Arthritis is a highly common senile disorder in aging societies. However, due to the degenerative nature of the disease, there exists no obvious method for diagnosis and treatment of arthritis. Development of new treatment strategy requires mechanistic understanding of the onset of the disease at the molecular level. Previous studies showed that double-stranded RNAs (dsRNAs) promote cartilage degeneration. In addition, protein kinase R (PKR), an immune response protein that becomes activated when bound to dsRNAs, is activated in many patients suffering from osteoarthritis (OA) (1-5). Nonetheless, targeting PKR is not a viable option and the upstream signal that leads to PKR activation is mostly unknown. Here, we show that mitochondrial RNAs (mtRNAs) may provide the key link that connects stress response to chondrocyte degeneration. We investigated that mtRNAs can form intermolecular dsRNAs and can activate PKR and its downstream signaling in response to stressors mimicking OA. Our results indicated that autophagy functions in the cytosol to remove released mtRNAs. Our work unveils an unexpected role of mtRNAs as molecular players in the onset and progression of OA and suggests targeting mtRNAs may provide a new direction in the diagnosis and treatment of arthritis.