Peroxiredoxin 6 Is a Crucial Factor in the Initial Step of Mitochondrial Clearance and Is Upstream of the PINK1-Parkin Pathway

Ma, Shuaipeng; Zhang, Xuefei; Zheng, Liangjun; Li, Zeyang; Zhao, Xuyang; Lai, Wenjia; Shen, Haoming; Lv, Junniao; Yang, Guofeng; Wang, Qingsong; Ji, Jianguo

doi:10.1089/ars.2015.6336

Cited by 71 publications

(51 citation statements)

References 53 publications

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“…Several reports involving animal and human models of skeletal muscle unloading and denervation have identified profound mitochondrial dysfunction and accompanying increases in ROS production that occur after the injury (65)(66)(67)(68). We also observed increased markers of ROS in injured muscles, including elevated levels of glutathionylated proteins, as well as an increase in the abundance of Prdx3 and Prdx6, which scavenge hydrogen peroxide in the mitochondria and cytoplasm, respectively (69,70). The production of ROS by dysfunctional mitochondria, as suggested by the elevation in Prdx3, likely further exacerbates the inflammatory environment within injured rotator cuff muscle fibers because elevated ROS has been linked to inhibition of protein synthesis signaling pathways, the induction of proteolytic and autophagic pathways, and fibrosis (71,72).…”

Section: Discussionsupporting

confidence: 65%

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

et al. 2019

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Myosteatosis is the pathologic accumulation of lipid that can occur in conjunction with atrophy and fibrosis following skeletal muscle injury. Little is known about the mechanisms by which lipid accumulates in myosteatosis, but many clinical studies have demonstrated that the degree of lipid infiltration negatively correlates with muscle function and regeneration. Our objective was to determine the pathologic changes that result in lipid accumulation in injured muscle fibers. We used a rat model of rotator cuff injury in this study because the rotator cuff muscle group is particularly prone to the development of myosteatosis after injury. Muscles were collected from uninjured controls or 10, 30, or 60 d after injury and analyzed using a combination of muscle fiber contractility assessments, RNA sequencing, and undirected metabolomics, lipidomics, and proteomics, along with bioinformatics techniques to identify potential pathways and cellular processes that are dysregulated after rotator cuff tear. Bioinformatics analyses indicated that mitochondrial function was likely disrupted after injury. Based on these findings and given the role that mitochondria play in lipid metabolism, we then performed targeted biochemical and imaging studies and determined that mitochondrial dysfunction and reduced fatty acid oxidation likely leads to the accumulation of lipid in myosteatosis.—Gumucio, J. P., Qasawa, A. H., Ferrara, P. J., Malik, A. N., Funai, K., McDonagh, B., Mendias, C. L. Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis. FASEB J. 33, 7863–7881 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 65%

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

et al. 2019

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“…Several reports involving animal and human models of skeletal muscle unloading and denervation have identified profound mitochondrial dysfunction and accompanying increases in ROS production that occur subsequent to the injury (60)(61)(62)(63). We also observed increased markers of ROS in injured muscles, including elevated levels of glutathionylated proteins, as well as an increase in the abundance of Prdx3 and Prdx6 which scavenge hydrogen peroxide in the mitochondria and cytoplasm, respectively (64,65). The production of ROS by dysfunctional mitochondria, as suggested by the elevation in Prdx3, likely further exacerbates the inflammatory environment within injured rotator cuff muscle fibers, as elevated ROS has been linked to inhibition of protein synthesis signaling pathways, the induction of proteolytic and autophagic pathways, and fibrosis (66,67).…”

Section: Discussionsupporting

confidence: 63%

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Gumucio

Qasawa

Ferrara

et al. 2018

Preprint

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Myosteatosis is the pathological accumulation of lipid that can occur in conjunction with atrophy and fibrosis following skeletal muscle injury. Little is known about the mechanisms by which lipid accumulates in myosteatosis, but many clinical studies have demonstrated the degree of lipid infiltration negatively correlates with muscle function and regeneration. Our objective was to determine the pathological changes that result in lipid accumulation in injured muscle fibers. We used a rat model of rotator cuff injury in this study, as the rotator cuff muscle group is particularly prone to the development of myosteatosis after injury. Muscles were collected from uninjured controls, or 10, 30, or 60 days after injury, and analyzed using a combination of muscle fiber contractility assessments, RNA sequencing, and undirected metabolomics, lipidomics and proteomics, along with bioinformatics techniques, to identify potential pathways and cellular processes that are dysregulated after rotator cuff tear. Bioinformatics analyses indicated that mitochondrial function was likely disrupted after injury. Based on these findings, and given the role that mitochondria play in lipid metabolism, we then performed targeted biochemical and imaging studies and determined that mitochondrial dysfunction and reduced fatty acid oxidation likely leads to the accumulation of lipid in myosteatosis.

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“…This has been hypothesized as the main mechanism underlying pancreatic dysfunction linked with a lack of PRDX6 since this enzyme may play a role at different cellular levels in controlling ROS production and therefore cellular functions, such as insulin secretion. In fact, a direct action of PRDX6 on mitochondria clearance [39] and in the modulation of electron transport chain [40] has been proposed, processes that are directly implicated with oxidative stress and oxidative stress-related diseases.…”

Section: Discussionmentioning

confidence: 99%

Peroxiredoxin 6 Is a Key Antioxidant Enzyme in Modulating the Link between Glycemic and Lipogenic Metabolism

Arriga

Pacifici

Capuani

et al. 2019

Oxidative Medicine and Cellular Longevity

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Insulin action and often glucose-stimulated insulin secretion are reduced in obesity. In addition, the excessive intake of lipids increases oxidative stress leading to overt type 2 diabetes mellitus (T2DM). Among the antioxidative defense systems, peroxiredoxin 6 (PRDX6) is able to reduce H2O2 and short chain and phospholipid hydroperoxides. Increasing evidences suggest that PRDX6 is involved in the pathogenesis of atherosclerosis and T2DM, but its role in the etiopathology of obesity and its complications is still not known. Therefore, in the present study, we sought to investigate this association by using PRDX6 knockout mice (PRDX6-/-). Metabolic parameters, like carbon dioxide (VCO2) production, oxygen consumption (VO2), and the respiratory exchange ratio (RER), were determined using metabolic cages. Intraperitoneal insulin and glucose tolerance tests were performed to evaluate insulin sensitivity and glucose tolerance, respectively. Liver and pancreas histochemical analyses were also evaluated. The expression of enzymes involved in lipid and glucose metabolism was analyzed by real-time PCR. Following 24 weeks of high-fat-diet (HFD), PRDX6-/- mice showed weight gain and higher food and drink intake compared to controls. VO2 consumption and VCO2 production decreased in PRDX6-/- mice, while the RER was lower than 0.7 indicating a prevalent lipid metabolism. PRDX6-/- mice fed with HFD showed a further deterioration on insulin sensitivity and glucose-stimulated insulin secretion. Furthermore, in PRDX6-/- mice, insulin did not suppress adipose tissue lipolysis with consequent hepatic lipid overload and higher serum levels of ALT, cholesterol, and triglycerides. Interestingly, in PRDX6-/- mice, liver and adipose tissue were associated with proinflammatory gene upregulation. Finally, PRDX6-/- mice showed a higher rate of nonalcoholic steatohepatitis (NASH) compared to control. Our results suggest that PRDX6 may have a functional and protective role in the development of obesity-related metabolic disorders such as liver diseases and T2DM and may be considered a potential therapeutic target against these illnesses.

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Peroxiredoxin 6 Is a Crucial Factor in the Initial Step of Mitochondrial Clearance and Is Upstream of the PINK1-Parkin Pathway

Cited by 71 publications

References 53 publications

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Peroxiredoxin 6 Is a Key Antioxidant Enzyme in Modulating the Link between Glycemic and Lipogenic Metabolism

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