Alterations of mitochondrial form and function caused by resistance against oxidative stress and cytoprotective, mitochondrial proteins
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Abstract
Mitochondria are crucial for cellular metabolism, a major source for reactive oxygen species and play a central role during cell death. This study showed that acute oxidative stress directly influences mitochondria and induces changes in mitochondrial form and function. Analysis of glutamate-resistant HT22R cells showed that adaptations against oxidative stress included a less fragmented mitochondrial shape, a reduced mitochondrial respiration, and an increase in pentose phosphate pathway activity for NADPH production used for recovery of the important antioxidant glutathione. Furthermore, two mitochondrial and cytoprotective proteins seem to influence mitochondria. In SH-SY5Y cells, oxidative stress-protecting, mitochondrial GDAP1 induced mitochondrial fission, but Charcot-Marie-Tooth disease-causing mutated GDAP1 R310Q did not change mitochondrial shape, whereas GDAP1 S34A with mutation of the predicted amino acid for potential glutathione transferase activity triggered strongly mitochondrial elongation. Silencing of GDAP1 influenced mitochondrial morphology, and strongly elevated mitochondrial respiration. The analysis of anti-apoptotic Bcl-xL demonstrated that in mouse embryonic fibroblasts deficiency of Bcl-xL induced mitochondrial fragmentation, reduced mitochondrial respiratory capacity, elevated total glutathione, and increased G6PD abundance and total NADP, which suggests an increase in pentose phosphate pathway activity. However, re-expression of mitochondrial Bcl-xL can prevent these changes.
These results indicate that mitochondrial form and function are affected by oxidative stress and that mechanisms against stress can induce mitochondrial alterations and metabolic adaptations.