VDAC1 is essential for neurite maintenance and the inhibition of its oligomerization protects spinal cord from demyelination and facilitates locomotor function recovery after spinal cord injury

Author(s)

Paschon, Vera ^[1] ; Morena, Beatriz Cintra ^[1] ; Correia, Felipe Fernandes ^[1] ; Beltrame, Giovanna Rossi ^[1] ; dos Santos, Gustavo Bispo ^[2] ; Cristante, Alexandre Fogaca ^[2] ; Kihara, Alexandre Hiroaki ^[1]

Affiliation

^[1] Univ Fed ABC, Ctr Matemat Comp & Cognicao, Sao Bernardo Do Campo, SP - Brazil

^[2] Univ Sao Paulo, Inst Ortopedia Traumatol, Fac Med, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 9, OCT 1 2019.
• Web of Science Citations: 0

Abstract

During the progression of the neurodegenerative process, mitochondria participates in several intercellular signaling pathways. Voltage-dependent anion-selective channel 1 (VDAC1) is a mitochondrial porin involved in the cellular metabolism and apoptosis intrinsic pathway in many neuropathological processes. In spinal cord injury (SCI), after the primary cell death, a secondary response that comprises the release of pro-inflammatory molecules triggers apoptosis, inflammation, and demyelination, often leading to the loss of motor functions. Here, we investigated the functional role of VDAC1 in the neurodegeneration triggered by SCI. We first determined that in vitro targeted ablation of VDAC1 by specific morpholino antisense nucleotides (MOs) clearly promotes neurite retraction, whereas a pharmacological blocker of VDAC1 oligomerization (4, 4'-diisothiocyanatostilbene-2, 2'-disulfonic acid, DIDS), does not cause this effect. We next determined that, after SCI, VDAC1 undergoes conformational changes, including oligomerization and N-terminal exposition, which are important steps in the triggering of apoptotic signaling. Considering this, we investigated the effects of DIDS in vivo application after SCI. Interestingly, blockade of VDAC1 oligomerization decreases the number of apoptotic cells without interfering in the neuroinflammatory response. DIDS attenuates the massive oligodendrocyte cell death, subserving undisputable motor function recovery. Taken together, our results suggest that the prevention of VDAC1 oligomerization might be beneficial for the clinical treatment of SCI. (AU)

• FAPESP's process: 17/26439-0 - An interdisciplnary approach on the role of gap junctions and miRNAs in the development and degeneration of the nervous system
• Grantee: Alexandre Hiroaki Kihara
• Support Opportunities: Regular Research Grants