2. Academic Validation
  3. hnRNPH1 maintains mitochondrial homeostasis by establishing NRF1/DRP1 retrograde signaling under mitochondrial stress

hnRNPH1 maintains mitochondrial homeostasis by establishing NRF1/DRP1 retrograde signaling under mitochondrial stress

  • Cell Death Differ. 2024 Jun 19. doi: 10.1038/s41418-024-01331-4.
Lili Zhao 1,  Xiaotian Zou 1,  Jiaqiang Deng 1,  Bin Sun 1,  Yan Li 1,  Li Zhao 1,  Hong Zhao 1,  Xiao Zhang 1,  Xieyong Yuan 1,  Xudong Zhao 2,  Fangdong Zou 3
Affiliations

Affiliations

  • 1 Department of Targeting Therapy and Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China.
  • 2 Department of Targeting Therapy and Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China. zhaoxudong@wchscu.cn.
  • 3 Department of Targeting Therapy and Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China. fundzou@scu.edu.cn.
PMID: 38898233 DOI: 10.1038/s41418-024-01331-4
Abstract

Mitochondrial homeostasis is coordinated through communication between mitochondria and the nucleus. In response to stress, mitochondria generate retrograde signals to protect against their dysfunction by activating the expression of nuclear genes involved in metabolic reprogramming. However, the mediators associated with mitochondria-to-nucleus communication pathways remain to be clarified. Here, we identified that hnRNPH1 functions as a pivotal mediator of mitochondrial retrograde signaling to maintain mitochondrial homeostasis. hnRNPH1 accumulates in the nucleus following mitochondrial stress in a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. Accordingly, hnRNPH1 interacts with the transcription factor NRF1 and binds to the DRP1 promoter, enhancing the transcription of DRP1. Furthermore, in the cytoplasm, hnRNPH1 directly interacts with DRP1 and enhances DRP1 Ser616 phosphorylation, thereby increasing DRP1 translocation to mitochondrial outer membranes and triggering mitochondrial fission. Collectively, our findings reveal a novel role for hnRNPH1 in the mitochondrial-nuclear communication pathway to maintain mitochondrial homeostasis under stress and suggest that it may be a potential target for mitochondrial dysfunction diseases.

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