Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling
- 1Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
- 2Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
- 3Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India; Corresponding author.
Abstract
Coordination of mitochondrial functional states with nuclear transcriptional programs remain critical for cellular adaptation. Here, we identify mitochondrial protein import capacity as a regulator of redox-dependent signalling in tumour cells. We show that the mitochondrial import motor component TIMM44, which is upregulated in angiogenesis-driven tumours, drives respiratory remodelling without increasing mitochondrial abundance. This mitochondrial reprogramming establishes a redox-competent state that activates ASK1-p38MAPK, resulting in SP1-dependent upregulation of VEGFA independently of HIF stabilization. Importantly, induction of mitochondrial biogenesis via PGC-1α fails to recapitulate this response despite increased active mitochondrial content, demonstrating that abundance of active mitochondria or generic metabolic activation is insufficient to drive this HIF-independent transcription. Collectively, our findings identify mitochondrial protein import process as an active signalling regulator rather than a passive housekeeping role, which links mitochondrial proteostasis to redox-sensitive kinase activation and transcriptional control. This work highlights a non-canonical mitochondrial signalling mechanism through which cells couple organelle remodelling to gene expression programs.
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BibTeX
@article{chaudhary2026noncanonical,
title = {{Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling}},
author = {Tanvi Chaudhary and Sharath Mohan Bhat and Priyadarshika Pradhan and Manjunath B. Joshi and Devanjan Sinha},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104381},
url = {https://doi.org/10.1016/j.redox.2026.104381},
note = {CC BY},
}
RIS
TY - JOUR
TI - Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling
AU - Tanvi Chaudhary
AU - Sharath Mohan Bhat
AU - Priyadarshika Pradhan
AU - Manjunath B. Joshi
AU - Devanjan Sinha
PY - 2026
DA - 2026/10/30
JO - Redox Biology
DO - 10.1016/j.redox.2026.104381
UR - https://doi.org/10.1016/j.redox.2026.104381
AB - Coordination of mitochondrial functional states with nuclear transcriptional programs remain critical for cellular adaptation. Here, we identify mitochondrial protein import capacity as a regulator of redox-dependent signalling in tumour cells. We show that the mitochondrial import motor component TIMM44, which is upregulated in angiogenesis-driven tumours, drives respiratory remodelling without increasing mitochondrial abundance. This mitochondrial reprogramming establishes a redox-competent state that activates ASK1-p38MAPK, resulting in SP1-dependent upregulation of VEGFA independently of HIF stabilization. Importantly, induction of mitochondrial biogenesis via PGC-1α fails to recapitulate this response despite increased active mitochondrial content, demonstrating that abundance of active mitochondria or generic metabolic activation is insufficient to drive this HIF-independent transcription. Collectively, our findings identify mitochondrial protein import process as an active signalling regulator rather than a passive housekeeping role, which links mitochondrial proteostasis to redox-sensitive kinase activation and transcriptional control. This work highlights a non-canonical mitochondrial signalling mechanism through which cells couple organelle remodelling to gene expression programs.
SN - 2213-2317
ER -