Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging

Area of Science:

• Mitochondrial biology
• Skeletal biology
• Metabolic pathways

Background:

• Mitochondrial respiratory chain (mtRC) dysfunction causes cartilage degeneration and impaired skeletal growth in mitochondrial diseases.
• The metabolic adaptations contributing to this phenotype are not well understood.

Purpose of the Study:

• To investigate the role of metabolic adaptations, specifically the reductive TCA cycle and mTORC1 signaling, in chondrocyte response to mtRC dysfunction.
• To understand how these adaptations contribute to skeletal growth defects and cartilage degeneration.

Main Methods:

• Utilized a mouse model with impaired mtRC in cartilage.
• Analyzed the activation of reductive/reverse TCA cycle segments and mechanistic target of rapamycin complex 1 (mTORC1) signaling.
• Investigated the impact of targeting reductive metabolism on chondrocyte survival and extracellular matrix secretion.

Main Results:

• Impaired mtRC in chondrocytes activates the reductive TCA cycle to support biosynthesis via mTORC1.
• Chronic mTORC1 hyperactivation suppresses autophagy and disrupts extracellular matrix secretion, leading to chondrocyte death.
• Targeting reductive metabolism ameliorates these detrimental effects.

Conclusions:

• Metabolic adaptations, including reductive TCA cycle activation and mTORC1 signaling, are crucial for chondrocytes facing mtRC dysfunction.
• While initially compensatory, sustained activation of these pathways leads to cartilage degeneration and skeletal aging.
• Targeting nutrient signaling pathways offers a potential therapeutic strategy for skeletal complications in mitochondrial diseases.