Role of Mitochondrial Dynamics In Bone Homeostasis

线粒体动力学在骨稳态中的作用

• 批准号: 9196224
• 负责人: DEBORAH J VEIS
• 金额: $ 35.97万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196224
• 关键词: Ablation; Address; Affect; Age; Aging; Autophagocytosis; Biological; Biology; Bone Marrow; Bone Resorption; Calcium; Cardiomegaly; Cell Aging; Cell Death; Cell Differentiation process; Cell Lineage; Cell Survival; Cell physiology; Cells; Cellular Structures; Cessation of life; Coupled; Cytosol; Data; Defect; Estrogens; Excision; Face; Goals; Guanosine Triphosphate Phosphohydrolases; Homeostasis; In Vitro; Lead; Life; Longevity; Maintenance; Mesenchymal; Mitochondria; Modeling; Mus; Muscular Atrophy; Nerve Degeneration; Organelles; Osteoblasts; Osteoclasts; Osteogenesis; Osteolysis; Outer Mitochondrial Membrane; Ovariectomy; Oxidative Stress; Pathway interactions; Pharmacologic Substance; Phenotype; Play; Premature aging syndrome; Process; Production; Reactive Oxygen Species; Recycling; Regulation; Reporting; Research Personnel; Resistance; Role; Stress; Structure; Subfamily lentivirinae; Testing; abstracting; age effect; age related; bone; bone cell; bone loss; bone mass; bone strength; cell type; design; human disease; in vitro Assay; in vivo; insight; mitochondrial dysfunction; mouse model; mutant; osteoblast differentiation; parkin gene/protein; progenitor; promoter; recombinase; response; stem

Project Summary/Abstract Mitochondria are critical components of cells, and they are the hub of energy production (ATP). Recent reports indicate that mitochondria also play a role in cell survival/death, calcium homeostasis, and reactive oxygen species (ROS) production/response to oxidative stress. A unique feature of mitochondria as organelles is their organization into a highly dynamic network within the cell characterized by the interrelated processes of tethering/fusion, fission and removal via mitophagy. Although still not completely understood, this dynamic regulation of the mitochondrial network seems to be important for the maintenance of healthy, properly functioning mitochondria. In human diseases as well as mouse models, mitochondrial defects lead to phenotypes of reduced lifespan or “premature aging”, including neural degeneration, muscle atrophy, heart enlargement, and bone loss. However, the relationship between mitochondrial function(s), aging, and the cellular activities of bone formation and resorption are largely unknown. The primary goal of this proposal is to establish the role of mitochondrial dynamics in the function of osteoclasts (OCs) and osteoblasts (OBs), and thereby in the maintenance of bone mass and strength with age. In order to study mitochondrial dynamics, we will manipulate mitofusin 2 (Mfn2), a molecule with important roles in both mitochondrial tethering and mitophagy that has not previously been examined in bone cells. Mfn2 is a GTPase located on the outer mitochondrial membrane, with a unique role in the recruitment of Parkin to promote mitophagy, the recycling of damaged mitochondria via the autophagy pathway. Mfn2 also has a tethering function as it faces the cytosol. Tethering between mitochondria leads to fusion, generating longer organelles and/or a more connected network. Mfn2 can also tether mitochondria to the ER, affecting Ca++ transfer between these structures and regulating cell death. All of these roles for Mfn2 can contribute to overall mitochondrial dysfunction in cells deficient in Mfn2, causing abnormal levels of ATP and ROS. Mitochondrial content increases in both OCs and OBs during differentiation from early precursors in vitro, and our preliminary data show that Mfn2 expression is upregulated in parallel. Further, conditional deletion of Mfn2 from OC lineage cells leads to high bone mass and resistance to stimulated osteolysis in mice. Removal of Mfn2 from mesenchymal progenitors in vitro also reduces osteoblastic differentiation. In this proposal, we test the hypothesis that Mfn2 controls mitochondrial dynamics in OCs (Aim 1) and OBs (Aim 2), via its role in mitophagy and/or tethering, to modulate bone homeostasis in vivo. The overall approach is to determine the effect of Mfn2 ablation using Mfn2fl/fl mice crossed to OC and OB lineage Cre lines, examining the bone phenotype with age and the effects on specific cell function using in vivo and in vitro analyses. By utilizing mutants that separate the major effector functions of Mfn2, we will address the specific mechanism that drives the phenotype in each cell lineage.

项目总结/文摘