# Role of Mitochondrial Dynamics In Bone Homeostasis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $336,433

## Abstract

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 se...

## Key facts

- **NIH application ID:** 9955186
- **Project number:** 5R01AR070030-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** DEBORAH J VEIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $336,433
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955186

## Citation

> US National Institutes of Health, RePORTER application 9955186, Role of Mitochondrial Dynamics In Bone Homeostasis (5R01AR070030-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9955186. Licensed CC0.

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