# Mitochondrial metabolism and bone formation

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $338,800

## Abstract

Our long-term goal is to understand the role and regulation of mitochondrial metabolism in bone physiology
and pathology. Unlike other fields, such as cardiovascular and muscle physiology and neuroscience, to date
very little effort has been directed towards mitochondrial research in the bone field. This presents an immense
knowledge gap and a critical barrier to developing novel mitochondria-targeted strategies for bone pathologies,
such as aging and trauma which are known to be associated with mitochondrial dysfunction. This also gives
special significance to our mitochondria-centered proposal. Our objective here is to determine the mechanism
controlling mitochondrial activity during osteoblastic (OB) differentiation of bone marrow stromal cells (BMSC,
a.k.a. bone marrow mesenchymal stem cells) and test if strategies aimed at improving mitochondrial metabo-
lism stimulate OB differentiation and bone formation. Our published and new unpublished data indicate that
during OB differentiation, mitochondria fuse into a network, a phenomenon known to maximize the fidelity for
oxidative phosphorylation (OxPhos). A dangerous byproduct of active OxPhos is oxidative stress which pro-
motes opening of a large Mitochondrial Permeability Transition Pore (MPTP). MPTP opening impairs mito-
chondrial integrity and function. Cyclophilin D (CypD) is a key positive regulator of MPTP. It is, thus beneficial
for cells undergoing a shift towards oxidative metabolism, e.g. BMSCs differentiating into OBs, to inactivate
CypD/MPTP. We indeed found that as mitochondria become fused and activated during OB differentiation,
CypD is downregulated at the mRNA level ensuring protection against oxidative stress and supporting OxPhos
and progression of OB program. Moreover, our data indicate that CypD genetic deletion in knockout (KO) mice
or pharmacological inhibition is especially efficient in supporting OB oxidative and bone forming function under
pathological stress, such as in aging and fracture. We recently reported that CypD KO mice are well protected
against bone loss in aging. This is consistent with the literature showing that brain, heart, and kidney tissues of
CypD KO mice are protected against degeneration in aging or ischemic injury. All this led us to hypothesize
that mitochondrial fusion and CypD downregulation leading to activation of OxPhos and inhibition of MPTP dur-
ing OB differentiation, are critical for OB differentiation. To test this hypothesis and fulfill our objective, we will:
1) characterize the mechanism by which mitochondria are activated during OB differentiation focusing on mito-
chondrial fusion; 2) characterize the role and regulation of CypD/MPTP during OB differentiation; and 3) evalu-
ate CypD as a therapeutic target to improve bone formation in fracture healing and aging. These studies will
provide comprehensive understanding of regulation of mitochondrial metabolism during OB differentiation and
a rationale for developing new mitochondria-...

## Key facts

- **NIH application ID:** 9848436
- **Project number:** 5R01AR072601-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Roman Eliseev
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,800
- **Award type:** 5
- **Project period:** 2018-03-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9848436

## Citation

> US National Institutes of Health, RePORTER application 9848436, Mitochondrial metabolism and bone formation (5R01AR072601-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9848436. Licensed CC0.

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