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Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control

ABSTRACT: The injury of type 2 alveolar epithelial cells (AEC2s) is the core of the pathological processes responsible for idiopathic pulmonary fibrosis (IPF). AEC2s from IPF patients have been shown to exhibit mitochondrial dysfunction. However, the mechanisms that regulate AEC2 mitochondrial homeostasis remain poorly understood. Here, we report a pivotal role of G protein-coupled receptor class C group 5 member A (GPRC5A) in mitochondrial quality control in AEC2s through promoting mitochondrial secretion in extracellular vesicles (EVs). Through analyzing exon sequencing data from clinical cohort studies, we found that GPRC5A variants could be involved in IPF pathogenesis. In accordance with clinical data, mice lacking GPRC5A in AEC2s aggravates bleomycin-induced pulmonary fibrosis. We further demonstrate that GPRC5A deficiency in AEC2s reduces secretion of mitochondria in EVs and disrupts mitochondrial functions both in vitro and in vivo. Mechanistically, we determine that the GPRC5A-MIRO2 pathway facilitates the transfer of mitochondrial fragments into late endosomes. Collectively, our findings provide evidence of the shedding of mitochondrial components dependent on GPRC5A as a pathway of mitochondrial quality control in AEC2s, which is crucial in the maintenance of epithelial physiological activities and lung tissue homeostasis.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lung

SUBMITTER: YUE HAN

LAB HEAD: Yue Han

PROVIDER: PXD065676 | Pride | 2025-11-15

REPOSITORIES: Pride

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			Action	DRS
	MGPRC5A.raw	Raw
	MOCK.raw	Raw
	Multiconsensus-from-2-Reports.txt	Txt
	checksum.txt	Txt

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