Mitochondrial genetics as a determinant of bone health

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Abstract The role of mitochondria in bone tissue physiology and pathology remains understudied. Our long-term goal is to fill this gap of knowledge and this high risk proposal is a step towards this goal. It will test if mitochondrial genetics (mtDNA haplotype) influences bone phenotype and function of osteoblasts (OB) and their precursors, bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs). The scientific premise here is that: 1) mitochondrial oxidative phosphorylation (OxPhos) is required for osteogenic differentiation; 2) mitochondrial dysfunction plays a significant role in bone aging; 3) patients with mitochondrial diseases have fragile bones; 4) Eurasians with ‘less efficient’ mtDNA haplogroups developed as an adaptation to cold climate, also have weaker bones when compared to people of African descent with ‘more efficient’ mtDNA haplogroup L; and 5) C3H/HeN (C3H) mice with more efficient mtDNA haplotype, also have stronger bones then C57BL/6J (C57) mice with less efficient mtDNA haplotype. To study contributions of nuclear vs mtDNA genome to a phenotype, we will use a delicate new genetic model, mitochondrial/nuclear exchange (MNX) mice. These MNX mice have C57 or C3H nuclear background but C3H and C57 mtDNA, respectively (C57n;C3Hmt and C3Hn;C57mt). Cells in these mice show OxPhos activity according to their mtDNA haplotype rather than their nuclear background. Our pilot data show that C57n;C3Hmt BMSCs have higher, while C3Hn;C57mt BMSCs have lower osteogenic potential than their corresponding controls, C57 and C3H, respectively. We also observed that bone accrual in 3 mo old F mice reflected their mtDNA haplogroup (C57n;C3Hmt > C57 while C3Hn;C57mt < C3H). Our central hypothesis that mitochondrial genetics is a strong determinant of BMSC osteogenic potential, OB bone-forming function, and bone phenotype. To test it, we will determine if MNX mice have altered bone phenotype (Aim 1) and altered BMSC osteogenic and OB bone-forming function and mitochondrio-nuclear communication (Aim 2) when compared to their wild type controls. If successful, this project will lay strong foundation for a new direction in our research and bone field in general, mitochondrial genetics of bone.