OPA1 protects intervertebral disc and knee joint health in aged mice by maintaining the structure and metabolic functions of mitochondria

Abstract

Due to their glycolytic nature and limited vascularity, nucleus pulposus (NP) cells of the intervertebral disc and articular chondrocytes were long thought to have minimal reliance on mitochondrial function. Recent studies have challenged this long-held view and highlighted the increasingly important role of mitochondria in the physiology of these tissues. We investigated the role of mitochondrial fusion protein OPA1 in maintaining the spine and knee joint health in aging mice. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate without affecting ATP synthesis. OPA1 governed the morphology of multiple organelles, and its loss resulted in the dysregulation of NP cell autophagy. Metabolic profiling and 13C-flux analyses revealed TCA cycle anaplerosis and altered metabolism in OPA1-deficient NP cells. Noteworthy, Opa1AcanCreERT2 mice showed age- dependent disc, and cartilage degeneration and vertebral osteopenia. Our findings suggest that OPA1 regulation of mitochondrial dynamics and multi-organelle interactions is critical in preserving metabolic homeostasis of disc and cartilage. TeaserOPA1 is necessary for the maintenance of intervertebral disc and knee joint health in aging mice