Abstract
Lon protease 1 (LONP1) is a highly conserved serine peptidase that plays an important role in the protein quality control system in mammalian mitochondria. LONP1 catalyzes the degradation of oxidized, dysfunctional, and misfolded matrix proteins inside mitochondria and regulates mitochondrial gene expression and genome integrity. Therefore, LONP1 is up-regulated and suppresses cell death in response to oxidative stress, heat shock, and nutrient starvation. On the other hand, translocation of high mobility group box 1 (HMGB1) and active caspase-3 into mitochondria is involved in apoptosis of parvalbumin (PV) cells (one of the GABAergic interneurons) and necrosis of CA1 neurons in the rat hippocampus, respectively, following status epilepticus (SE). In the present study, we investigated whether LONP1 may improve neuronal viability to prevent or ameliorate translocation of active caspase-3 and HMGB1 in mitochondria within PV and CA1 neurons. Following SE, LONP1 expression was up-regulated in mitochondria of PV and CA1 neurons. LONP1 knockdown deteriorated SE-induced neuronal death with mitochondrial accumulation of active caspase-3 and HMGB1 in PV cells and CA1 neurons, respectively. LONP1 knockdown did not affect the aberrant mitochondrial machinery induced by SE. Therefore, our findings suggest, for the first time, that LONP1 may contribute to the alleviation of mitochondrial overloads of active caspase-3 and HMGB1, and the maintenance of neuronal viability against SE.
Highlights
status epilepticus (SE) resulted in high mobility group box 1 (HMGB1) release from the nucleus in PV cells, which was rarely detected in fragmented mitochondria (Figure 1B)
2-fold of control animal levels (F(1,48) = 25.7, p < 0.001 vs. control animals, one-way ANOVA), while it reduced the form factor to 0.6-fold of control animal levels (F(1,48) = 14.2, p < 0.001 vs. control animals, one-way ANOVA; Figure 6A,D). Both the cumulative area/perimeter ratio and the form factor were unaffected by Lon protease 1 (LONP1) knockdown (Figure 6A,D). These findings indicate that SE may lead to mitochondrial elongation and their aggregation, indicating aberrant mitochondrial fusion, in CA1 neurons, and that LONP1 may not be involved in these phenomena
We demonstrated that active caspase-3 and HMGB1 were preferentially accumulated into fragmented and elongated mitochondria following SE, respectively
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Mitochondria have double membranes and are highly dynamic organelles, whose main function is the production of adenosine triphosphate (ATP) through oxidative phosphorylation. Mitochondria play important roles in cellular homeostasis, such as cell death, Ca2+ regulation, and reactive oxygen species (ROS) generation. Since matrix proteins and DNA are located in close proximity to the source of ROS, excessive oxidative ROS production results in denaturation (mutation, abnormal expression, or misfolding) of mitochondrial matrix proteins [1,2]. To counteract oxidized protein denaturation, mitochondrial quality control is very important for maintaining cellular homeostasis to avoid cell damage
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