Mitochondrial ROS Drive Adipogenic Differentiation in Osteoporosis by Suppressing Protein Synthesis

Authors:

Yueli Zhou, Hongling Wu, Xuzheng Liu, Yuqiang Wang, Chunxiao Jin, Jiqi Zheng, Yanyang Wei, Fangfang Song, Cui Huang

Keywords:

adipogenic differentiation; mitochondrial ROS; osteoporosis; SREBP1

Abstract:

Osteoporosis (OP) is a debilitating metabolic bone disorder, leading to disability in approximately 3.5 million individuals worldwide annually. While the bone-fat imbalance represents a hallmark of OP pathogenesis, the upstream molecular triggers remain elusive. Here, we identify mitochondrial reactive oxygen species (mtROS) as a pivotal regulator of adipogenesis in OP. We demonstrated significant accumulation of mtROS coinciding with lipid droplet formation in BMSCs isolated from osteoporotic mice. To delineate the mechanistic interplay between mtROS and lipid droplet homeostasis, four mtROS modulating cell models were developed: pharmacological induction of mtROS through Antimycin A and MitoParaquat (MitoPQ), genetic suppression of leucine-tRNA-synthetase-2 (Lars2) via siRNA-mediated knockdown, and mitochondrial antioxidant intervention using Mito-TEMPO. Complementary to these targeted approaches, we implemented intracellular ROS modulation through hydrogen peroxide (H₂O₂)-induced ROS elevation and glutathione (GSH) -mediated oxidative stress reduction to assess. Mechanistically, excessive mtROS disrupted global protein synthesis by suppressing phosphorylation of ribosomal protein S6, thereby restricting amino acid flux into de novo polypeptide assembly. A surplus of amino acids elevated the production of their key catabolic product, ammonia. This ammonia accumulation subsequently provoked activation of the lipogenic transcription factor SREBP1, thereby promoting lipogenesis. In ovariectomized mice, pharmacological mtROS scavenging with Mito-TEMPO not only reduced marrow adiposity but also significantly improved trabecular bone as quantified by Micro-CT and dynamic histomorphometry. Our findings demonstrated a novel mtROS-protein synthesis-ammonia-SREBP1 axis that drives pathogenic adipogenesis in osteoporosis, underscoring the translational potential of mtROS scavenging for osteoporosis treatment.

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