<scp>ER</scp> ‐Mitochondria Tethering and Calcium Flux: A Core Mechanism for Biomineralization

) serve not only as a fundamental component of the mineral phase but also as key signaling messengers that actively regulate the efficiency and progression of this process. The endoplasmic reticulum (ER) and mitochondria are two major organelles responsible for calcium ion storage and regulation within cells. Contact sites between mitochondria and ER, also called mitochondria-ER contacts (MERCs) or mitochondria-associated ER membranes (MAMs), have been identified as vital spots for calcium transfer. Existing research indicates that calcium ion transport from the ER to mitochondria occupies a pivotal position in biomineralization, but the relevance of MERC integrity in biomineralization is yet to be determined. This study revealed increased MERCs and calcium ion transport during mineralization in vivo and in vitro. Additionally, significantly impaired endoplasmic reticulum-mitochondrial interactions were observed in bone marrow mesenchymal stem cells (BMSCs) from ovariectomy-induced osteoporotic mice. Experimental enhancement of MERCs effectively increased mineralized nodule formation and alleviated ovariectomy-induced osteoporosis, whereas disruption of MERC integrity inhibited mineralization. Our findings indicate that endoplasmic reticulum-mitochondrial calcium ion transport plays a crucial role in biomineralization. This discovery provides a stronger theoretical foundation for elucidating the biomineralization process and may also identify novel therapeutic targets for related diseases.