Deletion of ATAD3A inhibits osteogenesis by impairing mitochondria structure and function in pre‐osteoblast

Background ATPase family AAA‐domain containing protein 3A (ATAD3A) is a nuclear encoded mitochondrial membrane protein that spans inner and outer membrane, and it has been shown to regulate mitochondrial dynamics and cholesterol metabolism. Since the mitochondrial functions have been implicated for...

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Bibliographic Details
Published in:Developmental dynamics 2022-12, Vol.251 (12), p.1982-2000
Main Authors: Lee, Hyeri, Kim, Dae‐Won
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - genetics
Adenosine Triphosphatases - metabolism
Animals
ATAD3A
ATPases Associated with Diverse Cellular Activities - genetics
ATPases Associated with Diverse Cellular Activities - metabolism
Bone mass
Cartilage
Cholesterol
Deletion
Differentiation (biology)
Homeostasis
lipid droplet
Lipid metabolism
Membrane proteins
Membrane Proteins - genetics
Membrane Proteins - metabolism
Membranes
Mesenchyme
Mice
Mice, Knockout
Mitochondria
Mitochondria - metabolism
Mitochondrial Proteins - genetics
Osteoblastogenesis
Osteoblasts
Osteoblasts - metabolism
Osteogenesis
Osteogenesis - genetics
Phenotypes
Protein 3a
Proteins
skeletal development
Structure-function relationships
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Summary:Background ATPase family AAA‐domain containing protein 3A (ATAD3A) is a nuclear encoded mitochondrial membrane protein that spans inner and outer membrane, and it has been shown to regulate mitochondrial dynamics and cholesterol metabolism. Since the mitochondrial functions have been implicated for osteogenic differentiation, a role of ATAD3A in skeletal development has been investigated. Results Mesenchyme‐specific ATAD3 knockout mice displayed severe defects in skeletal development. Additionally, osteoblast‐specific deletion of ATAD3 in mice caused significant reduction in bone mass, while cartilage‐specific ATAD3 knockout mice did not show any significant phenotypes. Consistent with these in vivo findings, ATAD3A knockdown impaired mitochondrial morphology and function in calvarial pre‐osteoblast cultures, which, in turn, suppressed osteogenic differentiation in vitro. Conclusions The current findings suggest that ATAD3A plays a crucial role in mitochondria homeostasis, which is required for osteogenic differentiation during skeletal development. Key Findings ATAD3A (ATPase family AAA‐domain containing protein 3A) is a nuclear encoded mitochondrial membrane protein that spans inner and outer membrane, and it has been shown to regulate mitochondrial dynamics and cholesterol metabolism. While the mitochondrial functions have been implicated for osteogenic differentiation, a role of ATAD3A in skeletal development has not been investigated. In this work, we demonstrate that ATAD3A is required for bone ossification in mice as well as pre‐osteoblast maturation in vitro.
ISSN:1058-8388
1097-0177
DOI:10.1002/dvdy.528