Haploinsufficiency for Stard7 Is Associated with Enhanced Allergic Responses in Lung and Skin

Yang, Li; Lewkowich, Ian P.; Apsley, Karen S.; Fritz, Jill M.; Wills‐Karp, Marsha; Weaver, Timothy E.

doi:10.4049/jimmunol.1500231

Cited by 18 publications

(18 citation statements)

References 42 publications

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“…These results suggest that Stard7 is an important component of a novel protective pathway that modulates allergic responses at critical mucosal-environmental interfaces. In support of this hypothesis, Stard7 expression was decreased by 50% in the nasal epithelia of human patients with an acute asthma exacerbation1415. Whether the pathogenesis of allergic airway disease is causally linked to mitochondrial dysfunction in Stard7-deficient cells remains unknown.…”

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confidence: 89%

The Phosphatidylcholine Transfer Protein Stard7 is Required for Mitochondrial and Epithelial Cell Homeostasis

Yang

Luo

et al. 2017

Sci Rep

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Mitochondria synthesize select phospholipids but lack the machinery for synthesis of the most abundant mitochondrial phospholipid, phosphatidylcholine (PC). Although the phospholipid transfer protein Stard7 promotes uptake of PC by mitochondria, the importance of this pathway for mitochondrial and cellular homeostasis represents a significant knowledge gap. Haploinsufficiency for Stard7 is associated with significant exacerbation of allergic airway disease in mice, including an increase in epithelial barrier permeability. To test the hypothesis that Stard7 deficiency leads to altered barrier structure/function downstream of mitochondrial dysfunction, Stard7 expression was knocked down in a bronchiolar epithelial cell line (BEAS-2B) and specifically deleted in lung epithelial cells of mice (Stard7epi∆/∆). Stard7 deficiency was associated with altered mitochondrial size and membrane organization both in vitro and in vivo. Altered mitochondrial structure was accompanied by disruption of mitochondrial homeostasis, including decreased aerobic respiration, increased oxidant stress, and mitochondrial DNA damage that, in turn, was linked to altered barrier integrity and function. Both mitochondrial and barrier defects were largely corrected by targeting Stard7 to mitochondria or treating epithelial cells with a mitochondrial-targeted antioxidant. These studies suggest that Stard7-mediated transfer of PC is crucial for mitochondrial homeostasis and that mitochondrial dysfunction contributes to altered barrier permeability in Stard7-deficient mice.

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confidence: 89%

The Phosphatidylcholine Transfer Protein Stard7 is Required for Mitochondrial and Epithelial Cell Homeostasis

Yang

Luo

et al. 2017

Sci Rep

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“…Yang et al (27) recently generated mice in which one allele of the StarD7 locus was globally disrupted (StarD7 ϩ/Ϫ mice) (28). Most StarD7 Ϫ/Ϫ mice died between embryonic days E10 and E11.…”

Section: Contmentioning

confidence: 99%

StarD7 Protein Deficiency Adversely Affects the Phosphatidylcholine Composition, Respiratory Activity, and Cristae Structure of Mitochondria

Horibata

Ando

Zhang

et al. 2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerPhosphatidylcholine (PC) is a major phospholipid of mitochondria, comprising 40 -50% of both the outer and the inner membranes. However, PC must be imported from its production organelles because mitochondria lack the enzymes essential for PC biosynthesis. In a previous study, we found that StarD7 mediates the intracellular transfer of PC to mitochondria. Therefore, in this study, we analyzed the contribution of StarD7 to the maintenance of mitochondrial phospholipid content and function using siRNA-mediated knockdown and knock-out (KO) of the StarD7 gene in HEPA-1 cells. Real time analysis of respiratory activity demonstrated that the oxygen consumption rate and activity of mitochondrial complexes were impaired in StarD7-KD cells. To confirm these results, we established StarD7-KO HEPA-1 cells by double nicking using CRISPR/Cas9n. As expected, StarD7-KD and -KO cells showed a significant reduction in mitochondrial PC content. The ATP level and growth rate of KO cells were notably lower compared with wild-type cells when cultured in glucose-free galactosecontaining medium to force cells to rely on mitochondrial ATP production. In KO cells, the level of the MTCO1 protein, a primary subunit of complex IV, was reduced without a concomitant decrease in its mRNA, but the level was restored when StarD7-I was overexpressed. StarD7-KO cells showed impaired formation of the mitochondrial supercomplexes and exhibited a disorganized cristae structure, with no changes in optic atrophy 1 protein. These findings indicate that StarD7 plays important roles in maintaining the proper composition of mitochondrial phospholipids as well as mitochondrial function and morphogenesis.

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“…STARD7 is a member of the START (StAR‐related lipid transfer) domain‐containing family of LTPs (Alpy & Tomasetto, ) and was shown to specifically transfer phosphatidylcholine (PC) between liposomes in vitro (Horibata & Sugimoto, ; Horibata et al , ). Mutations in STARD7 have been associated with acute asthma, and heterozygous Stard7 +/− mice show increased permeability of the lung epithelium (Yang et al , , ). The loss of STARD7 in mouse hepatoma cells impairs the accumulation of PC in mitochondrial membranes as well as mitochondrial ATP production and cristae morphogenesis (Horibata et al , ).…”

Section: Introductionmentioning

confidence: 99%

PARL partitions the lipid transfer protein STARD7 between the cytosol and mitochondria

et al. 2018

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Intramembrane-cleaving peptidases of the rhomboid family regulate diverse cellular processes that are critical for development and cell survival. The function of the rhomboid protease PARL in the mitochondrial inner membrane has been linked to mitophagy and apoptosis, but other regulatory functions are likely to exist. Here, we identify the START domain-containing protein STARD7 as an intramitochondrial lipid transfer protein for phosphatidylcholine. We demonstrate that PARL-mediated cleavage during mitochondrial import partitions STARD7 to the cytosol and the mitochondrial intermembrane space. Negatively charged amino acids in STARD7 serve as a sorting signal allowing mitochondrial release of mature STARD7 upon cleavage by PARL On the other hand, membrane insertion of STARD7 mediated by the TIM23 complex promotes mitochondrial localization of mature STARD7. Mitochondrial STARD7 is necessary and sufficient for the accumulation of phosphatidylcholine in the inner membrane and for the maintenance of respiration and cristae morphogenesis. Thus, PARL preserves mitochondrial membrane homeostasis via STARD7 processing and is emerging as a critical regulator of protein localization between mitochondria and the cytosol.

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Haploinsufficiency for Stard7 Is Associated with Enhanced Allergic Responses in Lung and Skin

Cited by 18 publications

References 42 publications

The Phosphatidylcholine Transfer Protein Stard7 is Required for Mitochondrial and Epithelial Cell Homeostasis

The Phosphatidylcholine Transfer Protein Stard7 is Required for Mitochondrial and Epithelial Cell Homeostasis

StarD7 Protein Deficiency Adversely Affects the Phosphatidylcholine Composition, Respiratory Activity, and Cristae Structure of Mitochondria

PARL partitions the lipid transfer protein STARD7 between the cytosol and mitochondria

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