Mitochondria are essential organelles responsible for cellular energy production, metabolism, signaling, and cell fate. As a result, mitochondrial dysfunction is associated with various human disorders, including cancer and neurodegenerative diseases. Hypoxia, a pathophysiological condition, impairs the electron transport chain, disrupts mitochondrial function, and produces harmful reactive oxygen species (ROS). The primary cellular proteolytic system, the ubiquitin-proteasome system (UPS), regulates mitochondrial health through several mechanisms: protein import, protein turnover, and mitophagy. In studying how hypoxia affects mitochondria, we found that hypoxia-induced mitochondrial ROS drives HIF-1α stabilization, promotes mitophagy, and leads to increased mitochondrial ubiquitination. However, hypoxia-triggered mitophagy was ubiquitin-independent. We discovered that most of the hypoxia-induced ubiquitin chains are mainly of a specific type: linear head-to-tail fusions (M1), recognized for their role in activating NF-κB signaling after cytokine stimulation. During hypoxia, these mitochondria-localized linear M1 chains activate NF-κB signaling and increase the expression of its target genes. Treating hypoxic cells with either the mitochondrial antioxidant Mitoquinone or an inhibitor of M1 chain formation reduces linear M1 ubiquitin chains and inhibits NF-κB activation. These results highlight an internal signaling mechanism that enables adaptation to mitochondrial stress and triggers an inflammatory response.