The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice

Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige K. Boneski, Hiromi Sesaki, Ruteja A. Barve, John A. Collins and Makarand V. Risbud ()
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Vedavathi Madhu: Thomas Jefferson University
Miriam Hernandaz-Meadows: Thomas Jefferson University
Ashley Coleman: Thomas Jefferson University
Kimheak Sao: Thomas Jefferson University
Kameron Inguito: Thomas Jefferson University
Owen Haslam: Thomas Jefferson University
Paige K. Boneski: Thomas Jefferson University
Hiromi Sesaki: Johns Hopkins University
Ruteja A. Barve: Washington University, School of Medicine
John A. Collins: Thomas Jefferson University
Makarand V. Risbud: Thomas Jefferson University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Recent studies have highlighted the importance of mitochondria in NP cells and articular chondrocyte health. Since the understanding of mechanisms governing mitochondrial dynamics in these tissues is lacking, we investigated the role of OPA1, a mitochondrial fusion protein, in their homeostasis. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate. OPA1 governed the morphology of multiple organelles, including peroxisomes, early endosomes and cis-Golgi and loss resulted in the dysregulation of 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 degeneration, osteoarthritis, and vertebral osteopenia. RNA-Sequencing of Opa1cKO NP tissue revealed dysregulation of metabolism, autophagy, cytoskeletal reorganization, and extracellular matrix and shared strong thematic similarities with a subset of human degenerative NP samples. Our findings underscore that maintenance of mitochondrial dynamics and multi-organelle cross-talk is critical in preserving metabolic homeostasis of disc and cartilage.

Date: 2025
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DOI: 10.1038/s41467-025-60933-9

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