Mitochondrial quality control of mesenchymal stem cells in bone-related diseases: from mechanisms to emerging therapeutic opportunities

Abstract Bone-related diseases represent a significant global health challenge characterized by compromised bone mass and dysregulated skeletal metabolism. Mesenchymal stem cells (MSCs) are indispensable for maintaining bone homeostasis and facilitating tissue repair. However, their regenerative capacity is severely compromised in pathological microenvironments. Recent evidence highlights that MSC functionality is intrinsically governed by a sophisticated mitochondrial quality control (MQC) network, primarily encompassing mitochondrial biogenesis, dynamics, and mitophagy. While the importance of MQC is recognized, a comprehensive understanding of how its specific dysregulation in MSCs drives major bone disorders remains limited. This review systematically summarizes how MQC dysregulation in MSCs contributes to the exacerbation of major bone disorders, including osteoporosis, osteonecrosis of the femoral head, osteoarthritis, intervertebral disc degeneration, and periodontitis. Furthermore, as mitochondrial restoration emerges as a critical factor for therapeutic outcomes, this review evaluates promising approaches, ranging from small molecule drugs to biomaterials and cell-based therapies, highlighting the underlying pathways by which they modulate MQC networks to rescue MSC function. We aim to provide mechanistic insights into the role of MSC-related MQC in bone health and explore potential therapeutic prospects for ameliorating bone diseases by restoring MQC homeostasis in MSCs.