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Updated: Sep 16, 2025
Author Spotlight: Decoding Mitochondrial Aging
Published on: June 30, 2023
NDP52 deficiency accelerates chondrocyte degeneration through promoting pathogenic mitochondrial ROS via reverse
Yutao Zhu1, Yaohan Xu2, Dinqi Xie1
1Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, PR China; Key Laboratory of Musculoskeletal System Degeneration, Regeneration Translational Research of Zhejiang Province, Hangzhou, PR China.
Abstract:
NDP52, a constituent of the selective autophagy receptors (SARs), was recognized for its involvement in facilitating substrate degradation via autophagic bridging. However, its autonomous function apart from autophagy remained largely unexplored. Here, we reported that NDP52 was down-regulated in degenerated chondrocytes. Besides, NDP52 deficiency promoted the extracellular matrix (ECM) degradation, inflammation, cell apoptosis and senescence via its autophagy-independent functions. The absence of NDP52 disrupted the flow of electron respiration chains and led to the production of intracellular mitochondrial reactive oxygen species (mtROS). Subsequent mechanistic investigations revealed that the downregulation of NDP52 upregulated the expression levels of mitochondrial complex Ⅰ by modulating MTIF3 expression, leading to reverse electron transport (RET) and mtROS production. Our research highlights the significance of NDP52 in facilitating chondrocyte degeneration and osteoarthritis, and provides insights into the distinctive mechanism by which autophagy receptors NDP52 induce intracellular mitochondrial ROS dysregulation via non-canonical pathways.
Insights
Nuclear dot protein 52 (NDP52) deficiency in chondrocytes promotes osteoarthritis by disrupting mitochondrial function and extracellular matrix degradation through non-autophagy pathways.
Area of Science:
- Cell Biology
- Biochemistry
- Pathology
Background:
- Nuclear dot protein 52 (NDP52) is known for its role in selective autophagy.
- Its functions independent of autophagy are not well understood.
- NDP52's role in chondrocyte degeneration and osteoarthritis requires further investigation.
Purpose of the Study:
- To investigate the autophagy-independent functions of NDP52 in chondrocytes.
- To elucidate the mechanism by which NDP52 deficiency contributes to chondrocyte degeneration and osteoarthritis.
- To explore the link between NDP52, mitochondrial function, and reactive oxygen species.
Main Methods:
- Analysis of NDP52 expression in degenerated chondrocytes.
- Assessment of extracellular matrix (ECM) degradation, inflammation, apoptosis, and senescence in NDP52-deficient chondrocytes.
- Investigation of mitochondrial electron transport chain (ETC) function and mitochondrial reactive oxygen species (mtROS) production.
- Examination of the modulation of mitochondrial complex I and MTIF3 expression.
Main Results:
- NDP52 was found to be downregulated in degenerated chondrocytes.
- NDP52 deficiency exacerbated ECM degradation, inflammation, apoptosis, and senescence via autophagy-independent pathways.
- Absence of NDP52 disrupted ETC flow, leading to increased mtROS production.
- NDP52 downregulation upregulated mitochondrial complex I via MTIF3, causing reverse electron transport (RET) and mtROS generation.
Conclusions:
- NDP52 plays a critical role in maintaining chondrocyte homeostasis and preventing osteoarthritis.
- NDP52 deficiency promotes chondrocyte degeneration through non-canonical pathways involving mitochondrial dysfunction and mtROS production.
- Targeting NDP52 may offer a novel therapeutic strategy for osteoarthritis.
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