Activation of BK channels prevents diabetes-induced osteopenia by regulating mitochondrial Ca²⁺ and SLC25A5/ANT2-PINK1-PRKN-mediated mitophagy

ABSTRACT

Osteopenia and osteoporosis are among the most common metabolic bone diseases and represent major public health problems, with sufferers having an increased fracture risk. Diabetes is one of the most common diseases contributing to osteopenia and osteoporosis. However, the mechanisms underlying diabetes-induced osteopenia and osteoporosis remain unclear. Bone reconstruction, including bone formation and absorption, is a dynamic process. Large-conductance Ca²⁺-activated K⁺ channels (BK channels) regulate the function of bone marrow-derived mesenchymal stem cells, osteoblasts, and osteoclasts. Our previous studies revealed the relationship between BK channels and the function of osteoblasts via various pathways under physiological conditions. In this study, we reported a decrease in the expression of BK channels in mice with diabetes-induced osteopenia. BK deficiency enhanced mitochondrial Ca²⁺ and activated classical PINK1 (PTEN induced putative kinase 1)-PRKN/Parkin (parkin RBR E3 ubiquitin protein ligase)-dependent mitophagy, whereas the upregulation of BK channels inhibited mitophagy in osteoblasts. Moreover, SLC25A5/ANT2 (solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 5), a critical inner mitochondrial membrane protein participating in PINK1-PRKN-dependent mitophagy, was also regulated by BK channels. Overall, these data identified a novel role of BK channels in regulating mitophagy in osteoblasts, which might be a potential target for diabetes-induced bone diseases.

Abbreviations: AGE, advanced glycation end products; Baf A1, bafilomycin A₁; BK channels, big-conductance Ca²⁺-activated K⁺ channels; BMSCs, bone marrow-derived mesenchymal stem cells; BSA, bovine serum albumin; FBG, fasting blood glucose; IMM, inner mitochondrial membrane; ITPR1, inositol 1,4,5-trisphosphate receptor 1; MAM, mitochondria-associated ER membrane; OMM, outer mitochondrial membrane; PINK1, PTEN induced putative kinase 1; PPID/CyP-D, peptidylprolyl isomerase D (cyclophilin D); PRKN/PARK2, parkin RBR E3 ubiquitin protein ligase; ROS, reactive oxygen species; SLC25A5/ANT2, solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 5; STZ, streptozotocin.

KEYWORDS:

• Adenine nucleotide translocator
• BK channel
• mitochondrial calcium
• mitophagy
• PINK1-PRKN pathway

Acknowledgements

We would like to thank Shanghai Institute of Materia Medica for providing the plasmids related to the mechanism of ubiquitin.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2024.2367184

Correction Statement

* These authors contributed equally.This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The current study was supported by grants from the National Natural Science Foundation of China (No. 81973385); Shanghai Science and Technology Innovation (No. 20410713300) and the Department of Veteran Affairs MERIT Award 5I01BX000994.