MICU1-dependent mitochondrial calcium uptake regulates lung alveolar type 2 cell plasticity and lung regeneration.

Mir Ali,John W Elrod,Xiaoying Zhang,Ying Tian,Ryan Lacanna,Dhanendra Tomar

doi:10.1172/jci.insight.154447

Abstract

Lung alveolar type 2 (AT2) cells are progenitors for alveolar type 1 (AT1) cells. Although many factors regulate AT2 cell plasticity, the role of mitochondrial calcium (mCa2+) uptake in controlling AT2 cells remains unclear. We previously identified that the miR-302 family supports lung epithelial progenitor cell proliferation and less differentiated phenotypes during development. Here, we report that a sustained elevation of miR-302 in adult AT2 cells decreases AT2-to-AT1 cell differentiation during the Streptococcus pneumoniae–induced lung injury repair. We identified that miR-302 targets and represses the expression of mitochondrial Ca2+ uptake 1 (MICU1), which regulates mCa2+ uptake through the mCa2+ uniporter channel by acting as a gatekeeper at low cytosolic Ca2+ levels. Our results reveal a marked increase in MICU1 protein expression and decreased mCa2+ uptake during AT2-to-AT1 cell differentiation in the adult lung. Deletion of Micu1 in AT2 cells reduces AT2-to-AT1 cell differentiation during steady-state tissue maintenance and alveolar epithelial regeneration after bacterial pneumonia. These studies indicate that mCa2+ uptake is extensively modulated during AT2-to-AT1 cell differentiation and that MICU1-dependent mCa2+ uniporter channel gating is a prominent mechanism modulating AT2-to-AT1 cell differentiation.

Highlights

The mammalian lung alveolar epithelium comprises two main cell types: gas-exchanging squamous alveolar type 1 (AT1) cells and cuboidal alveolar type 2 (AT2) cells
Sustained elevation of miR-302 in AT2 cells decreases the differentiation of AT2 cells into AT1 cells. miR-302 is expressed in embryonic lungs but declines rapidly after embryonic day 14.5 and is undetectable in the postnatal lung [29]
We examined the differentiation of AT2 cells into AT1 cells by quantifying the percentage of GFP+ alveolar surface area covered by AT2-derived AT1 cells (GFP+/T1α+) on sectioned lungs

Summary

Introduction

The mammalian lung alveolar epithelium comprises two main cell types: gas-exchanging squamous alveolar type 1 (AT1) cells and cuboidal alveolar type 2 (AT2) cells. Models of lung damage in mice have demonstrated that AT2 cells increase their proliferation and differentiation into AT1 cells in response to injury. These AT2 cell activities are vital to alveolar epithelial repair and regeneration [1, 2]. Because AT2 cells are the key player of alveolar epithelial repair and regeneration after injury, it is important to define the molecular mechanisms that mediate their function. Mitochondrial calcium (mCa2+) regulates bioenergetics by activating dehydrogenases in the Krebs cycle and modulating components of the electron transport chain [8,9,10]. The role of mCa2+ uptake in AT2 cell function remains elusive, in part because the molecular identity of the mtCU has been only recently determined [7, 13,14,15,16,17]

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Results

Conclusion