Abstract
Mitochondrial mutations cause bioenergetic defects associated with failures to use the electron transfer chain and oxidize substrates. These defects are exacerbated under energetic stress conditions and ultimately cause cell deterioration and death. However, little is known about cellular strategies that rescue mitochondrial stress failures and maintain cell survival under these conditions. Here, we have designed and performed a high-throughput chemical screen to identify small molecules that rescue human mitochondrial complex I mutations from energetic stress-induced cell death. The top positive hits were a series of sulfonylureas that efficiently maintain prolonged cell survival and growth under energetic stress conditions. The addition of galactose instead of glucose, to experimentally force mitochondrial respiration, triggered an initial ER stress response that was associated with IRE1α-dependent inflammatory signals including JNK and p38 MAP kinases in mutant cells. Sulfonylureas, similar to inhibition of IRE1α and p38 MAP kinase, potently blocked this ER stress inflammatory and cell death pathway and maintained viability and cell growth under severe energetic stress conditions. These studies reveal that sulfonylureas and specific inhibition of the IRE1α inflammatory pathway protect against cell death and can be used to rescue bioenergetic failures in mitochondrial complex I-mutated cells under stress conditions.
Highlights
Mitochondrial diseases encompass a large group of heterogeneous disorders stemming from mutations in either nuclear or mitochondrial genomes and result in an overall impairment in the oxidative phosphorylation (OXPHOS) system[1]
Short-term treatment of control cells in galactose with glimepiride had no effect on cell proliferation at 72 h or after 1 week, treatment did lead to a slight decrease in cell growth after 2 weeks of treatment (Supplementary 1)
At 48 h, both active p-JNK and p-p38 levels where highly induced in ND1 cells cultured in galactose compared to cells cultured in glucose or ND1 cells cultured in galactose with glimepiride (Fig. 2c). We found that this increase in MAPK activation was specific to ND1-mutant cells, as control cells did not induce activation of either MAPK when cultured in galactose (Supplementary 3A)
Summary
Mitochondrial diseases encompass a large group of heterogeneous disorders stemming from mutations in either nuclear or mitochondrial genomes and result in an overall impairment in the oxidative phosphorylation (OXPHOS) system[1]. Of the different complexes that make up the mitochondrial respiratory chain, complex I (CI) is the largest and mutations in CI are the most common OXPHOS defects in patients[3]. While OXPHOS is the major pathway for generating ATP, many different cell types predominantly utilize glycolysis in vitro, making it difficult to study defects in mitochondrial respiration. To circumvent this challenge, cells can be cultured in media containing galactose instead of glucose. Cells can be cultured in media containing galactose instead of glucose
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