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-Méndez, 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:	Mitochondrial heteroplasmy, the co-existence of different mitochondrial genomes within a cell, is linked to aging and disease. Patients with heteroplasmy due to mitochondrial mutations experience multiple organ complications, particularly poor bone health and bone structure defects. However, the mechanisms involved are generally unknown, due largely to the difficulty of manipulating mtDNA in vivo. To overcome this, we leveraged a heteroplasmic mouse model and discovered that mitochondrial heteroplasmy affects a fundamental developmental process. Specifically, the differentiation of osteoclasts, which resorb bone tissue and maintain bone homeostasis. Mechanistically, there was a reduced localization of specifically respiratory complex I subunits in mitochondria in heteroplasmic mice, disrupting ATP production and osteoclast differentiation. In addition, autophagic flux is exhausted, and the autophagy inducer spermidine restores mitochondrial health and rescues osteoclast activity, both in mice and in cells from patients with primary mitochondrial disease. Together, we identify the mechanisms by which mitochondrial heteroplasmy impacts osteoclastogenesis and discover spermidine as a modulator of this process, which presents a potential treatment for human heteroplasmic conditions such as mitochondrial diseases, which are largely untreatable.
Keywords:	Osteoclasts, Mitochondrial DNA, Heteroplasmy, Complex I, Autophagy, Spermidine, Animals, Mice
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2025.05.02.651799v3
Date:	2 August 2025
Official Publication:	https://doi.org/10.1101/2025.05.02.651799

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