Mitochondrial heterogeneity disrupts osteoclast differentiation and bone resorption by impairing respiratory complex I

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Item Type:	Preprint
Title:	Mitochondrial heterogeneity disrupts osteoclast differentiation and bone resorption by impairing respiratory complex I
Creators Name:	Leng, H., Jiang, J., Gassner, K., Midha, S., Justo-Mendez, R., Zheng, J., Hall, T., Luo, L., West, S.D., Vincent, T.L., Wann, A., Patel, K.A., Poulton, J., O'Callaghan, C.A., Lechuga-Vieco, A.V. and Simon, A.K.
Abstract:	Mitochondria are required to meet the high energy demands of osteoclast differentiation and adapt to hypoxia, inflammatory signals and oxidative stress. Heteroplasmy, the coexistence of different mitochondrial DNAs (mtDNAs) in one cell disrupts energy balance and causes metabolic stress. Using a genetically engineered mouse model, we demonstrate that heteroplasmy impairs osteoclast differentiation and subsequently reduces bone resorption. Mechanistically, we find that heteroplasmic cells accumulate complex I subunits of the electron transport chain in the cytoplasm, which severely disrupts ATP production and leads to premature termination of osteoclastogenesis. Importantly, we show that stimulating autophagy and improving mitochondrial quality using spermidine alleviates the dysfunction in both the murine heteroplasmic model and in human heteroplasmic osteoclasts carrying m.3242A>G mutations, partially through enhanced mitochondrial selection. Overall, our work highlights the role of mtDNA in osteoclast function and introduces potential therapeutic approaches for mitochondrial and bone disorders.
Keywords:	Complex I, Osteoclasts, Mitochondrial DNA, Heteroplasmy, Spermidine, Autophagy, Animals, Mice
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2025.05.02.651799v2
Date:	15 May 2025
Official Publication:	https://doi.org/10.1101/2025.05.02.651799

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