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

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.