Scientists at Northwestern University, Chicago, USA, and Dongguk University, Korea, have discovered in collaboration that mitochondria regulate critical cellular signaling for the development of lung epithelial cells, cells that perform the exchange of oxygen and carbon dioxide to meet the metabolic demand of our body. The study appears in the journal Nature in August 2023. 

The lung is susceptible to injury, yet has remarkable capacity to repair and regenerate. It is largely unknown which metabolic and cellular signaling pathways control the proliferation and differentiation of the lung epithelial stem/progenitor cells during lung development and repair after injury, and we have limited knowledge of how to therapeutically manipulate the reparative processes. Work led by Prof. SeungHye Han, in collaboration with Prof. Minho Lee, identified a novel mechanism for the regulation of alveolar epithelial cell fate during lung development. 

In the current study, the investigators used genetic knockout techniques to delete a mitochondrial electron transport chain complex I subunit, called Ndufs2, in lung epithelial cells in gestational mice. Next, using single-cell RNA sequencing, the team observed that mitochondrial stress activates the integrated stress response (ISR), a cellular function that's activated to cope with metabolic stress or proteotoxicity, or the accumulation of misfolded proteins.

When mitochondria malfunctioned, the ISR increased activation and inhibited the differentiation of alveolar epithelial cells in post-natal mice, ultimately leading to respiratory failure in the mice. Interestingly, the team also noted that the cells without functional mitochondria did not die, but instead remained in a state of stalled cell differentiation, which is commonly observed in a variety of lung diseases.

Prof. Lee said that “New technology like single-cell RNA sequencing analysis allows us to dissect biological function at a single-cell level and identify molecular signaling pathways considering heterogenous cell populations. 

"We're now examining whether mitochondria-dependent ISR signaling is disrupted and inhibits alveolar epithelial repair in diseased lungs including pulmonary fibrosis or prolonged viral pneumonia. If this is true, it could open new avenues for treatments that target mitochondria-dependent ISR signaling in diseases involving lung damage and repair," Prof. Han said.

Lung histology images that display aberrant alveolar structures in mice without functional mitochondria. Credit: SeungHye Han, MD, MPH

[Reference] Han, S., Lee, M., Shin, Y. et al. Mitochondrial integrated stress response controls lung epithelial cell fate. Nature (2023). https://doi.org/10.1038/s41586-023-06423-8   

[Main Author] Seunghye Han(Northwestern University), Minho Lee(Dongguk University)

* Contact : Prof. SeungHye Han (shan@northwestern.edu)