Deregulation of Mitochondria-Shaping Proteins Opa-1 and Drp-1 in Manganese-Induced Apoptosis

Abstract

Mitochondria are dynamic organelles that undergo fusion and fission processes. These events are regulated by mitochondria-shaping proteins. Changes in the expression and/or localization of these proteins lead to a mitochondrial dynamics impairment and may promote apoptosis. Increasing evidence correlates the mitochondrial dynamics disruption with the occurrence of neurodegenerative diseases. Therefore, we focused on this topic in Manganese (Mn)-induced Parkinsonism, a disorder associated with Mn accumulation preferentially in the basal ganglia where mitochondria from astrocytes represent an early target. Using MitoTracker Red staining we observed increased mitochondrial network fission in Mn-exposed rat astrocytoma C6 cells. Moreover, Mn induced a marked decrease in fusion protein Opa-1 levels as well as a dramatic increase in the expression of fission protein Drp-1. Additionally, Mn provoked a significant release of high MW Opa-1 isoforms from the mitochondria to the cytosol as well as an increased Drp-1 translocation to the mitochondria. Both Mdivi-1, a pharmacological Drp-1 inhibitor, and rat Drp-1 siRNA reduced the number of apoptotic nuclei, preserved the mitochondrial network integrity and prevented cell death. CsA, an MPTP opening inhibitor, prevented mitochondrial Δψm disruption, Opa-1 processing and Drp-1 translocation to the mitochondria therefore protecting Mn-exposed cells from mitochondrial disruption and apoptosis. The histological analysis and Hoechst 33258 staining of brain sections of Mn-injected rats in the striatum showed a decrease in cellular mass paralleled with an increase in the occurrence of apoptotic nuclei. Opa-1 and Drp-1 expression levels were also changed by Mn-treatment. Our results demonstrate for the first time that abnormal mitochondrial dynamics is implicated in both in vitro and in vivo Mn toxicity. In addition we show that the imbalance in fusion/fission equilibrium might be involved in Mn-induced apoptosis. This knowledge may provide new therapeutic tools for the treatment of Manganism and other neurodegenerative diseases.

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

“…The activity of Drp-1 regulates mitochondrial fragmentation, and inhibition of it decreases mitochondrial fission and apoptosis (25)(26)(27)42). Drp-1 is crucially involved in the induction of mitochondrial fission, apoptotic cell death, and neurodegeneration (38 -41, 46) through its translocation from the cytosol to mitochondria (34,41,42). Studies suggested that autophagy is critically involved in the control of Drp-1 levels (35).…”

“…Similarly, ethanol, a well established neurotoxicant also induced mitochondrial fission through enhanced Drp-1 mitochondrial translocation (56). In addition, manganese disrupted the mitochondrial network toward to an exacerbated fragmentation by enhancing the levels of Drp-1 (41,57). Inhibition of excessive mitochondrial fission reduces aberrant autophagy and prevents neurodegeneration (58).…”

“…However, in the present study we observed that BPA-induced cytotoxicity results from alteration in the mitochondrial dynamics involving enhanced mitochondrial fission and increased levels of mitochondrial fission protein Drp-1. Several previous studies suggested that translocation of Drp-1 in the mitochondria enhances fission and apoptosis (25,(41)(42)(43)(44). Similarly, enhanced Drp-1 mitochondrial translocation is also associated with enhanced neurodegeneration and pathogenesis of neurodegenerative disorders (25,45,46).…”

“…Accumulated evi- dence suggested that Drp-1 is crucially involved in inducing apoptosis-mediated cell death (25, 38 -41). Additionally, mitochondrial translocation of Drp-1 from the cytosol leads to the mitochondrial fission and apoptosis (25,(41)(42)(43). Intriguingly, silencing the expression of Drp-1 results with the inhibition of mitochondrial fission and also delayed cellular apoptosis (42).…”

Inhibition to DRP1 translocation can mitigate p38 MAPK-signaling pathway activation in GMC induced by hyperglycemia

“…Mitochondrial fusion is mediated by Mitofusin 2 and OPA1, 17,18 and its fission is regulated by dynamin-related protein (DRP1). 19 Mitochondrial fission and fusion balance is essential for maintaining the stability of its structure and function. When mitochondrial balance disorders, especially in divided state, mitochondrial membrane potentially decreases, membrane permeability increases, ROS is produced, ATP generation goes down and a large number of apoptotic factors are released.…”