Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
Journal
EBioMedicine
Journal Volume
110
ISSN
2352-3964
Date Issued
2024-11-29
Author(s)
Li, Chia-Yi
Chen, Li-Wen
Tsai, Meng-Che
Chou, Yen-Yin
Lin, Pei-Xuan
Chang, Yu-Ming
Lin, Ju-Li
Su, Pen-Hua
Hsieh, Tzung-Chien
Klinkhammer, Hannah
Wang, Yi-Chieh
Huang, Yi-Ting
Krawitz, Peter M
Lin, Sheng-Hsiang
Huang, Lynn L H
Chiang, Po-Min
Shih, Min-Hsiu
Chen, Peng-Chieh
Abstract
Impaired mitochondrial protein import machinery leads to phenotypically heterogeneous diseases. Here, we report a recurrent homozygous missense variant in the gene that encodes the translocase of outer mitochondrial membrane 7 (TOMM7) in nine patients with microcephaly, short stature, facial dysmorphia, atrophic macular scarring, and moyamoya disease from seven unrelated families. To prove the causality of the TOMM7 variant, mitochondrial morphology, proteomics, and respiration were investigated in CRISPR/Cas9-edited iPSCs-derived endothelial cells. Cerebrovascular defects and mitochondrial respiration were also examined in CRISPR/Cas9-edited zebrafish. iPSC-derived endothelial cells with homozygous TOMM7 p.P29L showed increased TOM7 stability, enlarged mitochondria, increased senescence, and defective tube formation. In addition, proteomic analysis revealed a reduced abundance of mitochondrial proteins involved in ATP synthesis or coordinating TCA cycle and gluconeogenesis. Moreover, mitochondrial respiration was slightly decreased while ATP production from glycolysis was significantly increased. Furthermore, deletion of tomm7 in zebrafish caused craniofacial and cerebrovascular defects that recapitulated human phenotypes. Notably, homozygous iPSCs differentially expressed genes involved in glycolysis and response to hypoxia. Finally, the metabolic imbalance was evidenced by decreased oxygen consumption, increased level of hexokinase 2, and enhanced glycolysis in endothelial cells derived from the patient's iPSCs. These results revealed the essential role of TOMM7 in balancing cellular sources of energy production at both proteomic and transcriptomic levels and provided the molecular mechanisms through which TOMM7 p.P29L variant leads to an autosomal recessive microcephalic osteodysplastic dwarfism with moyamoya disease. This work is supported by National Science and Technology Council grants and National Cheng Kung University Hospital.
Subjects
Cerebrovascular disease
Glycolysis
Mitochondrial protein import
Mitochondrial respiration
TOM complex
iPSC-derived endothelial cells
Type
journal article