Role of Mitochondria in Physiology of Chondrocytes and Diseases of Osteoarthritis and Rheumatoid Arthritis

Abstract

Purpose of review: Mitochondria are recognized to be one of the most important organelles in chondrocytes for their role in triphosphate (ATP) generation through aerobic phosphorylation. Mitochondria also participate in many intracellular processes involving modulating reactive oxygen species (ROS), responding to instantaneous hypoxia stress, regulating cytoplasmic transport of calcium ion, and directing mitophagy to maintain the homeostasis of individual chondrocytes.

Designs: To summarize the specific role of mitochondria in chondrocytes, we screened related papers in PubMed database and the search strategy is ((mitochondria) AND (chondrocyte)) AND (English [Language]). The articles published in the past 5 years were included and 130 papers were studied.

Results: In recent years, the integrity of mitochondrial structure has been regarded as a prerequisite for normal chondrocyte survival and defect in mitochondrial function has been found in cartilage-related diseases, such as osteoarthritis (OA) and rheumatoid arthritis (RA). However, the understanding of mitochondria in cartilage is still largely limited. The mechanism on how the changes in mitochondrial structure and function directly lead to the occurrence and development of cartilage-related diseases remains to be elusive.

Conclusion: This review aims to summarize the role of mitochondria in chondrocytes under the physiological and pathological changes from ATP generation, calcium homeostasis, redox regulation, mitophagy modulation, mitochondria biogenesis to immune response activation. The enhanced understanding of molecular mechanisms in mitochondria might offer some new cues for cartilage remodeling and pathological intervention.

Keywords: cartilage; chondrocyte; mitochondria; pathology; physiology.

Figure 1.

Mitochondrial structure in chondrocytes. (A) The schematic diagram of the articular cartilage structure. Cartilage is composed of dense ECM and chondrocytes. ECM mainly contains aggrecan and type II collagen. (B) Mitochondria are randomly distributed in the cytoplasm of chondrocytes under physiological conditions. The distribution of mitochondria in chondrocytes is related to the demand of ATP. (C) The general morphology of mitochondrion. Mitochondrion is a kind of double-membrane organelle. Mitochondrial inner membrane folds to form cristae. (D) Mitochondrial double-membrane structure. The OMM contains membrane pore proteins and Bcl-2 family proteins. The IMM mainly contains complexes I, II, III, and IV of ETC and ATP synthase. Functional proteins in the intermembrane space between OMM and IMM include but are not limited to Cyto c, AIF, Smac, and proteases 3 and 9. The mitochondrial matrix contains mtDNA and proteins related to energy metabolism. ECM = extracellular matrix; ATP = adenosine triphosphate; OMM = outer mitochondrial membrane; Bcl-2 = B-cell leukemia/lymphoma-2; IMM = inner mitochondrial membrane; ETC = electron transport chain; Cyto c = cytochrome c; AIF = apoptosis-inducing factor; Smac = second mitochondrial-derived activator of caspases; mtDNA = mitochondrial deoxyribonucleic acid.

Figure 2.

The function of mitochondria in chondrocytes. (A) I. Mitochondria in chondrocytes synthesize ATP and provide energy by executing TCA and OXPHOS. ATP is synthesized from ADP via ATP synthase which is located in the ETC. In the process of OXPHOS, the enzyme complexes involved in electron transport in the respiratory chain are located in the IMM. The 4 electron transport chain complexes (respiratory chain complexes I-IV) in the IMM cooperate to generate ATP. II. Due to the leakage of protons in the ETC, mitochondria produce oxygen free radicals, also known as mtROS. As a participant in the intracellular signal transduction mechanism, mtROS is an important cellular messenger for gene regulation and cell cycle. Mitochondrial ROS also contributes to maintain chondrocyte homeostasis and to regulate cell apoptosis. In normal chondrocytes, mitochondria have a highly efficient antioxidant defense system to maintain a relatively low mtROS level. (B) III. Mitochondria are kind of critical organelles in the regulation of calcium homeostasis. Normally, driven by an electrical gradient, Ca²⁺ is transported to the mitochondrial matrix through the IMM. And TCA cycle is activated by Ca²⁺ to stimulate ATP production. Ca²⁺ also participates in a series of metabolic reactions associated with ECM calcification. (C) IV. Damaged mitochondria are wrapped in a double-layer membrane structure and fuse with lysosomes to form autophagosomes. Through the process of mitochondrial autophagy, cell-selective autophagy can quickly remove damaged or redundant mitochondria. Mitophagy maintains the normal physiological functions of cells and the stability of the intracellular space. ATP = adenosine triphosphate; TCA = tricarboxylic acid cycle; OXPHOS = oxidative phosphorylation; ADP = adenosine diphosphate; ETC = electron transport chain; IMM = inner mitochondrial membrane; mtROS = mitochondrial reactive oxygen species; ROS = reactive oxygen species; ECM = extracellular matrix; Bcl-2 = B-cell leukemia/lymphoma-2; Cyto c = cytochrome c; AIF = apoptosis-inducing factor; Smac = second mitochondrial-derived activator of caspases; ER = endoplasmic reticulum.

Figure 3.

Schematic diagram of mitochondrial function of chondrocyte in OA. Cytokines and other stimuli mainly lead to chondrocytes apoptosis through mitochondrial apoptosis pathway. The key chondrocyte signal transduction pathways include the JNK pathway, the PI-3K/Akt pathway, the NF-κB pathway, and the p38/MAPK pathway. Phosphorylation and inactivation of the anti-apoptotic protein Bcl-2 could suppress its anti-apoptotic activity and induce the escape of Cyto c. The JNK and NF-κB pathways promote p53 to upregulate pro-apoptotic genes such as Bax and Bim. The aggregations of these pro-apoptotic molecules and pro-inflammatory cytokines further impair mitochondrial integrity. Compared with normal chondrocytes, the MRC of OA chondrocytes showed that the activity of complexes I, II, and III and ΔΨm were significantly decreased. Inhibition of MRC can lead to insufficient electron transport, causing a decrease in ATP production. Mitochondrial damage not only reduces the efficiency of bioenergy production, but also increases the ROS production. Antioxidant defense system cannot eliminate excessive ROS and lead to oxidative stress. Then, oxidative stress interferes with cell regulation mechanism and further causes cell apoptosis. Excessive mtROS also increases the risk of mtDNA mutations and ATP synthesis disorders, which deteriorating mitochondrial dysfunction. At the same time, mitochondrial dysfunction disrupts Ca²⁺ homeostasis. Excessive accumulation of Ca²⁺ leads to the opening of mitochondrial PTP and the damage of mitochondrial membrane structure. The entry of H₂O molecules into the mitochondria leads to an increase in mitochondrial mass, which ultimately results in the swelling and the degradation of mitochondria. In damaged mitochondria, pro-apoptotic cytokines such as Cyto c escape from the mitochondrial intermembrane space via membrane pore proteins and bind to cytoplasmic scaffolding protein Apaf-1 to activate protease 9 and 3. Pro-apoptotic proteins induce the occurrence of the mitochondrial-mediated apoptosis pathway. Finally, chondrocyte apoptosis promotes the occurrence of OA. OA = osteoarthritis; JNK = c-Jun N-terminal kinase; PI-3K/Akt = phosphatidylinositol-3-kinase-protein kinase B; NF-κB = nuclear factor-κB; MAPK = mitogen-activated protein kinase; Bcl-2 = B-cell leukemia/lymphoma-2; Bax = Bcl-2-associated X protein; Bim = Bcl-2 interacting mediator of cell death; MRC = mitochondrial respiratory chain; ΔΨm = mitochondrial membrane potential; ATP = adenosine triphosphate; ROS = reactive oxygen species; mtROS = mitochondrial reactive oxygen species; mtDNA = mitochondrial deoxyribonucleic acid; PTP = permeability transition pores; Cyto c = cytochrome c; Apaf-1 = apoptotic protease activating factor-1; AIF = apoptosis-inducing factor; Smac = second mitochondrial-derived activator of caspases; MMPs = matrix metalloproteinases.

Figure 4.

Schematic diagram of mitochondrial function in RA. In RA, the microvascular disorders of synovial tissue cause hypoxia. Hypoxia induces mitochondrial dysfunction that promotes the release of ROS. The accumulation of ROS promotes the occurrence of chondrocyte apoptosis. At the same time, the aggregation of pro-inflammatory mediators and inflammatory cells induces the inflammatory response of synovial cells. These inflammatory mediators released by mitochondrial dysfunction stimulate normal cells to cause mitochondrial damage, forming a vicious cycle. Abnormal mitochondrial structure and function also inhibit the apoptosis of synoviocytes and promote cells proliferation. RA = rheumatoid arthritis; ROS = reactive oxygen species; TNF-α = tumor necrosis factor-α; IL = interleukin; Cyto c = cytochrome c; AIF = apoptosis-inducing factor; Smac = second mitochondrial-derived activator of caspases; ATP = adenosine triphosphate; PTP = permeability transition pores; MLS = macrophage-like synoviocytes; FLS = fibroblast-like synoviocytes.