VDAC1 regulates neuronal cell loss after retinal trauma injury by a mitochondria-independent pathway

Abstract

The voltage-dependent anion channel 1 (VDAC1) was first described as a mitochondrial porin that mediates the flux of metabolites and ions, thereby integrating both cell survival and death signals. In the nervous system, the functional roles of VDAC1 remain poorly understood. Herein, the rat retina was employed to study VDAC1. First, it was observed that even subtle changes in VDAC1 levels affect neuronal survival, inducing severe alterations in the retinal morphology. We next examined the regulation of VDAC1 after traumatic retinal injury. After mechanical trauma, SOD1 translocates towards the nucleus, which is insufficient to contain the consequences of oxidative stress, as determined by the evaluation of protein carbonylation. Using in vitro models of oxidative stress and mechanical injury in primary retinal cell cultures, it was possible to determine that inhibition of VDAC1 oligomerization by 4′-diisothiocyano-2,2′-disulfonic acid stilbene (DIDS) rescues cell viability, impacting microglial cell activation. We next focused on the regulation of VDAC1 after retinal mechanical injury. VDAC1 was promptly upregulated 2 h after lesion in the plasma membrane and endoplasmic reticulum rather than in the mitochondria, and multimers of VDAC1 were assembled after lesion. DIDS intraocular application decreased apoptosis and prevented microglial polarization, which confirmed in vitro observations. Considering the role of microglia in neuroinflammation, multiplex evaluation of cytokines showed that DIDS application disorganized the inflammatory response 2 h after the lesion, matching the fast regulation of VDAC1. Taken together, data disclosed that fine regulation of VDAC1 influences neuronal survival, and pharmacological inhibition after trauma injury has neuroprotective effects. This protection may be attributed to the effects on VDAC1 abnormal accumulation in the plasma membrane, thereby controlling the activation of microglial cells. We concluded that VDAC1 is a putative therapeutic target in neuronal disorders since it integrates both death and survival cellular signaling.

Inhibition of VDAC1 prevents oxidative stress and apoptosis induced by bisphenol A in spermatogonia via AMPK/mTOR signaling pathway

“…A study found that VDAC1 silencing protectes cardiomyocyte from cytotoxic effect of H 2 O 2 as evidenced by reducing in LDH activity and dead cell number (Jiang et al, 2018). Knockdown of VDAC1 inhibits cell death on in vitro model of oxidative stress (de Sousa et al, 2022). Moreover, VDAC1 inhibitor suppresses the generation of intracellular ROS in macrophages (Chen et al, 2014).…”

Structural insights into human EMC and its interaction with VDAC

“…Our analysis reveals that the EMC-associated VDAC1 is located at mitochondria-ER contact sites and the EMC-VDAC1 interaction is evolutionarily conserved from yeast to human, implying that it likely occurs under physiological conditions. Intriguingly, there is an increase in the translocation of VDAC1 under certain pathological conditions [ 46 , 52 ]. We propose that the association between EMC and VDAC1 may potentially strengthen under these abnormal conditions, and the EMC-VDAC1 complex may assist VDAC1 in translocation or carrying out non-classical functions.…”

“…VDAC1 biogenesis on the outer mitochondrial membrane is well-established and involves a complex pathway with the Tim/Tom import machinery, sTIM chaperones and the SAM/TOB complex [45]. Previous studies also unveiled that a portion of VDAC1 appears on other membrane systems [46][47][48][49], including the ER and plasm membrane [50][51][52], especially in conditions like type 2 diabetes [46], Alzheimer's disease [31], and virus infection [53]. However, the mechanism of VDAC1 translocation remains unclear.…”

VDAC in Retinal Health and Disease

“…Staining using another anti-VDAC was strong in most layers (the ganglion cell layer was not in the picture) but weaker in the inner segments [ 29 ]. Another attempt to reveal the localization of VDAC1 showed strong staining in the inner segments, OPL, and IPL and faint staining in the somas in the INL [ 46 ]. The inconsistent staining patterns indicate that when using immunocytochemistry, most antibodies against VDAC are not sufficiently specific for the VDAC isoforms.…”

“…While the precise localization of VDAC1 in the retina is still questionable, its function in retina was investigated by knocking it down using morpholino antisense RNA [ 46 ]. In these experiments, VDAC1 expression as measured by Western blots was reduced by about 45%, and this reduction greatly affected retinal structure: the retina was thinner, cells in the nuclear layers were undergoing apoptosis (as labeled by the TUNEL assay), and the number of three tested cell types (photoreceptors, horizontal cells, and ganglion cells, but not rod bipolar cells) was greatly reduced.…”