As the most common form of arthritis, osteoarthritis (OA) has become a major cause of severe joint pain, physical disability, and quality of life impairment in the affected population. To date, precise pathogenesis of OA has not been fully clarified, which leads to significant obstacles in developing efficacious treatments such as failures in finding disease-modifying OA drugs (DMOADs) in the last decades. Given that diarthrodial joints primarily display the weight-bearing and movement-supporting function, it is not surprising that mechanical stress represents one of the major risk factors for OA. However, the inner connection between mechanical stress and OA onset/progression has yet to be explored. Mitochondrion, a widespread organelle involved in complex biological regulation processes such as adenosine triphosphate (ATP) synthesis and cellular metabolism, is believed to have a controlling role in the survival and function implement of chondrocytes, the singular cell type within cartilage. Mitochondrial dysfunction has also been observed in osteoarthritic chondrocytes. In this review, we systemically summarize mitochondrial alterations in chondrocytes during OA progression and discuss our recent progress in understanding the potential role of mitochondria in mediating mechanical stress-associated osteoarthritic alterations of chondrocytes. In particular, we propose the potential signaling pathways that may regulate this process, which provide new views and therapeutic targets for the prevention and treatment of mechanical stress-associated OA.Copyright © 2018. Published by Elsevier Inc.