Hypertensive mt. tRNA
5 affiliations
- 1Senior Department of Cardiology, The Six Medical Center, Chinese PLA General Hospital, Beijing, 100048, China; Department of Cardiology, General Hospital of Central Theater Command, Wuhan, 430070, China
- 2Senior Department of Cardiology, The Six Medical Center, Chinese PLA General Hospital, Beijing, 100048, China
- 3Division of Medical Genetics and Genomics, The Children's Hospital Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, 310058, China; Institute of Genetics Zhejiang University, International School of Medicine, Hangzhou, 310058, China
- 4Department of Cardiology, General Hospital of Central Theater Command, Wuhan, 430070, China
- 5Senior Department of Cardiology, The Six Medical Center, Chinese PLA General Hospital, Beijing, 100048, China; Corresponding author. Chinese PLA General Hospital, No.28 Fuxing Road, 100080, Beijing, China.
Abstract
The pathogenic mechanism underlying diseases caused by mitochondrial DNA (mtDNA) mutation, including hypertension, persists as an unresolved global challenge. Although mutation-induced mitochondrial defects have been well characterized, how these mito-perturbations are converted into critical intermediary signaling cascades and contribute to diseases remain unknown. Here, using human induced pluripotent stem cell (hiPSC)-derived vascular organoids (VOs) and vascular cells, the hypertensive mt. tRNA Ile 4263A > G mutation was identified to induce vascular senescence, apoptosis and vascular-specific dysfunction through mitochondria-endoplasmic reticulum (ER) interaction. For the first time, this study mapped the transcriptional reprogramming landscape of human VOs carrying this mutation. Through systematic screening and functional validation, ER stress was screened out, together with downstream mitochondria-associated ER membranes-mitochondrial Ca 2+ overload resulting in vascular abnormality. Pathological reactive oxygen species (ROS) elevation, driven by tRNA Ile destabilization and bioenergetic failure, acts as the primary instigator of maladaptive ER stress activation in this cascade. Pharmacological targeting of this axis—using mito-Tempol (a mitochondria-targeted ROS scavenger), Tauro Ursodeoxycholic Acid (an ER stress inhibitor), or RU265 (a highly-selective mitochondrial calcium uniporter inhibitor)—rescues vascular abnormality. This study highlights mt. tRNA Ile 4263A > G mutation orchestrates vascular pathology through ROS induced activation of inter-organelle communication, resolving a long-standing knowledge gap between mtDNA mutations and diseases and establishing therapeutic nexuses for mtDNA mutation-related cardiovascular diseases.
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BibTeX
@article{cao2026hypertensive,
title = {{Hypertensive mt. tRNA}},
author = {Nian Cao and Haijing Zhao and Zhengfeng Wu and Shuanglei Li and Wei Tong and Lihao Jin and Ming Wu and Jie Liu and Aihong Liu and Meng Wang and Changfu Liu and Yuqi Liu and Yundai Chen},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104360},
url = {https://doi.org/10.1016/j.redox.2026.104360},
note = {CC BY},
}
RIS
TY - JOUR
TI - Hypertensive mt. tRNA
AU - Nian Cao
AU - Haijing Zhao
AU - Zhengfeng Wu
AU - Shuanglei Li
AU - Wei Tong
AU - Lihao Jin
AU - Ming Wu
AU - Jie Liu
AU - Aihong Liu
AU - Meng Wang
AU - Changfu Liu
AU - Yuqi Liu
AU - Yundai Chen
PY - 2026
DA - 2026/10/30
JO - Redox Biology
DO - 10.1016/j.redox.2026.104360
UR - https://doi.org/10.1016/j.redox.2026.104360
AB - The pathogenic mechanism underlying diseases caused by mitochondrial DNA (mtDNA) mutation, including hypertension, persists as an unresolved global challenge. Although mutation-induced mitochondrial defects have been well characterized, how these mito-perturbations are converted into critical intermediary signaling cascades and contribute to diseases remain unknown. Here, using human induced pluripotent stem cell (hiPSC)-derived vascular organoids (VOs) and vascular cells, the hypertensive mt. tRNA Ile 4263A > G mutation was identified to induce vascular senescence, apoptosis and vascular-specific dysfunction through mitochondria-endoplasmic reticulum (ER) interaction. For the first time, this study mapped the transcriptional reprogramming landscape of human VOs carrying this mutation. Through systematic screening and functional validation, ER stress was screened out, together with downstream mitochondria-associated ER membranes-mitochondrial Ca 2+ overload resulting in vascular abnormality. Pathological reactive oxygen species (ROS) elevation, driven by tRNA Ile destabilization and bioenergetic failure, acts as the primary instigator of maladaptive ER stress activation in this cascade. Pharmacological targeting of this axis—using mito-Tempol (a mitochondria-targeted ROS scavenger), Tauro Ursodeoxycholic Acid (an ER stress inhibitor), or RU265 (a highly-selective mitochondrial calcium uniporter inhibitor)—rescues vascular abnormality. This study highlights mt. tRNA Ile 4263A > G mutation orchestrates vascular pathology through ROS induced activation of inter-organelle communication, resolving a long-standing knowledge gap between mtDNA mutations and diseases and establishing therapeutic nexuses for mtDNA mutation-related cardiovascular diseases.
SN - 2213-2317
ER -