Unraveling Biochemical Pathways Affected by Mitochondrial Dysfunctions Using Metabolomic Approaches

Demine, Stéphane; Reddy, Nagabushana; Renard, Patricia; Raes, Martine; Arnould, Thierry

doi:10.3390/metabo4030831

Cited by 30 publications

(21 citation statements)

References 273 publications

(353 reference statements)

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“…Mitochondrial lipid oxidation appears reduced after rotator cuff tears, but metabolites involved in glycolysis are enriched 30 and 60 days after injury. Genes involved in glycolytic metabolism, such as phosphofructokinase, aldolase A, GAPDH, phosphoglycerate, and enolase 3 (58), were down at 10 days, but recovered to some extent by 60 days after injury, although glycolytic metabolites remained elevated. The net increase in glycolytic metabolites corresponded with a greater ability of mitochondria to oxidize pyruvate in vitro, and these findings in combination with the reduced abundance of acylcarnitines suggest muscle fibers are using much less lipid for oxidation.…”

Section: Discussionmentioning

confidence: 98%

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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Section: Discussionmentioning

confidence: 98%

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Gumucio

Qasawa

Ferrara

et al. 2018

Preprint

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“…Abiotic stresses can disrupt these network pathways, resulting in their uncoupling. For example, extremely high or low temperatures might inhibit a subset of enzymes in the same or connected pathways [3], and hence various intermediate compounds might accumulate as a result of this functional uncoupling of metabolic pathways [4]. These intermediate compounds could be converted to toxic by-products that might affect the cell's survival or longevity [5].…”

Section: Introductionmentioning

confidence: 99%

Jasmonic Acid Signaling Pathway in Response to Abiotic Stresses in Plants

Ali

Baek

2020

IJMS

283

156

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Plants as immovable organisms sense the stressors in their environment and respond to them by means of dedicated stress response pathways. In response to stress, jasmonates (jasmonic acid, its precursors and derivatives), a class of polyunsaturated fatty acid-derived phytohormones, play crucial roles in several biotic and abiotic stresses. As the major immunity hormone, jasmonates participate in numerous signal transduction pathways, including those of gene networks, regulatory proteins, signaling intermediates, and proteins, enzymes, and molecules that act to protect cells from the toxic effects of abiotic stresses. As cellular hubs for integrating informational cues from the environment, jasmonates play significant roles in alleviating salt stress, drought stress, heavy metal toxicity, micronutrient toxicity, freezing stress, ozone stress, CO 2 stress, and light stress. Besides these, jasmonates are involved in several developmental and physiological processes throughout the plant life. In this review, we discuss the biosynthesis and signal transduction pathways of the JAs and the roles of these molecules in the plant responses to abiotic stresses.

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“…Increased kynurenic acid (KYNA) is found in late stage of chronic kidney disease [33]. Increased creatinine is the most common clinical biomarker of renal dysfunction [29,34], also found in Toni–Debré–Fanconi syndrome, which is a typical tubulopathy linked to several different mutations in BCS1L in newborn infants [35] and other mitochondrial diseases [36,37]. The increase of these biomarkers in homozygous mice on HCD suggests a more severe renal dysfunction than in mice fed with SD.…”

Section: Discussionmentioning

confidence: 99%

Effect of High-Carbohydrate Diet on Plasma Metabolome in Mice with Mitochondrial Respiratory Chain Complex III Deficiency

Rajendran

Tomašić

Kotarsky

et al. 2016

IJMS

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Mitochondrial disorders cause energy failure and metabolic derangements. Metabolome profiling in patients and animal models may identify affected metabolic pathways and reveal new biomarkers of disease progression. Using liver metabolomics we have shown a starvation-like condition in a knock-in (Bcs1lc.232A>G) mouse model of GRACILE syndrome, a neonatal lethal respiratory chain complex III dysfunction with hepatopathy. Here, we hypothesized that a high-carbohydrate diet (HCD, 60% dextrose) will alleviate the hypoglycemia and promote survival of the sick mice. However, when fed HCD the homozygotes had shorter survival (mean ± SD, 29 ± 2.5 days, n = 21) than those on standard diet (33 ± 3.8 days, n = 30), and no improvement in hypoglycemia or liver glycogen depletion. We investigated the plasma metabolome of the HCD- and control diet-fed mice and found that several amino acids and urea cycle intermediates were increased, and arginine, carnitines, succinate, and purine catabolites decreased in the homozygotes. Despite reduced survival the increase in aromatic amino acids, an indicator of liver mitochondrial dysfunction, was normalized on HCD. Quantitative enrichment analysis revealed that glycine, serine and threonine metabolism, phenylalanine and tyrosine metabolism, and urea cycle were also partly normalized on HCD. This dietary intervention revealed an unexpected adverse effect of high-glucose diet in complex III deficiency, and suggests that plasma metabolomics is a valuable tool in evaluation of therapies in mitochondrial disorders.

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Unraveling Biochemical Pathways Affected by Mitochondrial Dysfunctions Using Metabolomic Approaches

Cited by 30 publications

References 273 publications

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Jasmonic Acid Signaling Pathway in Response to Abiotic Stresses in Plants

Effect of High-Carbohydrate Diet on Plasma Metabolome in Mice with Mitochondrial Respiratory Chain Complex III Deficiency

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