The Role of Mitochondrial Permeability Transition in Bone Metabolism, Bone Healing, and Bone Diseases

Abstract

Bone is a dynamic organ with an active metabolism and high sensitivity to mitochondrial dysfunction. The mitochondrial permeability transition pore (mPTP) is a low-selectivity channel situated in the inner mitochondrial membrane (IMM), permitting the exchange of molecules of up to 1.5 kDa in and out of the IMM. Recent studies have highlighted the critical role of the mPTP in bone tissue, but there is currently a lack of reviews concerning this topic. This review discusses the structure and function of the mPTP and its impact on bone-related cells and bone-related pathological states. The mPTP activity is reduced during the osteogenic differentiation of mesenchymal stem cells (MSCs), while its desensitisation may underlie the mechanism of enhanced resistance to apoptosis in neoplastic osteoblastic cells. mPTP over-opening triggers mitochondrial swelling, regulated cell death, and inflammatory response. In particular, mPTP over-opening is involved in dexamethasone-induced osteoblast dysfunction and bisphosphonate-induced osteoclast apoptosis. In vivo, the mPTP plays a significant role in maintaining bone homeostasis, with many bone disorders linked to its excessive opening. Genetic deletion or pharmacological inhibition of the over-opening of mPTP has shown potential in enhancing bone injury recovery and alleviating bone diseases. Here, we review the findings on the relationship of the mPTP and bone at both the cellular and disease levels, highlighting novel avenues for pharmacological approaches targeting mitochondrial function to promote bone healing and manage bone-related disorders.

Keywords: bone healing; inflammatory bone loss; mitochondria; mitochondrial dysfunction; mitochondrial permeability transition pore; osteoporosis.

Figure 1

mPTP structure and the consequences of mPTP opening. The mitochondrial permeability transition pore (mPTP) has different conductance states. In its low-conductance state, the mPTP, potentially formed by the adenine nucleotide translocator (ANT), allows for the passage of ions and small metabolites. Ca²⁺ efflux in this state limits the Ca²⁺-dependent tricarboxylic acid (TCA) cycle. In its high-conductance state, the mPTP is formed by a rearrangement of the F₁F_o ATP synthase complex. This state has more detrimental effects on cellular function. The release of mitochondrial DNA (mtDNA) through the mPTP triggers inflammatory responses. Extensive water influx causes mitochondrial swelling and subsequently induces outer membrane permeabilisation and the release of pro-apoptotic cofactors, leading to apoptosis or necrosis and TCA cycle collapse. ↓(orange downward arrow) represents downregulation of the TCA cycle.

Figure 2

Diverse roles of mPTP opening in bone-related cells. The mitochondrial permeability transition pore (mPTP) is crucial in various functions within bone-related cells. In bone marrow-derived mesenchymal stem cells (BMSCs), cyclophilin D (CypD) downregulation and subsequent mPTP activity decline are required for osteogenic differentiation. In osteoblasts, mPTP over-opening is involved in several drug-induced regulated cell deaths (RCDs) in an ROS-dependent or ROS-independent manner. The mechanism by which osteosarcoma cells are resistant to apoptosis is, at least in part, due to desensitisation to the mPTP. Several studies have indicated that the mPTP is also involved in osteoclast apoptosis. ↑(black upward arrow) and ↓(black downward arrow) represents upregulation and downregulation of mPTP opening, respectively.