Cyclophilin D, regulator of the mitochondrial permeability transition, impacts bone development and fracture repair.

Rubens Sautchuk, John Martinez, Sarah E Catheline, Roman A Eliseev

Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14624, USA.Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14624, USA. · pubmed

Paper

Abstract

Mitochondrial Permeability Transition Pore (MPTP) and its key positive regulator, Cyclophilin D (CypD), control activity of cell oxidative metabolism important for differentiation of stem cells of various lineages including osteogenic lineage. Our previous work (Sautchuk et al., 2022) showed that CypD gene, Ppif, is transcriptionally repressed during osteogenic differentiation by regulatory Smad transcription factors in BMP canonical pathway, a major driver of osteoblast (OB) differentiation. Such a repression favors closure of the MPTP, priming OBs to higher usage of mitochondrial oxidative metabolism. The physiological role of CypD/MPTP regulation was demonstrated by its inverse correlation with BMP signaling in aging and bone fracture healing in addition to the negative effect of CypD gain-of-function (GOF) on bone maintenance. Here we show evidence that CypD GOF also negatively affects bone development and growth as well as fracture healing in adult mice. Developing craniofacial and long bones presented with delayed ossification and decreased growth rate, respectively, whereas in fracture, bony callus volume was diminished. Given that Genome Wide Association Studies showed that PPIF locus is associated with both body height and bone mineral density, our new data provide functional evidence for the role of PPIF gene product, CypD, and thus MPTP in bone growth and repair.

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Research summary

The paper investigates the role of Cyclophilin D and the mitochondrial permeability transition pore in bone development and fracture repair, linking these processes to aging and bone health. While it addresses mechanisms that could influence longevity through bone maintenance and repair, the findings are more focused on specific biological processes rather than directly targeting the root causes of aging or lifespan extension. Thus, it presents solid research but with limited broader implications for longevity research.

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