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Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss

Lookup NU author(s): Dr Philip Dobson, Dr Ella Dennis, Dan Hipps, Dr Amy Reeve, Dr Alex LaudeORCiD, Carla Bradshaw, Dr Craig Stamp, Anna Smith, Professor David Deehan, Emeritus Professor Doug Turnbull, Professor Laura GreavesORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2020, The Author(s).The pathogenesis of declining bone mineral density, a universal feature of ageing, is not fully understood. Somatic mitochondrial DNA (mtDNA) mutations accumulate with age in human tissues and mounting evidence suggests that they may be integral to the ageing process. To explore the potential effects of mtDNA mutations on bone biology, we compared bone microarchitecture and turnover in an ageing series of wild type mice with that of the PolgAmut/mut mitochondrial DNA ‘mutator’ mouse. In vivo analyses showed an age-related loss of bone in both groups of mice; however, it was significantly accelerated in the PolgAmut/mut mice. This accelerated rate of bone loss is associated with significantly reduced bone formation rate, reduced osteoblast population densities, increased osteoclast population densities, and mitochondrial respiratory chain deficiency in osteoblasts and osteoclasts in PolgAmut/mut mice compared with wild-type mice. In vitro assays demonstrated severely impaired mineralised matrix formation and increased osteoclast resorption by PolgAmut/mut cells. Finally, application of an exercise intervention to a subset of PolgAmut/mut mice showed no effect on bone mass or mineralised matrix formation in vitro. Our data demonstrate that mitochondrial dysfunction, a universal feature of human ageing, impairs osteogenesis and is associated with accelerated bone loss.

Publication metadata

Author(s): Dobson PF, Dennis EP, Hipps D, Reeve A, Laude A, Bradshaw C, Stamp C, Smith A, Deehan DJ, Turnbull DM, Greaves LC

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2020

Volume: 10

Issue: 1

Online publication date: 15/07/2020

Acceptance date: 24/06/2020

Date deposited: 30/07/2020

ISSN (electronic): 2045-2322

Publisher: Nature Research

URL: https://doi.org/10.1038/s41598-020-68566-2

DOI: 10.1038/s41598-020-68566-2

PubMed id: 32669663

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