TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response

Mitochondrial damage is involved in many pathophysiological processes, such as tumor development, metabolism, and neurodegenerative diseases. The mitochondrial unfolded protein response (mtUPR) is the first stress-protective response initiated by mitochondrial damage, and it repairs or clears misfolded proteins to alleviate this damage. Studies have confirmed that the sirtuin family is essential for the mitochondrial stress response; in particular, SIRT1, SIRT3, and SIRT7 participate in the mtUPR in different axes. This article summarizes the associations of sirtuins with the mtUPR as well as specific molecular targets related to the mtUPR in different disease models, which will provide new inspiration for studies on mitochondrial stress, mitochondrial function protection, and mitochondria-related diseases, such as neurodegenerative diseases.

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FUS interacts with ATP synthase beta subunit and induces mitochondrial unfolded protein response in cellular and animal models

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1806655115 ◽

2018 ◽

Vol 115 (41) ◽

pp. E9678-E9686 ◽

Cited By ~ 25

Author(s):

Jianwen Deng ◽

Peng Wang ◽

Xiaoping Chen ◽

Haipeng Cheng ◽

Jianghong Liu ◽

...

Keyword(s):

Unfolded Protein Response ◽

Atp Synthase ◽

Molecular Mechanisms ◽

Atp Synthesis ◽

Mitochondrial Damage ◽

Early Event ◽

Unfolded Protein ◽

Mitochondrial Atp Synthase ◽

Protein Response ◽

Mitochondrial Unfolded Protein Response

FUS (fused in sarcoma) proteinopathy is a group of neurodegenerative diseases characterized by the formation of inclusion bodies containing the FUS protein, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Previous studies show that mitochondrial damage is an important aspect of FUS proteinopathy. However, the molecular mechanisms by which FUS induces mitochondrial damage remain to be elucidated. Our biochemical and genetic experiments demonstrate that FUS interacts with the catalytic subunit of mitochondrial ATP synthase (ATP5B), disrupts the formation of ATP synthase complexes, and inhibits mitochondrial ATP synthesis. FUS expression activates the mitochondrial unfolded protein response (UPRmt). Importantly, down-regulating expression of ATP5B or UPRmt genes in FUS transgenic flies ameliorates neurodegenerative phenotypes. Our data show that mitochondrial impairment is a critical early event in FUS proteinopathy, and provide insights into the pathogenic mechanism of FUS-induced neurodegeneration.

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The mitochondrial unfolded protein response and its diverse roles in cellular stress

The International Journal of Biochemistry & Cell Biology ◽

10.1016/j.biocel.2021.105934 ◽

2021 ◽

Vol 133 ◽

pp. 105934

Author(s):

Ioannis Smyrnias

Keyword(s):

Unfolded Protein Response ◽

Cellular Stress ◽

Unfolded Protein ◽

Protein Response ◽

Mitochondrial Unfolded Protein Response

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Copper exposure induces mitochondrial dynamic disorder and oxidative stress via mitochondrial unfolded protein response in pig fundic gland

Ecotoxicology and Environmental Safety ◽

10.1016/j.ecoenv.2021.112587 ◽

2021 ◽

Vol 223 ◽

pp. 112587

Author(s):

Haihua Huo ◽

Shuzhou Wang ◽

Yuman Bai ◽

Jianzhao Liao ◽

Xinrun Li ◽

...

Keyword(s):

Oxidative Stress ◽

Unfolded Protein Response ◽

Fundic Gland ◽

Copper Exposure ◽

Mitochondrial Dynamic ◽

Dynamic Disorder ◽

Unfolded Protein ◽

Protein Response ◽

Mitochondrial Unfolded Protein Response ◽

And Oxidative Stress

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At the heart of mitochondrial quality control: many roads to the top

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03772-3 ◽

2021 ◽

Author(s):

Roberta A. Gottlieb ◽

Honit Piplani ◽

Jon Sin ◽

Savannah Sawaged ◽

Syed M. Hamid ◽

...

Keyword(s):

Quality Control ◽

Unfolded Protein Response ◽

Mitochondrial Biogenesis ◽

Mitochondrial Dynamics ◽

Mitochondrial Quality Control ◽

Unfolded Protein ◽

Selective Elimination ◽

Protein Response ◽

Mitochondrial Unfolded Protein Response

AbstractMitochondrial quality control depends upon selective elimination of damaged mitochondria, replacement by mitochondrial biogenesis, redistribution of mitochondrial components across the network by fusion, and segregation of damaged mitochondria by fission prior to mitophagy. In this review, we focus on mitochondrial dynamics (fusion/fission), mitophagy, and other mechanisms supporting mitochondrial quality control including maintenance of mtDNA and the mitochondrial unfolded protein response, particularly in the context of the heart.

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