Mitochondrial Point Mutation m.3243A>G Associates With Lower Bone Mineral Density, Thinner Cortices, and Reduced Bone Strength: A Case-Control Study

Mitochondrial dysfunction is associated with several clinical manifestations including diabetes mellitus (DM), neurological disorders, renal and hepatic diseases, and myopathy. Although mitochondrial dysfunction is associated with increased bone resorption and decreased bone formation in mouse models, effects of alterations in mitochondrial function on bone remodeling and mass have not been investigated in humans. We recruited 45 carriers (29 females, 16 males) with the m.3243A>G mutation and healthy controls matched for gender, age, height, and menopausal status. DXA and HRpQCT scans were performed, and bone turnover markers (BTMs) P1NP and CTX were measured. Cases and controls were well matched except for body weight, which was lower in cases (63.6 ± 18.1 kg versus 74.6 ± 14.8 kg, p < 0.01), and manifest DM was present in 25 of 45 cases (none in controls). Bone scans showed lower BMD at the lumbar spine, total hip, and femoral neck in cases. Mean lumbar spine, total hip, and femoral neck T-scores were –1.5, –1.3, and –1.6 in cases, respectively, and –0.8, –0.3, and –0.7 in controls (all p < 0.05). The m.3243A>G mutation was associated with lower BMD, cortical but not trabecular density, cortical thickness, and estimated bone strength. Furthermore, BTMs were lower in the m.3243A>G group before but not after adjustment for DM. The mitochondrial point mutation m.3243A>G was associated with decreased bone mass and strength. Although the coexistence of DM may have influenced bone turnover, the bone phenotype observed in m.3243A>G cases appeared to mirror age-related deterioration in bone, suggesting that mitochondrial dysfunction may cause a premature aging of bone.