Mitochondria are the power plants of the cell, the evolved descendants of ancient symbiotic bacteria. They generate the chemical energy store molecules needed to power cellular processes. The herd of hundreds of mitochondria in every cell replicate like bacteria, and carry a small remnant circular genome, the mitochondrial DNA. Mice engineered to lack a functional PolgA gene exhibit defective mitochondrial DNA repair, and as a consequence accumulate mutations in their mitochondrial DNA at a rapid pace. Random mutation and declining mitochondrial function is a feature of aging, and these mitochondrial mutator mice exhibit accelerated aging as a consequence of the more rapid damage they suffer to this vital cell component.

Here, researchers examine just one feature of this accelerated aging, the more rapid onset of osteoporosis, the characteristic loss of bone mass and strength that occurs with age. Bone is a dynamic tissue, constantly remodeled by osteoblasts that create bone and osteoclasts that break it down. Damage to mitochondrial function causes a decline in osteoblast activity, favoring bone destruction over bone creation. Over time this leads to osteporosis and all of its consequences.

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 PolgA 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 PolgA 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 PolgA mice compared with wild-type mice. In vitro assays demonstrated severely impaired mineralised matrix formation and increased osteoclast resorption by PolgA cells.

Finally, application of an exercise intervention to a subset of PolgA 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.