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Stabilization of HIF-1? alleviates osteoarthritis via enhancing mitophagy.

ABSTRACT: Mitochondrial dysfunction leads to osteoarthritis (OA) and disc degeneration. Hypoxia inducible factor-1? (HIF-1?) mediated mitophagy has a protective role in several diseases. However, the underlying mechanism of HIF-1? mediated mitophagy in OA remains largely unknown. This current study was performed to determine the effect of HIF-1? mediated mitophagy on OA. Therefore, X-ray and tissue staining including HE staining, safranin O-fast green (S-O) and Alcian Blue were used to assess imageology and histomorphology differences of mouse knee joint. Transcriptional analysis was used to find the possible targets in osteoarthritis. Western blot analysis, RT-qPCR and immunofluorescence staining were used to detect the changes in gene and protein levels in the vitro experiment. The expression of HIF-1? was increased in human and mouse OA cartilage. HIF-1? knockdown by siRNA further impair the hypoxia-induced mitochondrial dysfunction; In contrast, HIF-1? mediated protective role was reinforced by prolylhydroxylase (PHD) inhibitor dimethyloxalylglycine (DMOG). In addition, HIF-1? stabilization could alleviate apoptosis and senescence via mitophagy in chondrocytes under hypoxia condition, which could also ameliorate surgery-induced cartilage degradation in mice OA model. In conclusion, HIF-1? mediated mitophagy could alleviate OA, which may serve as a promising strategy for OA treatment.

SUBMITTER: Hu S

PROVIDER: S-EPMC7316774 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Stabilization of HIF-1α alleviates osteoarthritis via enhancing mitophagy.

Hu Sunli S Zhang Chunwu C Ni Libin L Huang Chongan C Chen Dingwen D Shi Keqing K Jin Haiming H Zhang Kairui K Li Yao Y Xie Ling L Fang Mingqiao M Xiang Guangheng G Wang Xiangyang X Xiao Jian J

Cell death & disease 20200625 6

Mitochondrial dysfunction leads to osteoarthritis (OA) and disc degeneration. Hypoxia inducible factor-1α (HIF-1α) mediated mitophagy has a protective role in several diseases. However, the underlying mechanism of HIF-1α mediated mitophagy in OA remains largely unknown. This current study was performed to determine the effect of HIF-1α mediated mitophagy on OA. Therefore, X-ray and tissue staining including HE staining, safranin O-fast green (S-O) and Alcian Blue were used to assess imageology a ...[more]

PMID: 32587244

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Project description:RATIONALE:Mitochondrial dysfunction plays an important role in heart failure (HF). However, the molecular mechanisms regulating mitochondrial functions via selective mitochondrial autophagy (mitophagy) are poorly understood. OBJECTIVE:We sought to determine the role of AMPK (AMP-activated protein kinase) in selective mitophagy during HF. METHODS AND RESULTS:An isoform shift from AMPK?2 to AMPK?1 was observed in failing heart samples from HF patients and transverse aortic constriction-induced mice, accompanied by decreased mitophagy and mitochondrial function. The recombinant adeno-associated virus Serotype 9-mediated overexpression of AMPK?2 in mouse hearts prevented the development of transverse aortic constriction-induced chronic HF by increasing mitophagy and improving mitochondrial function. In contrast, AMPK?2-/- mutant mice exhibited an exacerbation of the early progression of transverse aortic constriction-induced HF via decreases in cardiac mitophagy. In isolated adult mouse cardiomyocytes, AMPK?2 overexpression mechanistically rescued the impairment of mitophagy after phenylephrine stimulation for 24 hours. Genetic knockdown of AMPK?2, but not AMPK?1, by short interfering RNA suppressed the early phase (6 hours) of phenylephrine-induced compensatory increases in mitophagy. Furthermore, AMPK?2 specifically interacted with phosphorylated PINK1 (PTEN-induced putative kinase 1) at Ser495 after phenylephrine stimulation. Subsequently, phosphorylated PINK1 recruited the E3 ubiquitin ligase, Parkin, to depolarized mitochondria, and then enhanced the role of the PINK1-Parkin-SQSTM1 (sequestosome-1) pathway involved in cardiac mitophagy. This increase in cardiac mitophagy was accompanied by the elimination of damaged mitochondria, improvement in mitochondrial function, decrease in reactive oxygen species production, and apoptosis of cardiomyocytes. Finally, Ala mutation of PINK1 at Ser495 partially suppressed AMPK?2 overexpression-induced mitophagy and improvement of mitochondrial function in phenylephrine-stimulated cardiomyocytes, whereas Asp (phosphorylation mimic) mutation promoted mitophagy after phenylephrine stimulation. CONCLUSIONS:In failing hearts, the dominant AMPK? isoform switched from AMPK?2 to AMPK?1, which accelerated HF. The results show that phosphorylation of Ser495 in PINK1 by AMPK?2 was essential for efficient mitophagy to prevent the progression of HF.

Dataset Information

Stabilization of HIF-1? alleviates osteoarthritis via enhancing mitophagy.

Publications

Stabilization of HIF-1α alleviates osteoarthritis via enhancing mitophagy.

Similar Datasets

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