PUBLICATION

Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis

Authors
Shi, D., Qi, M., Zhou, L., Li, X., Ni, L., Li, C., Yuan, T., Wang, Y., Chen, Y., Hu, C., Liang, D., Li, L., Liu, Y., Li, J., Chen, Y.H.
ID
ZDB-PUB-181026-10
Date
2018
Source
Arteriosclerosis, Thrombosis, and Vascular Biology   38: 2665-2677 (Journal)
Registered Authors
Li, Jun, Li, Xiang
Keywords
endothelium, homeostasis, mitochondria, mitochondrial protein, zebrafish
MeSH Terms
  • Gene Expression Regulation, Enzymologic
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Mitochondrial Proteins/genetics
  • Mitochondrial Proteins/metabolism
  • Mice, Knockout
  • Cells, Cultured
  • Signal Transduction
  • Endothelial Cells/enzymology*
  • Carrier Proteins/genetics
  • Carrier Proteins/metabolism*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Gene Expression Regulation, Developmental
  • Neuropeptides/genetics
  • Neuropeptides/metabolism*
  • Endothelium, Vascular/embryology
  • Endothelium, Vascular/enzymology*
  • Brain/blood supply*
  • Mitochondria/enzymology*
  • Cerebrovascular Disorders/enzymology
  • Cerebrovascular Disorders/genetics
  • Animals
  • Neovascularization, Physiologic*/genetics
  • Humans
  • rac1 GTP-Binding Protein/genetics
  • rac1 GTP-Binding Protein/metabolism*
(all 30)
PubMed
30354240 Full text @ Arterio., Thromb., and Vas. Bio.
Abstract
Objective- Mitochondria are the important yet most underutilized target for cardio-cerebrovascular function integrity and disorders. The Tom (translocases of outer membrane) complex are the critical determinant of mitochondrial homeostasis for making organs acclimate physiological and pathological insults; however, their roles in the vascular system remain unknown.

Approach and Results- A combination of studies in the vascular-specific transgenic zebrafish and genetically engineered mice was conducted. Vascular casting and imaging, endothelial angiogenesis, and mitochondrial protein import were performed to dissect potential mechanisms. A loss-of-function genetic screening in zebrafish identified that selective inactivation of the tomm7 (translocase of outer mitochondrial membrane 7) gene, which encodes a small subunit of the Tom complex, specially impaired cerebrovascular network formation. Ablation of the ortholog Tomm7 in mice recapitulated cerebrovascular abnormalities. Restoration of the cerebrovascular anomaly by an endothelial-specific transgenesis of tomm7 further indicated a defect in endothelial function. Mechanistically, Tomm7 deficit in endothelial cells induced an increased import of Rac1 (Ras-related C3 botulinum toxin substrate 1) protein into mitochondria and facilitated the mitochondrial Rac1-coupled redox signaling, which incurred angiogenic impairment that underlies cerebrovascular network malformation.

Conclusions- Tomm7 drives brain angiogenesis and cerebrovascular network formation through modulating mitochondrial Rac1 signaling within the endothelium.

Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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Citation
Shi, D., Qi, M., Zhou, L., Li, X., Ni, L., Li, C., Yuan, T., Wang, Y., Chen, Y., Hu, C., Liang, D., Li, L., Liu, Y., Li, J., Chen, Y.H. (2018) Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis. Arteriosclerosis, Thrombosis, and Vascular Biology. 38:2665-2677.