Protein import-driven mitochondrial hyperactivation dictates angiogenesis independently of HIF-1α

Abstract

Angiogenesis is essential for sustained neoplastic progression, yet its initiation has largely been framed through hypoxia-dependent HIF signalling. In OXPHOS driven tumours, how mitochondrial function contributes to angiogenic induction remains poorly understood. Here, we uncover a non-canonical mechanism linking tumour cell mitochondrial hyperactivity to a pro-angiogenic response. Mitochondrial function critically depends on the import of nuclear-encoded proteins, largely mediated by TIM23 translocase. We found Timm44, the central scaffold of this translocase, to be broadly upregulated across angiogenesis-dependent malignancies. Using gain-of-function system that recapitulate tumour-associated Timm44 amplification, we enhanced mitochondrial protein import capacity, thereby remodelling mitochondrial gene expression and driving hyperactivation of the electron transport chain, particularly Complex I. This hyperactive mitochondrial state generated a signalling-competent ROS-enrich environment that induces VEGFA expression independently of HIF-1 stabilization, via a redox-licensed TRX-ASK1-p38MAPK-SP1 axis, thereby promoting endothelial sprouting and proliferation. These findings define protein import-driven mitochondrial hyperfunction as an alternative driver of tumour angiogenesis, extending current paradigms beyond classical hypoxia-dependent mechanisms and highlighting new therapeutic vulnerabilities.