Potential role of natural compounds modulating bone formation by mitochondrial oxidative phosphorylation
image: Osteoblasts derived from MSCs are cells required for bone formation. Oxidative phosphorylation produces a lot of ATP and other products including NAD+ and ROS. These factors play important roles in the regulation of osteogenesis through different mechanisms, such as Wnt/β-catenin signaling. Natural compounds including resveratrol and others modulate osteogenesis by regulating oxidative phosphorylation in mitochondria. ATP, adenosine triphosphate; LRP, low-density lipoprotein receptor-related protein; MSC, mesenchymal stem cell; NAD+, nicotinamide adenine dinucleotide; ROS, reactive oxygen species; RUNX2, runt-related transcription factor 2; TCA, tricarboxylic acid cycle; Wnt, Wingless-type MMTV integration site family.
Credit: Liangliang Xu, Meilin Du
Mitochondria are central to cellular energy production through the process of oxidative phosphorylation, crucial for generating adenosine triphosphate (ATP). Besides their role in energy metabolism, mitochondria are involved in regulating other cellular processes such as reactive oxygen species (ROS) production and apoptosis. These functions are vital for maintaining bone homeostasis. Recent research has focused on how mitochondria regulate bone homeostasis and the potential of natural compounds to modulate mitochondrial functions and, consequently, bone formation. This review highlights recent findings on mitochondrial oxidative phosphorylation's role in bone formation and the effects of natural compounds like resveratrol, quercetin, and curcumin on this process, revealing their therapeutic implications for bone disorders.
Mitochondrial Oxidative Phosphorylation and Bone Formation
Oxidative phosphorylation involves the transfer of electrons from reduced nicotinamide adenine dinucleotide (NADH) and reduced flavine adenine dinucleotide (FADH2) to oxygen through a series of electron carriers, resulting in ATP production. This process is crucial for energy metabolism in cells. Defects in oxidative phosphorylation can disrupt mitochondrial energy metabolism, impacting various cellular functions and leading to diseases.
Recent studies indicate that oxidative phosphorylation plays a critical role in osteogenesis, the process by which new bone is formed. During osteogenic induction, cells shift their energy metabolism from glycolysis to mitochondrial oxidative phosphorylation, increasing respiratory enzymes, mitochondrial DNA copy number, oxygen consumption, and intracellular ATP content. Bone morphogenetic protein 2 (BMP2) has been shown to trigger metabolic adaptations in mesenchymal stem cells (MSCs), characterized by successive activation of glycolysis and oxidative phosphorylation. NAD+ levels and the NAD+/NADH ratio are crucial for mitochondrial function, linking cellular metabolism to transcriptional events and signaling pathways. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, promotes osteogenesis and reduces adipogenesis in MSCs, protecting bone from aging and damage.
Reactive Oxygen Species and Bone Formation
ROS are byproducts of oxidative phosphorylation. While low levels of ROS function as signaling molecules necessary for cell viability and differentiation, excessive ROS can cause oxidative stress and cell death. Dysfunctional mitochondria and senescent cells produce higher ROS levels, implicating ROS in various cellular damages, including the suppression of osteogenic differentiation and increased adipogenesis.
Antioxidant agents such as vitamin K, glutathione, and N-acetyl cysteine can inhibit the destructive effects of ROS. Cells have intrinsic mechanisms to balance oxidative phosphorylation and antioxidant enzyme activity, preventing excess ROS production during osteogenesis.
Natural Compounds and Mitochondrial Function
Several natural compounds have shown potential in modulating mitochondrial function and promoting bone formation.
- Resveratrol: This polyphenolic compound, found in grapes and berries, is known for its antioxidant properties. It has been shown to induce the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis, enhancing bone formation and combating bone diseases.
- Quercetin: Found in many fruits and vegetables, quercetin also exhibits antioxidant properties. It modulates mitochondrial function, potentially aiding in bone formation by regulating oxidative phosphorylation and reducing ROS levels.
- Curcumin: A phenolic compound from Curcuma longa, curcumin acts as a protonophoric uncoupler, reducing ATP biosynthesis in mitochondria. Despite contradictory evidence regarding its effects on osteogenesis, some studies suggest curcumin preserves mitochondrial function and ameliorates oxidative stress-induced apoptosis in osteoblasts.
Discussion
The regulation of oxidative phosphorylation by natural compounds presents a promising avenue for enhancing bone formation and treating bone disorders. However, the effects of these compounds can vary based on different cell models and conditions, necessitating further research to clarify their roles and optimize their use.
Future studies should focus on identifying new natural compounds that modulate mitochondrial function and exploring their mechanisms of action. Additionally, understanding the interplay between oxidative phosphorylation and other metabolic pathways in bone formation will provide a more comprehensive approach to developing effective treatments for bone disorders.
Conclusions
Mitochondrial oxidative phosphorylation is integral to bone formation, with natural compounds like resveratrol, quercetin, and curcumin showing potential in modulating this process. These compounds' therapeutic implications for bone disorders highlight the need for further research to fully harness their benefits and address any inconsistencies in their effects.
Full text:
https://www.xiahepublishing.com/2835-6357/FIM-2023-00046
The study was recently published in the Future Integrative Medicine.
Future Integrative Medicine (FIM) publishes both basic and clinical research, including but not limited to randomized controlled trials, intervention studies, cohort studies, observational studies, qualitative and mixed method studies, animal studies, and systematic reviews.
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