ABSTRACT
Mitochondria must maintain adequate amounts of metabolites for protective and biosynthetic functions. However, how mitochondria sense the abundance of metabolites and regulate metabolic homeostasis is not well understood. In this work, we focused on glutathione (GSH), a critical redox metabolite in mitochondria, and identified a feedback mechanism that controls its abundance through the mitochondrial GSH transporter, SLC25A39. Under physiological conditions, SLC25A39 is rapidly degraded by mitochondrial protease AFG3L2. Depletion of GSH dissociates AFG3L2 from SLC25A39, causing a compensatory increase in mitochondrial GSH uptake. Genetic and proteomic analyses identified a putative iron-sulfur cluster in the matrix-facing loop of SLC25A39 as essential for this regulation, coupling mitochondrial iron homeostasis to GSH import. Altogether, our work revealed a paradigm for the autoregulatory control of metabolic homeostasis in organelles.
Subject(s)
ATP-Dependent Proteases , ATPases Associated with Diverse Cellular Activities , Glutathione , Mitochondria , Mitochondrial Proteins , Phosphate Transport Proteins , Glutathione/metabolism , Homeostasis , Iron/metabolism , Mitochondria/metabolism , Mitochondrial Membrane Transport Proteins/metabolism , Proteomics , Feedback, Physiological , Mitochondrial Proteins/metabolism , Phosphate Transport Proteins/metabolism , Humans , Iron-Sulfur Proteins/metabolism , Proteolysis , HEK293 Cells , ATP-Dependent Proteases/genetics , ATP-Dependent Proteases/metabolism , ATPases Associated with Diverse Cellular Activities/genetics , ATPases Associated with Diverse Cellular Activities/metabolismABSTRACT
Considering the difficulties associated with the conventional 'trial and error' method for a complete analysis of a giant molecular space, we took the aid of computational pathway (DFT) in screening a large space search of 780 (12×13×5) molecules to search for a host for the blue emitter. The selection process was completed in three Tiers with the conditions of highest theoretical triplet energy (>2.81â eV), aligned HOMO/LUMO levels w.r.t blue dopant (FIrpic), and position of substituents to meet the optimal requirements as host materials. Tier 1 screened twelve different imidazole heterocycle derivatives as base space groups which resulted in the selection of 4,5-diphenyl-1H-imidazole. Tier 2 process converged the search to mCN-CZ having the highest triplet energy and appropriate HOMO/LUMO level relative to FIrpic and ETL. Further, the carbazole of mCN-CZ was replaced with different aromatic hydrocarbons to find the other best compound in terms of triplet energy and HOMO/LUMO. Tier 3 resulted in another promising candidate (mCN-FL) as possible host materials. The band alignment with guest predicted mCN-FL and mCN-CZ to have optimal device performances compared to CZ-CZ and the experimentally observed device performance was in accordance with virtual screening results when TAPC was utilized as the hole transporter. The device results of mCN-CZ and mCN-FL were better than the reference host TCTA. The obtained results thus proved that a virtual screening process will be a useful tool for synthetic chemists in designing task-specific materials.
