Abstract
Transient receptor potential canonical channel-6 (TRPC6) is one of the Ca2+-permeable non-selective cation channels. TRPC6 is mainly expressed in dentate granule cell (DGC), which is one of the most resistant neuronal populations to various harmful stresses. Although TRPC6 knockdown evokes the massive DGC degeneration induced by status epilepticus (a prolonged seizure activity, SE), the molecular mechanisms underlying the role of TRPC6 in DGC viability in response to SE are still unclear. In the present study, hyperforin (a TRPC6 activator) facilitated mitochondrial fission in DGC concomitant with increases in Lon protease-1 (LONP1, a mitochondrial protease) expression and extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation under physiological conditions, which were abrogated by U0126 (an ERK1/2 inhibitor) co-treatment. TRPC6 knockdown showed the opposite effects on LONP1 expression, ERK1/2 activity, and mitochondrial dynamics. In addition, TRPC6 siRNA and U0126 evoked the massive DGC degeneration accompanied by mitochondrial elongation following SE, independent of seizure severity. However, LONP1 siRNA exacerbated SE-induced DGC death without affecting mitochondrial length. These findings indicate that TRPC6-ERK1/2 activation may increase DGC invulnerability to SE by regulating LONP1 expression as well as mitochondrial dynamics. Therefore, TRPC6-ERK1/2-LONP1 signaling pathway will be an interesting and important therapeutic target for neuroprotection from various neurological diseases.
Highlights
Mitochondria are essential organelles for cellular bioenergetics, which are responsible for producing nearly 95% of cellular ATP through oxidative phosphorylation
Together with the data obtained from Transient receptor potential canonical channel-6 (TRPC6) knockdown, these findings indicate that TRPC6 activity may regulate Lon protease 1 (LONP1) expression and mitochondrial dynamics through extracellular-signal-regulated kinase 1/2 (ERK1/2) activation
TRPC6 activates ERK1/2 [15,30], which is involved in mitochondrial dynamics and LONP1 we found that TRPC6 siRNA effectively reduced ERK1/2 activity and LONP1 expression [9,31,32,33,34,35,36]
Summary
Mitochondria are essential organelles for cellular bioenergetics, which are responsible for producing nearly 95% of cellular ATP through oxidative phosphorylation. A progressive decrease in the mitochondrial integrity abrogates respiratory capacities and increases production of free radicals, leading to aberrant structural and/or functional changes in mitochondria. The maintenance of mitochondrial redox status is very important for cell viability [1,2,3,4,5]. Lon protease 1 (LONP1) belongs to the ATPases associated with diverse cellular activities (AAA+) protease family in the mitochondrial matrix that has a proteolytic activity of oxidized, dysfunctional, and misfolded proteins in ATP-dependent manner. LONP1 is rapidly up-regulated to prevent accumulation and aggregation of abnormal mitochondrial proteins under pathophysiological conditions [3,4,5,6,7]. LONP1 over-expression activates extracellular signal regulated kinase 1/2
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