrial uncoupling as indicated by a decrease in the respiratory control ratio (50). Importantly, two independent studies have confirmed that prolonged MV also results in mitochondrial damage in the human diaphragm (80,106). Finally, treatment of animals with a mitochondrialtargeted antioxidant prevents the MV-induced activation of several proteolytic systems and prevents VIDD (82).…”

Section: R468mentioning

confidence: 91%

Ventilator-induced diaphragm dysfunction: cause and effect

Powers

Wiggs

Sollanek

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

143

156

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Powers SK, Wiggs MP, Sollanek KJ, Smuder AJ. Ventilator-induced diaphragm dysfunction: cause and effect. Am J Physiol Regul Integr Comp Physiol 305: R464 -R477, 2013. First published July 10, 2013 doi:10.1152/ajpregu.00231.2013 is used clinically to maintain gas exchange in patients that require assistance in maintaining adequate alveolar ventilation. Common indications for MV include respiratory failure, heart failure, drug overdose, and surgery. Although MV can be a life-saving intervention for patients suffering from respiratory failure, prolonged MV can promote diaphragmatic atrophy and contractile dysfunction, which is referred to as ventilator-induced diaphragm dysfunction (VIDD). This is significant because VIDD is thought to contribute to problems in weaning patients from the ventilator. Extended time on the ventilator increases health care costs and greatly increases patient morbidity and mortality. Research reveals that only 18 -24 h of MV is sufficient to develop VIDD in both laboratory animals and humans. Studies using animal models reveal that MV-induced diaphragmatic atrophy occurs due to increased diaphragmatic protein breakdown and decreased protein synthesis. Recent investigations have identified calpain, caspase-3, autophagy, and the ubiquitin-proteasome system as key proteases that participate in MV-induced diaphragmatic proteolysis. The challenge for the future is to define the MV-induced signaling pathways that promote the loss of diaphragm protein and depress diaphragm contractility. Indeed, forthcoming studies that delineate the signaling mechanisms responsible for VIDD will provide the knowledge necessary for the development of a pharmacological approach that can prevent VIDD and reduce the incidence of weaning problems. respiratory muscle; atrophy; mechanical ventilation; weaning; muscle wasting MECHANICAL VENTILATION (MV) is used clinically to achieve sufficient pulmonary gas exchange in patients unable to sustain adequate alveolar ventilation on their own. Common indications for MV include respiratory failure due to chronic obstructive pulmonary disease, status asthmaticus, and/or heart failure. In addition, MV is often an essential intervention in patients suffering from acute drug overdose, neuromuscular diseases, sepsis, and during surgery along with postsurgical recovery.The number of patients receiving prolonged MV in the United States exceeds more than 300,000 each year in the intensive care unit (ICU) (20). Although MV can be a lifesaving measure, prolonged MV results in the rapid development of diaphragmatic weakness due to both atrophy and contractile dysfunction. This detrimental impact of prolonged MV on the diaphragm has been termed ventilator-induced diaphragmatic dysfunction (VIDD) and VIDD is predicted to be a major contributor to problems in weaning patients from the ventilator (26, 114). Although previous reports describing the impact of prolonged MV on the diaphragm have appeared in the literature, advances in our understanding of the mechanisms responsible for VIDD h...

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“…The precise pathways involved in MV-induced diaphragm weakness remain partially understood. Animal models suggest that oxidative stress plays a major role in VIDD (7,8) and recent studies have identified mitochondria as an essential source of reactive oxygen species (ROS) implicated in VIDD (9,10). ROS production is linked to activation of proteolytic systems such as caspases and calpains (11), which play significant roles in degrading cytoskeletal proteins in muscle (6,12,13) directly involved in the development of MVinduced diaphragm muscle fiber atrophy and injury (7,14,15).…”

mentioning

confidence: 99%

Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation

Matecki

Dridi

Jung

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Ventilator-induced diaphragmatic dysfunction (VIDD) refers to the diaphragm muscle weakness that occurs following prolonged controlled mechanical ventilation (MV). The presence of VIDD impedes recovery from respiratory failure. However, the pathophysiological mechanisms accounting for VIDD are still not fully understood. Here, we show in human subjects and a mouse model of VIDD that MV is associated with rapid remodeling of the sarcoplasmic reticulum (SR) Ca 2+ release channel/ryanodine receptor (RyR1) in the diaphragm. The RyR1 macromolecular complex was oxidized, S-nitrosylated, Ser-2844 phosphorylated, and depleted of the stabilizing subunit calstabin1, following MV. These posttranslational modifications of RyR1 were mediated by both oxidative stress mediated by MV and stimulation of adrenergic signaling resulting from the anesthesia. We demonstrate in the murine model that such abnormal resting SR Ca 2+ leak resulted in reduced contractile function and muscle fiber atrophy for longer duration of MV. Treatment with β-adrenergic antagonists or with S107, a small molecule drug that stabilizes the RyR1-calstabin1 interaction, prevented VIDD. Diaphragmatic dysfunction is common in MV patients and is a major cause of failure to wean patients from ventilator support. This study provides the first evidence to our knowledge of RyR1 alterations as a proximal mechanism underlying VIDD (i.e., loss of function, muscle atrophy) and identifies RyR1 as a potential target for therapeutic intervention.excitation-contraction coupling | beta adrenergic signaling | calcium | VIDD | skeletal muscle

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Mitochondrial Dysfunction and Lipid Accumulation in the Human Diaphragm during Mechanical Ventilation

Cited by 189 publications

References 62 publications

Mitochondrial morphology transitions and functions: implications for retrograde signaling?

Mitochondrial morphology transitions and functions: implications for retrograde signaling?

Ventilator-induced diaphragm dysfunction: cause and effect

Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation

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