PMID- 36779737
OWN - NLM
STAT- MEDLINE
DCOM- 20230414
LR  - 20240402
IS  - 1523-4681 (Electronic)
IS  - 0884-0431 (Print)
IS  - 0884-0431 (Linking)
VI  - 38
IP  - 4
DP  - 2023 Apr
TI  - Role of the Mitochondrial Permeability Transition in Bone Metabolism and Aging.
PG  - 522-540
LID - 10.1002/jbmr.4787 [doi]
AB  - The mitochondrial permeability transition pore (MPTP) and its positive regulator, 
      cyclophilin D (CypD), play important pathophysiological roles in aging. In bone 
      tissue, higher CypD expression and pore activity are found in aging; however, a 
      causal relationship between CypD/MPTP and bone degeneration needs to be 
      established. We previously reported that CypD expression and MPTP activity are 
      downregulated during osteoblast (OB) differentiation and that manipulations in 
      CypD expression affect OB differentiation and function. Using a newly developed 
      OB-specific CypD/MPTP gain-of-function (GOF) mouse model, we here present 
      evidence that overexpression of a constitutively active K166Q mutant of CypD 
      (caCypD) impairs OB energy metabolism and function, and bone morphological and 
      biomechanical parameters. Specifically, in a spatial-dependent and sex-dependent 
      manner, OB-specific CypD GOF led to a decrease in oxidative phosphorylation 
      (OxPhos) levels, higher oxidative stress, and general metabolic adaptations 
      coincident with the decreased bone organic matrix content in long bones. 
      Interestingly, accelerated bone degeneration was present in vertebral bones 
      regardless of sex. Overall, our work confirms CypD/MPTP overactivation as an 
      important pathophysiological mechanism leading to bone degeneration and fragility 
      in aging. (c) 2023 American Society for Bone and Mineral Research (ASBMR).
CI  - (c) 2023 American Society for Bone and Mineral Research (ASBMR).
FAU - Sautchuk, Rubens Jr
AU  - Sautchuk R Jr
AUID- ORCID: 0000-0002-0302-7562
AD  - Center for Musculoskeletal ResearchUniversity of Rochester, Rochester, NY, USA.
FAU - Yu, Chen
AU  - Yu C
AD  - Center for Musculoskeletal ResearchUniversity of Rochester, Rochester, NY, USA.
FAU - McArthur, Matthew
AU  - McArthur M
AD  - Center for Musculoskeletal ResearchUniversity of Rochester, Rochester, NY, USA.
FAU - Massie, Christine
AU  - Massie C
AD  - Center for Musculoskeletal ResearchUniversity of Rochester, Rochester, NY, USA.
AD  - Department of Biomedical Engineering, University of Rochester, Rochester, NY, 
      USA.
FAU - Brookes, Paul S
AU  - Brookes PS
AUID- ORCID: 0000-0002-8639-8413
AD  - Department of Anesthesiology and Perioperative Medicine, University of Rochester, 
      Rochester, NY, USA.
AD  - Department of Pharmacology & Physiology, University of Rochester, Rochester, NY, 
      USA.
FAU - Porter, George A Jr
AU  - Porter GA Jr
AD  - Department of Pediatrics, Division of Cardiology, University of Rochester, 
      Rochester, NY, USA.
FAU - Awad, Hani
AU  - Awad H
AUID- ORCID: 0000-0003-2197-2610
AD  - Center for Musculoskeletal ResearchUniversity of Rochester, Rochester, NY, USA.
AD  - Department of Biomedical Engineering, University of Rochester, Rochester, NY, 
      USA.
FAU - Eliseev, Roman A
AU  - Eliseev RA
AUID- ORCID: 0000-0002-6783-7388
AD  - Center for Musculoskeletal ResearchUniversity of Rochester, Rochester, NY, USA.
AD  - Department of Pharmacology & Physiology, University of Rochester, Rochester, NY, 
      USA.
AD  - Department of Pathology, University of Rochester, Rochester, NY, USA.
LA  - eng
GR  - R21 AR070928/AR/NIAMS NIH HHS/United States
GR  - R21 AR080291/AR/NIAMS NIH HHS/United States
GR  - P30 AR069655/AR/NIAMS NIH HHS/United States
GR  - R01 AR070613/AR/NIAMS NIH HHS/United States
GR  - R01 AG076786/AG/NIA NIH HHS/United States
GR  - NH/NIH HHS/United States
GR  - R01 AR072601/AR/NIAMS NIH HHS/United States
GR  - R01 HL071158/HL/NHLBI NIH HHS/United States
GR  - R90 DE022529/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230309
PL  - England
TA  - J Bone Miner Res
JT  - Journal of bone and mineral research : the official journal of the American 
      Society for Bone and Mineral Research
JID - 8610640
RN  - 0 (Mitochondrial Membrane Transport Proteins)
RN  - 0 (Mitochondrial Permeability Transition Pore)
RN  - 0 (Peptidyl-Prolyl Isomerase F)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Mitochondrial Membrane Transport Proteins/genetics/metabolism
MH  - *Mitochondrial Permeability Transition Pore
MH  - Mitochondrial Transmembrane Permeability-Driven Necrosis
MH  - Peptidyl-Prolyl Isomerase F
MH  - Aging
PMC - PMC10101909
MID - NIHMS1874809
OTO - NOTNLM
OT  - AGING
OT  - DISEASES AND DISORDERS OF/RELATED TO BONE
OT  - MITOCHONDRIA
OT  - OSTEOBLASTS
OT  - OSTEOPOROSIS
COIS- DISCLOSURE The Authors do not have any potential conflicts to disclose.
EDAT- 2023/02/14 06:00
MHDA- 2023/04/14 06:41
PMCR- 2024/04/01
CRDT- 2023/02/13 09:05
PHST- 2023/02/02 00:00 [revised]
PHST- 2022/07/26 00:00 [received]
PHST- 2023/02/07 00:00 [accepted]
PHST- 2023/04/14 06:41 [medline]
PHST- 2023/02/14 06:00 [pubmed]
PHST- 2023/02/13 09:05 [entrez]
PHST- 2024/04/01 00:00 [pmc-release]
AID - 10.1002/jbmr.4787 [doi]
PST - ppublish
SO  - J Bone Miner Res. 2023 Apr;38(4):522-540. doi: 10.1002/jbmr.4787. Epub 2023 Mar 
      9.