Hypoxia-induced mitoROS triggers M1 linear ubiquitin chains and activates NF-κB signaling.

Mitochondria are essential organelles responsible for cellular energy production and metabolism. Hypoxia, a pathophysiological condition, impairs the electron transport chain, disrupts mitochondrial function, and produces harmful reactive oxygen species (ROS). Ubiquitin signaling regulates mitochondrial health through several mechanisms, including protein degradation and mitophagy. Here, we show that hypoxia-induced mitophagy occurs independently of ubiquitination. However, mitochondria are heavily ubiquitinated under hypoxic stress. A significant portion of these hypoxia-induced ubiquitin chains constitute a specific type: linear head-to-tail fusions (M1), which are known for their role in NF-κB activation during cytokine signaling. We demonstrate that hypoxia-induced mitochondrial ROS leads to the accumulation of these M1 chains, activating NF-κB signaling and increasing the expression of its target genes. These findings reveal a critical internal signal that helps cells adapt to mitochondrial stress and triggers an inflammatory response.