Role of Mitochondrial Quality Control in Bone Homeostasis and Disease

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PROJECT SUMMARY/ABSTRACT Altered mitochondria quality control in osteoblasts and osteoclasts has been implicated in the loss of bone mass associated with aging and estrogen deficiency – the two most important causes of osteoporosis in humans, however the underlying mechanisms remain unclear. Sirtuin-3 (Sirt3) is the primary mitochondrial protein deacetylase and plays a critical role in mitochondrial quality control, including mitochondrial biogenesis, mitochondrial dynamics, and mitophagy—all of which are affected in age-related metabolic diseases. Earlier work aiming to elucidate the role of Sirt3 in bone has produced conflicting results with some studies suggesting that Sirt3 is critical for skeletal homeostasis while others found no physiological role of Sirt3 in bone. We have shown that deletion of Sirt3 or pharmacologic inhibition of Sirt3 in mice prevents the loss of bone mass caused by aging and estrogen deficiency and this is associated with decreased bone resorption. Osteoclasts lacking Sirt3 exhibit impaired mitophagy and increased acetylation of the mitophagy protein PTEN-induced kinase 1 (PINK1). Moreover, the mitophagy inhibitor mdivi-1 mimics the effects of Sirt3 deletion or Sirt3 inhibition on osteoclast generation and bone resorption. We have also obtained proteomic evidence to suggest that the protective effects of Sirt3 deletion on bone mass are mediated by its posttranslational regulation of ATPase inhibitory factor 1 (ATPIF1), an essential protein for mitophagy. Notably, ATPIF1 silencing osteoclast progenitors exhibit impaired polykaryon formation and resorptive activity as well as decreased mitophagy. We hypothesize that Sirt3-mediated deacetylation of ATPIF1 promotes osteoclast function via PINK1-dependent or independent mitophagy and that this process contributes to the excessive bone resorption that occurs with aging and estrogen deficiency. In Aim 1 we will determine the contribution of Sirt3/PINK1-mediated mitophagy to the development of osteoporosis in aged or ovariectomized mice with PINK1 loss-of-function. We will also quantify mitophagy and mitochondrial architecture in vivo using a mitochondria reporter mouse. In Aim 2 we will determine the role of ATPIF1 in the actions of Sirt3 on osteoclast function. Successful completion of this work should establish novel molecular and cellular mechanisms that contribute to osteoclast function and osteoporosis. These studies also should elucidate a previously unappreciated deleterious role of Sirt3 in age- related metabolic diseases.