Piezo1 stimulates mitochondrial function via cAMP signaling.

Mechanical signals stimulate mitochondrial function but the molecular mechanisms are not clear. Here, we show that the mechanically sensitive ion channel Piezo1 plays a critical role in mitochondrial adaptation to mechanical stimulation. The activation of Piezo1 induced mitochondrial calcium uptake and oxidative phosphorylation (OXPHOS). In contrast, loss of Piezo1 reduced the mitochondrial oxygen consumption rate (OCR) and adenosine triphosphate (ATP) production in calvarial cells and these changes were associated with increased expression of the phosphodiesterases Pde4a and lower cyclic AMP (cAMP) levels. In addition, Piezo1 increased cAMP production and the activation of a cAMP-responsive transcriptional reporter. Consistent with this, cAMP was sufficient to increase mitochondrial OCR and the inhibition of phosphodiesterases augmented the increase in OCR induced by Piezo1. Moreover, the inhibition of cAMP production or activity of protein kinase A, a kinase activated by cAMP, prevented the increase in OCR induced by Piezo1. These results demonstrate that cAMP signaling contributes to the increase in mitochondrial OXPHOS induced by activation of Piezo1.

New Advances in Osteocyte Mechanotransduction.

PURPOSE OF REVIEW: Skeletal adaptation to mechanical loading plays a critical role in bone growth and the maintenance of bone homeostasis. Osteocytes are postulated to serve as a hub orchestrating bone remodeling. The recent findings on the molecular mechanisms by which osteocytes sense mechanical loads and the downstream bone-forming factors are reviewed. RECENT FINDINGS: Calcium channels have been implicated in mechanotransduction in bone cells for a long time. Efforts have been made to identify a specific calcium channel mediating the skeletal response to mechanical loads. Recent studies have revealed that Piezo1, a mechanosensitive ion channel, is critical for normal bone growth and is essential for the skeletal response to mechanical loading. Identification of mechanosensors and their downstream effectors in mechanosensing bone cells is essential for new strategies to modulate regenerative responses and develop therapies to treat the bone loss related to disuse or advanced age.