COBRE in Mesenchymal and Neural Regulation of Metabolic Networks

COBRE PROJECTS

Project 2:  The essential role for mitophagy in osteoblast differentiation.  Dr. Anyonya Guntur

Project significance – Our long term objective is to understand how mitophagy (mitochondrial specific autophagy), regulated by cellular and whole body metabolism, regulates bone development and disease. We have made progress by clarifying the bioenergetic pathways utilized during osteoblast differentiation (1,2,3).  We also utilized a transgenic mitophagy reporter mouse (MitoQC) to document high levels of basal mitophagy in osteoblasts and osteocytes in vivo, and activation of mitophagy during in vitro osteoblast differentiation.  

We have focused mechanistic studies on one mitophagy receptor, BNip3, which is associated with osteogenic differentiation . The major aims of this proposal are to test the hypothesis that mitophagy plays a dual role in peak bone mass acquisition and maintenance; first, osteoblast differentiation upregulates mitophagy to reign in mitochondrial energy generation and second, during pathological conditions mimicking metabolic syndrome we theorize that BNip3 plays a protective role by eliminating dysfunctional mitochondria. These studies are expected to provide the first mechanistic link between osteoblast differentiation, bone remodeling, and the process of mitophagy.  In addition, we will characterize novel mouse models to study interactions of BNip3 within this network, with an emphasis on physiological conditions of metabolic imbalance.  An understanding of molecular targets that control mitophagy within the bone cellular microenvironment, particularly with regards to current therapeutic anabolic agents, will promote strategies to improve bone health.

  1. Guntur AR, Le PT, Farber CR, Rosen CJ. Bioenergetics during calvarial osteoblast differentiation reflect strain differences in bone mass. Endocrinology. 2014;155(5):1589-95. Epub 2014/01/21. doi: 10.1210/en.2013-1974. PubMed PMID: 24437492; PMCID: PMC3990840.
  2. Guntur AR, Gerencser AA, Le PT, DeMambro VE, Bornstein SA, Mookerjee SA, Maridas DE, Clemmons DE, Brand MD, Rosen CJ. Osteoblast-like MC3T3-E1 Cells Prefer Glycolysis for ATP Production but Adipocyte-like 3T3-L1 Cells Prefer Oxidative Phosphorylation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2018;33(6):1052-65. Epub 2018/01/18. doi: 10.1002/jbmr.3390. PubMed PMID: 29342317; PMCID: PMC6002892.
  3. Lee WC, Guntur AR, Long F, Rosen CJ. Energy Metabolism of the Osteoblast: Implications for Osteoporosis. Endocrine reviews. 2017;38(3):255-66. Epub 2017/05/05. doi: 10.1210/er.2017-00064. PubMed PMID: 28472361; PMCID: PMC5460680.

Hypoxia induces BNIP3 in preosteoblasts. A) MC3T3E1C4 cells treated with vehicle or CoCl2 overnight increase BNIP3 (green), surrounding doughnut shaped mitochondria (red). The mitochondria are tubular and long as opposed to the CoCl2 treated samples (quantified in B). C) Bioenergetic measurements show a decrease in mitochondrial OxPhos and a shift to glycolysis as measured by extracellular acidification rate (ECAR) (D). *p value <0.05