TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus via Regulating Lon Protease-1 Expression and Mitochondrial Dynamics

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.

LONP1 Regulates Mitochondrial Accumulations of HMGB1 and Caspase-3 in CA1 and PV Neurons Following Status Epilepticus

“…Impairment of LONP1 results in the accumulation of toxic oxidized proteins in the brain, which can cause severe neuronal damage [ 7 ]. Consistent with our previous study [ 24 , 28 ], the present data show that SE up-regulated the mitochondrial LONP1 level in PV and CA1 neurons, while LONP1 knockdown did not affect the viability and mitochondrial dynamics in both neurons under physiological and post-SE conditions. Since LONP1 plays a direct role in the turnover of isoform 1 of COX subunit 4 (COX4-1) to COX4-2 for enhancing mitochondrial respiration [ 29 ], LONP1 may act as one of the important housekeeping enzymes by maintaining mitochondrial respiration at tolerable levels under pathological conditions, independent of mitochondrial dynamics.…”

“…Since LONP1 plays a direct role in the turnover of isoform 1 of COX subunit 4 (COX4-1) to COX4-2 for enhancing mitochondrial respiration [ 29 ], LONP1 may act as one of the important housekeeping enzymes by maintaining mitochondrial respiration at tolerable levels under pathological conditions, independent of mitochondrial dynamics. Indeed, dysfunction of LONP1 in mitochondria has been associated with a number of neurological disorders including Parkinson’s disease, Friedreich ataxia, and amyotrophic lateral sclerosis [ 24 , 28 , 30 , 31 , 32 ]. In particular, LONP1 downregulation results in extensive (although not universal) apoptosis with the classic hallmark of caspase-3 activation.…”

“…Recently, we reported that LONP1 knockdown deteriorates SE-induced neuronal death [ 24 ]. Considering the degradation of human mitochondrial transcription factor A (TFAM, a high-mobility group (HMG) protein) by LONP1 [ 25 ], it is assumed that the neuroprotective effects of LONP1 may be relevant to the elimination or degradation of the translocated active caspase-3 and HMGB1 in mitochondria, which has been elusive.…”

Contribution of TRPC Channels in Neuronal Excitotoxicity Associated With Neurodegenerative Disease and Ischemic Stroke

“…Previously, an inhibitory effect of presenilin 2 and its Alzheimer’s-disease-linked variants on receptor-operated TRPC6 function has been demonstrated in heterologous expression systems, suggesting functional interaction between presenilins and TRPC6 ( Lessard et al, 2005 ). In status epilepticus, TRPC6 serves to protect granule neurons of dentate gyrus from degeneration through activation of ERK1/2 and the subsequent phosphorylation of dynamin-related proteins 1 (DRP1) at Ser-616 ( Ko and Kang, 2017 ) and an increase in the expression of a mitochondrial protease, Lon protease-1 ( Kim et al, 2019 ). In the absence of TRPC6, the hypo-phosphorylation of DRP1 and reduction in Lon protease-1 then lead to mitochondrial elongation and dysfunction, which increase the vulnerability of granule cells to seizure-induced death ( Kim and Kang, 2015 ).…”

Mitochondria in Health and Diseases

“…Neurological disorders: A study by Kim et al [16] described a novel mechanism potentially regulating mitochondrial dynamics and seizure activity in the central nervous system. They provide novel evidence that transient receptor potential canonical channel-6 (TRPC6) regulates mitochondrial Lon protease 1 (LONP1) expression via the ERK1/2-mediated pathway.…”