MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity

Kusminski, Christine M.; Holland, William L.; Sun, Kai; Park, Jiyoung; Spurgin, Stephen B.; Lin, Ying; Askew, G. Roger; Simcox, Judith; McClain, Donald A.; Cai, Li; Scherer, Philipp E.

doi:10.1038/nm.2899

Cited by 404 publications

(460 citation statements)

References 57 publications

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“…Unlike other tissues or organs, adipose tissue seems to have a vast ability to expand, as seen in many striking gain-and lossof-function mouse models (45)(46)(47)(48), as well as in morbidly obese humans (49,50). The mechanism controlling the size of fat mass is not well understood.…”

Section: Discussionmentioning

confidence: 99%

C1q/Tumor Necrosis Factor-related Protein 11 (CTRP11), a Novel Adipose Stroma-derived Regulator of Adipogenesis

Wei

Seldin

Natarajan

et al. 2013

Journal of Biological Chemistry

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Background: CTRP11 is a novel member of the C1q family with poorly defined function. Results: CTRP11 inhibits 3T3-L1 adipocyte differentiation by inhibiting mitotic clonal expansion and adipogenic gene expression. Conclusion: Adipose stroma-derived CTRP11 is a regulator of adipogenesis. Significance: CTRP11 mediates potential paracrine cross-talk between adipocytes and cells of the stromal vascular compartment.

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Section: Discussionmentioning

confidence: 99%

C1q/Tumor Necrosis Factor-related Protein 11 (CTRP11), a Novel Adipose Stroma-derived Regulator of Adipogenesis

Wei

Seldin

Natarajan

et al. 2013

Journal of Biological Chemistry

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“…NAF-1 and mNT function as iron-cluster transfer proteins, and mNT is responsible for iron homeostasis in mitochondria (10,11,14,15,18,19). Maintaining a balanced iron level in mitochondria is necessary to maintain mitochondrial membrane potential and regulation of mitochondrial ROS levels.…”

Section: Accumulation Of Iron and Ros In Mitochondria Of Human Epithementioning

confidence: 99%

“…The involvement of mitochondria in cancer cell function could be linked to the enhanced accumulation of iron and reactive oxygen species (ROS) in mitochondria of cancer cells, which is thought to result from the increased metabolic and energetic demands of the transformed phenotype (7). An interesting, recently discovered group of proteins that could link iron and ROS homeostasis with mitochondrial function in cancer cells are NEET proteins (8)(9)(10)(11)(12)(13)(14)(15).…”

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confidence: 99%

NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth

Sohn

Tamir

Song

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

179

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Mitochondria are emerging as important players in the transformation process of cells, maintaining the biosynthetic and energetic capacities of cancer cells and serving as one of the primary sites of apoptosis and autophagy regulation. Although several avenues of cancer therapy have focused on mitochondria, progress in developing mitochondria-targeting anticancer drugs nonetheless has been slow, owing to the limited number of known mitochondrial target proteins that link metabolism with autophagy or cell death. Recent studies have demonstrated that two members of the newly discovered family of NEET proteins, NAF-1 (CISD2) and mitoNEET (mNT; CISD1), could play such a role in cancer cells. NAF-1 was shown to be a key player in regulating autophagy, and mNT was proposed to mediate iron and reactive oxygen homeostasis in mitochondria. Here we show that the protein levels of NAF-1 and mNT are elevated in human epithelial breast cancer cells, and that suppressing the level of these proteins using shRNA results in significantly reduced cell proliferation and tumor growth, decreased mitochondrial performance, uncontrolled accumulation of iron and reactive oxygen in mitochondria, and activation of autophagy. Our findings highlight NEET proteins as promising mitochondrial targets for cancer therapy.M itochondria play a key role in many human diseases related to their functions in cellular energy production, biosynthesis of essential cellular compounds, and involvement in autophagy and/or apoptosis regulation (1). Contrary to previously held beliefs, recent studies have demonstrated that mitochondria are also key players in the transformation process of cancer cells and may be used as targets for anticancer therapy (2-6). The involvement of mitochondria in cancer cell function could be linked to the enhanced accumulation of iron and reactive oxygen species (ROS) in mitochondria of cancer cells, which is thought to result from the increased metabolic and energetic demands of the transformed phenotype (7). An interesting, recently discovered group of proteins that could link iron and ROS homeostasis with mitochondrial function in cancer cells are NEET proteins (8-15).NEET proteins [mitoNEET (mNT; CISD1), Nutrient-deprivation autophagy factor-1 (NAF-1; CISD2), and CISD3] are a class of iron-sulfur proteins involved in several human pathologies, including diabetes, cystic fibrosis, Wolfram syndrome 2, neurodegeneration, and muscle atrophy (16)(17)(18)(19)(20)(21)(22). mNT and NAF-1 are localized to the outer mitochondrial membrane. NAF-1 is also localized to the endoplasmic reticulum, where it interacts with BCL-2 and Beclin 1 to regulate autophagy and apoptosis (8-13). Deficiency in mNT causes the accumulation of iron and ROS in mitochondria of animal and plant cells, and deficiency in NAF-1 results in decreased mitochondrial function and stability, as well as activation of autophagy in mice and human cells (13-16, 20, 21).Interestingly, levels of mNT and NAF-1 mRNA are increased significantly in many different human cancer c...

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“…In addition to its putative role in diabetes, mNEET has been implicated in tumor development: mNEET and miner1 are overexpressed in breast cancer cells, and their downregulation reduces cell proliferation and tumor growth (10). mNEET has also been overexpressed experimentally in adipocytes and in pancreatic cells to modulate their physiology (11,12). However, the exact function of mNEET remains elusive, as well as the effect of its overexpression on cellular physiology.…”

mentioning

confidence: 99%

MitoNEET-dependent formation of intermitochondrial junctions

Vernay

Marchetti

Sabra

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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MitoNEET (mNEET) is a dimeric mitochondrial outer membrane protein implicated in many facets of human pathophysiology, notably diabetes and cancer, but its molecular function remains poorly characterized. In this study, we generated and analyzed mNEET KO cells and found that in these cells the mitochondrial network was disturbed. Analysis of 3D-EM reconstructions and of thin sections revealed that genetic inactivation of mNEET did not affect the size of mitochondria but that the frequency of intermitochondrial junctions was reduced. Loss of mNEET decreased cellular respiration, because of a reduction in the total cellular mitochondrial volume, suggesting that intermitochondrial contacts stabilize individual mitochondria. Reexpression of mNEET in mNEET KO cells restored the WT morphology of the mitochondrial network, and reexpression of a mutant mNEET resistant to oxidative stress increased in addition the resistance of the mitochondrial network to H 2 O 2 -induced fragmentation. Finally, overexpression of mNEET increased strongly intermitochondrial contacts and resulted in the clustering of mitochondria. Our results suggest that mNEET plays a specific role in the formation of intermitochondrial junctions and thus participates in the adaptation of cells to physiological changes and to the control of mitochondrial homeostasis.mitoNEET | CISD1 | mitochondria | intermitochondrial junctions | endoplasmic reticulum

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MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity

Cited by 404 publications

References 57 publications

C1q/Tumor Necrosis Factor-related Protein 11 (CTRP11), a Novel Adipose Stroma-derived Regulator of Adipogenesis

C1q/Tumor Necrosis Factor-related Protein 11 (CTRP11), a Novel Adipose Stroma-derived Regulator of Adipogenesis

NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth

MitoNEET-dependent formation of intermitochondrial junctions

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