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Altered mitochondria-associated ER membranes (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS)- BioID Data

ABSTRACT: Mitochondrial function is modulated by its functional interaction with the endoplasmic reticulum. Recent research indicates that these contacts are disrupted in familial models of amyotrophic lateral sclerosis. We report here this impairment in the crosstalk between mitochondria and the endoplasmic reticulum impedes the use of glucose-derived pyruvate as mitochondrial fuel, causing a shift to fatty acids to sustain energy production. Over time, this deficiency alters mitochondrial electron flow and the active/dormant status of complex I in spinal cord tissues, but not in the brain. These findings suggest MAM plays a crucial role in regulating cellular glucose metabolism and that its dysfunction may underlie the bioenergetic deficits observed in ALS.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Fibroblast

SUBMITTER: Taekyung Yun

LAB HEAD: Estela Area-Gomez

PROVIDER: PXD053415 | Pride | 2024-07-19

REPOSITORIES: Pride

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			Action	DRS
	Experiment_RA912_6MAM_from_RA912_66MAM.mzid.gz	Mzid
	Experiment_RA912_6MAM_from_RA912_66MAM.mzid_Experiment_RA912_6MAM_from_RA912_66MAM.MGF	Mzid
	Experiment_RA912_6TH_from_RA912_66TH.mzid.gz	Mzid
	Experiment_RA912_6TH_from_RA912_66TH.mzid_Experiment_RA912_6TH_from_RA912_66TH.MGF	Mzid
	Experiment_RA912_7MAM_from_RA912_67MAM.mzid.gz	Mzid

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Project description:Background: Metabolic dysregulation has been implicated in bronchopulmonary dysplasia development. Taurine is an essential amino acid for neonates and is critically involved in glucose and fatty acid metabolism. Neonatal tissue obtains taurine mainly through the taurine transporter. The biological role of taurine in neonatal lung development has never been explored. As glucose metabolism mechanistically modulates angiogenesis and angiogenesis is the central player for neonatal lung development, we hypothesize that taurine depletion contributes to bronchopulmonary dysplasia development. Results: Although most genes and proteins for oxidative phosphorylation were enriched in hyperoxia pup lungs, the complex-1 activity decreased. The decrease in taurine-dependent complex-1 core subunits, ND5 and ND6, in hyperoxia lungs reasonably explained the discrepancy. Metabolomics analysis demonstrated decreased lung taurine with increased blood taurine of hyperoxia pups, compatible with the decreased taurine transporter expression. Decreased glycosylation and increased degradation explained the decreased taurine transporter expression. The results of the complementary study using tunicamycin and tauroursodeoxycholic acid studies supported that endoplasmic reticulum stress contributes to decreased taurine transporter expression in hyperoxia lungs. The effect of taurine treatment on reducing endoplasmic reticulum stress, increasing ND5 and ND6 expression, angiogenesis, and, most importantly, the alveolar formation is beneficial to hyperoxia rat pups. Conclusion: Hyperoxia exposure causes endoplasmic reticulum stress, increases taurine transporter degradation, and leads to taurine depletion in the neonatal lungs with subsequent metabolic dysregulation, resulting in poor alveolar formation of the neonatal lungs. We provide evidence of the never-being-reported protective role of taurine in neonatal lung development. The fact that taurine attenuates the severity of bronchopulmonary dysplasia by reducing hyperoxia-induced endoplasmic reticulum stress and mitochondrial dysfunction indicates its therapeutic potential for treating bronchopulmonary dysplasia.

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Altered mitochondria-associated ER membranes (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS)- BioID Data

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