HIF1α-dependent mitophagy facilitates cardiomyoblast differentiation.

IF 4.1 Q2 CELL BIOLOGY Cell Stress Pub Date : 2020-03-04 DOI:10.15698/cst2020.05.220
Jin-Feng Zhao, Catherine E Rodger, George F G Allen, Simone Weidlich, Ian G Ganley
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Abstract

Mitophagy is thought to play a key role in eliminating damaged mitochondria, with diseases such as cancer and neurodegeneration exhibiting defects in this process. Mitophagy is also involved in cell differentiation and maturation, potentially through modulating mitochondrial metabolic reprogramming. Here we examined mitophagy that is induced upon iron chelation and found that the transcriptional activity of HIF1α, in part through upregulation of BNIP3 and NIX, is an essential mediator of this pathway in SH-SY5Y cells. In contrast, HIF1α is dispensable for mitophagy occurring upon mitochondrial depolarisation. To examine the role of this pathway in a metabolic reprogramming and differentiation context, we utilised the H9c2 cell line model of cardiomyocyte maturation. During differentiation of these cardiomyoblasts, mitophagy increased and required HIF1α-dependent upregulation of NIX. Though HIF1α was essential for expression of key cardiomyocyte markers, mitophagy was not directly required. However, enhancing mitophagy through NIX overexpression, accelerated marker gene expression. Taken together, our findings provide a molecular link between mitophagy signalling and cardiomyocyte differentiation and suggest that although mitophagy may not be essential per se, it plays a critical role in maintaining mitochondrial integrity during this energy demanding process.

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依赖于 HIF1α 的有丝分裂促进了心肌母细胞的分化。
人们认为,线粒体吞噬在消除受损线粒体方面发挥着关键作用,癌症和神经变性等疾病都表现出这一过程的缺陷。有丝分裂还参与了细胞的分化和成熟,这可能是通过调节线粒体代谢重编程实现的。在这里,我们研究了铁螯合诱导的有丝分裂,发现在 SH-SY5Y 细胞中,HIF1α 的转录活性(部分通过 BNIP3 和 NIX 的上调)是这一途径的重要介质。相反,HIF1α对于线粒体去极化时发生的有丝分裂是不可或缺的。为了研究这一途径在代谢重编程和分化过程中的作用,我们利用了心肌细胞成熟的 H9c2 细胞系模型。在这些心肌母细胞的分化过程中,有丝分裂增加,需要 HIF1α 依赖性上调 NIX。虽然 HIF1α 对关键心肌细胞标志物的表达至关重要,但有丝分裂并不是直接必需的。然而,通过过量表达 NIX 来增强有丝分裂可加速标记基因的表达。综上所述,我们的研究结果提供了有丝分裂信号与心肌细胞分化之间的分子联系,并表明尽管有丝分裂本身可能不是必需的,但它在这一需要能量的过程中对维持线粒体完整性起着关键作用。
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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