scholarly journals Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Eran Mick ◽  
Denis V Titov ◽  
Owen S Skinner ◽  
Rohit Sharma ◽  
Alexis A Jourdain ◽  
...  
Keyword(s):  
Stress Response ◽  
Mitochondrial Dysfunction ◽  
Nadh Oxidation ◽  
Integrated Stress Response ◽  
Metabolic State ◽  
Membrane Hyperpolarization ◽  
Mitochondrial Inhibitors ◽  
Mitochondrial Inner Membrane ◽  
Transport Chain ◽  
Multiple Paths

Mitochondrial dysfunction is associated with activation of the integrated stress response (ISR) but the underlying triggers remain unclear. We systematically combined acute mitochondrial inhibitors with genetic tools for compartment-specific NADH oxidation to trace mechanisms linking different forms of mitochondrial dysfunction to the ISR in proliferating mouse myoblasts and in differentiated myotubes. In myoblasts, we find that impaired NADH oxidation upon electron transport chain (ETC) inhibition depletes asparagine, activating the ISR via the eIF2α kinase GCN2. In myotubes, however, impaired NADH oxidation following ETC inhibition neither depletes asparagine nor activates the ISR, reflecting an altered metabolic state. ATP synthase inhibition in myotubes triggers the ISR via a distinct mechanism related to mitochondrial inner-membrane hyperpolarization. Our work dispels the notion of a universal path linking mitochondrial dysfunction to the ISR, instead revealing multiple paths that depend both on the nature of the mitochondrial defect and on the metabolic state of the cell.

scholarly journals Neuronal Mitochondrial Dysfunction Activates the Integrated Stress Response to Induce Fibroblast Growth Factor 21

Cell Reports ◽  
2018 ◽  
Vol 24 (6) ◽  
pp. 1407-1414 ◽  
Author(s):  
Lisa Michelle Restelli ◽  
Björn Oettinghaus ◽  
Mark Halliday ◽  
Cavit Agca ◽  
Maria Licci ◽  
...  
Keyword(s):  
Stress Response ◽  
Growth Factor ◽  
Mitochondrial Dysfunction ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Integrated Stress Response ◽  
Fibroblast Growth

Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance

2008 ◽  
Vol 295 (3) ◽  
pp. E678-E685 ◽  
Author(s):  
Muhammad A. Abdul-Ghani ◽  
Florian L. Muller ◽  
Yuhong Liu ◽  
Alberto O. Chavez ◽  
Bogdan Balas ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Atp Synthesis ◽  
Insulin Resistant ◽  
Palmitoyl Carnitine ◽  
Mitochondrial Inner Membrane ◽  
Transport Chain ◽  
Mitochondrial Defects ◽  
Ffa Metabolism

Insulin resistance is a characteristic feature of type 2 diabetes and obesity. Insulin-resistant individuals manifest multiple disturbances in free fatty acid (FFA) metabolism and have excessive lipid accumulation in insulin target tissues. Although much evidence supports a causal role for altered FFA metabolism in the development of insulin resistance, i.e., “lipotoxicity”, the intracellular mechanisms by which elevated plasma FFA levels cause insulin resistance have yet to be completely elucidated. Recent studies have implicated a possible role for mitochondrial dysfunction in the pathogenesis of insulin resistance in skeletal muscle. We examined the effect of FFA metabolites [palmitoyl carnitine (PC), palmitoyl-coenzyme A (CoA), and oleoyl-CoA] on ATP synthesis in mitochondria isolated from mouse and human skeletal muscle. At concentrations ranging from 0.5 to 2 μM, these FFA metabolites stimulated ATP synthesis; however, above 5 μM, there was a dose-response inhibition of ATP synthesis. Furthermore, 10 μM PC inhibits ATP synthesis from pyruvate. Elevated PC concentrations (≥10 μM) inhibit electron transport chain activity and decrease the mitochondrial inner membrane potential. These acquired mitochondrial defects, caused by a physiological increase in the concentration of FFA metabolites, provide a mechanistic link between lipotoxicity, mitochondrial dysfunction, and muscle insulin resistance.

scholarly journals Mitochondrial dysfunction is signaled to the integrated stress response by OMA1, DELE1 and HRI

2019 ◽  
Author(s):  
Xiaoyan Guo ◽  
Giovanni Aviles ◽  
Yi Liu ◽  
Ruilin Tian ◽  
Bret A. Unger ◽  
...  
Keyword(s):  
Stress Response ◽  
Mitochondrial Dysfunction ◽  
Mammalian Cells ◽  
Fine Tuning ◽  
Integrated Stress Response ◽  
Inner Mitochondrial Membrane ◽  
Alternative Response ◽  
Mitochondrial Stress ◽  
Eif2α Phosphorylation ◽  
Eif2α Kinase

AbstractIn mammalian cells, mitochondrial dysfunction triggers the integrated stress response (ISR), in which eIF2α phosphorylation upregulates the transcription factor ATF4. However, how mitochondrial stress is relayed to the ISR is unknown. We found that HRI is the eIF2α kinase necessary and sufficient for this relay. Using an unbiased CRISPRi screen, we identified factors upstream of HRI: OMA1, a mitochondrial stress-activated protease, and DELE1, a little-characterized protein we found to be associated with the inner mitochondrial membrane. Mitochondrial stress stimulates the OMA1-dependent cleavage of DELE1, leading to its accumulation in the cytosol, where it interacts with HRI and activates its eIF2α kinase activity. Blockade of the OMA1-DELE1-HRI pathway is beneficial during some, but not all types of mitochondrial stress, and leads to an alternative response that induces specific molecular chaperones. Therefore, this pathway is a potential therapeutic target enabling fine-tuning of the ISR for beneficial outcomes in diseases involving mitochondrial dysfunction.

Sign in / Sign up

Export Citation Format

Share Document