Dataset Information

Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology.

ABSTRACT: The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of growth. Mammalian TOR complex 2 (mTORC2) regulates AGC kinase family members and is implicated in various disorders, including cancer and diabetes. Here we report that mTORC2 is localized to the endoplasmic reticulum (ER) subcompartment termed mitochondria-associated ER membrane (MAM). mTORC2 localization to MAM was growth factor-stimulated, and mTORC2 at MAM interacted with the IP3 receptor (IP3R)-Grp75-voltage-dependent anion-selective channel 1 ER-mitochondrial tethering complex. mTORC2 deficiency disrupted MAM, causing mitochondrial defects including increases in mitochondrial membrane potential, ATP production, and calcium uptake. mTORC2 controlled MAM integrity and mitochondrial function via Akt mediated phosphorylation of the MAM associated proteins IP3R, Hexokinase 2, and phosphofurin acidic cluster sorting protein 2. Thus, mTORC2 is at the core of a MAM signaling hub that controls growth and metabolism.

SUBMITTER: Betz C

PROVIDER: S-EPMC3732980 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma (FUS) gene, which can lead to both juvenile and late onset ALS. Although ALS results from MN’s death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a FUSR521H or a FUSP525L mutation and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette as described previously in our lab. Mutant and control iPSC differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Subsequent lipidomics studies demonstrated defects in myelin lipids, with a reduction of phospholipids in mutant OPCs. Among them, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most two abundant phospholipid in mammalian cells and regulate the mitochondria-associated ER membrane (MAM) integrity. Interestingly, FUSR521H mutant OPCs displayed a decrease in the PC/PE ratio, known to be associated with maintaining membrane (mitochondria) integrity. Proximity ligation assay further indicated that MAM was diminished in mutant OPCs. Moreover, mutant OPCs displayed stronger activation of unfolded protein response markers, a hallmark of increased susceptibility to endoplasmic reticulum (ER) stress, when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca2+ signaling from ER Ca2+ stores. Taken together, these results demonstrate that FUS mutant OPCs display defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and suppressed physiological Ca2+ signaling events.

Dataset Information

Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets