Ineke Luijten, Xiong Weng, Ula Kibildyte, Jana Buchan, Ami Onishi, Jake Mann, Eleanor McKay, David Savage, Robert K Semple
{"title":"治疗mfn2相关脂肪营养不良的候选“杀死或治愈”策略的临床前评估。","authors":"Ineke Luijten, Xiong Weng, Ula Kibildyte, Jana Buchan, Ami Onishi, Jake Mann, Eleanor McKay, David Savage, Robert K Semple","doi":"10.1186/s10020-025-01314-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The mitofusin 2 (MFN2) R707W mutation causes debilitating human lipodystrophy featuring lower body adipose loss, upper body adipose hyperplasia, and dyslipidaemic insulin resistance. Mechanical complications include airway compromise due to head and neck adipose overgrowth. This condition, sometimes called Multiple Symmetrical Lipomatosis (MSL), is also seen in sporadic form strongly associated with excess ethanol consumption. Mitigating the cellular pathology, or, conversely, exacerbating it, inducing selective death of affected adipocytes, are potential therapeutic strategies.</p><p><strong>Methods: </strong>Candidate exacerbating and mitigating approaches to MFN2-MSL were tested in human MFN2<sup>R707W/R707W</sup> fibroblasts, and in Mfn2<sup>R707W/R707W</sup> mice and derived preadipocytes. Cell survival, mitochondrial network morphology and integrated stress response markers were assessed in cells, and body composition and metabolic indices in mice.</p><p><strong>Results: </strong>Forcing galactose metabolism in human MFN2<sup>R707W/R707W</sup> dermal fibroblasts did not replicate the overt adipose mitochondrial phenotype. 50mmol ethanol had little effect on Mfn2<sup>R707W/R707W</sup> white preadipocytes, but increased mitochondrial content and blunted mitolysosome formation in Mfn2<sup>R707W/R707W</sup> brown preadipocytes. 20% EtOH consumption increased brown adipose tissue in female Mfn2<sup>R707W/R707W</sup> mice, and serum lactate in males. Rapamycin - a candidate mitigating treatment - increased size and mitolysosome content of WT preadipocytes, and to a lesser degree of Mfn2<sup>R707W/R707W</sup> preadipocytes. In male Mfn2<sup>R707W/R707W</sup> mice, rapamycin reduced weight gain, brown adipose mass, and increased serum Fgf21. Finally, a panel of mitochondrial stressors solicited no selective death or ISR in Mfn2<sup>R707W/R707W</sup> preadipocytes.</p><p><strong>Conclusions: </strong>Ethanol mildly exacerbates murine MFN2-related MSL, while rapamycin is tolerated. MFN2-related MSL may not be solely attributable to compromised oxidative phosphorylation.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"273"},"PeriodicalIF":6.4000,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320274/pdf/","citationCount":"0","resultStr":"{\"title\":\"Preclinical evaluation of candidate \\\"kill or cure\\\" strategies to treat MFN2-related lipodystrophy.\",\"authors\":\"Ineke Luijten, Xiong Weng, Ula Kibildyte, Jana Buchan, Ami Onishi, Jake Mann, Eleanor McKay, David Savage, Robert K Semple\",\"doi\":\"10.1186/s10020-025-01314-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The mitofusin 2 (MFN2) R707W mutation causes debilitating human lipodystrophy featuring lower body adipose loss, upper body adipose hyperplasia, and dyslipidaemic insulin resistance. Mechanical complications include airway compromise due to head and neck adipose overgrowth. This condition, sometimes called Multiple Symmetrical Lipomatosis (MSL), is also seen in sporadic form strongly associated with excess ethanol consumption. Mitigating the cellular pathology, or, conversely, exacerbating it, inducing selective death of affected adipocytes, are potential therapeutic strategies.</p><p><strong>Methods: </strong>Candidate exacerbating and mitigating approaches to MFN2-MSL were tested in human MFN2<sup>R707W/R707W</sup> fibroblasts, and in Mfn2<sup>R707W/R707W</sup> mice and derived preadipocytes. Cell survival, mitochondrial network morphology and integrated stress response markers were assessed in cells, and body composition and metabolic indices in mice.</p><p><strong>Results: </strong>Forcing galactose metabolism in human MFN2<sup>R707W/R707W</sup> dermal fibroblasts did not replicate the overt adipose mitochondrial phenotype. 50mmol ethanol had little effect on Mfn2<sup>R707W/R707W</sup> white preadipocytes, but increased mitochondrial content and blunted mitolysosome formation in Mfn2<sup>R707W/R707W</sup> brown preadipocytes. 20% EtOH consumption increased brown adipose tissue in female Mfn2<sup>R707W/R707W</sup> mice, and serum lactate in males. Rapamycin - a candidate mitigating treatment - increased size and mitolysosome content of WT preadipocytes, and to a lesser degree of Mfn2<sup>R707W/R707W</sup> preadipocytes. In male Mfn2<sup>R707W/R707W</sup> mice, rapamycin reduced weight gain, brown adipose mass, and increased serum Fgf21. Finally, a panel of mitochondrial stressors solicited no selective death or ISR in Mfn2<sup>R707W/R707W</sup> preadipocytes.</p><p><strong>Conclusions: </strong>Ethanol mildly exacerbates murine MFN2-related MSL, while rapamycin is tolerated. MFN2-related MSL may not be solely attributable to compromised oxidative phosphorylation.</p>\",\"PeriodicalId\":18813,\"journal\":{\"name\":\"Molecular Medicine\",\"volume\":\"31 1\",\"pages\":\"273\"},\"PeriodicalIF\":6.4000,\"publicationDate\":\"2025-08-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320274/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s10020-025-01314-2\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s10020-025-01314-2","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Preclinical evaluation of candidate "kill or cure" strategies to treat MFN2-related lipodystrophy.
Background: The mitofusin 2 (MFN2) R707W mutation causes debilitating human lipodystrophy featuring lower body adipose loss, upper body adipose hyperplasia, and dyslipidaemic insulin resistance. Mechanical complications include airway compromise due to head and neck adipose overgrowth. This condition, sometimes called Multiple Symmetrical Lipomatosis (MSL), is also seen in sporadic form strongly associated with excess ethanol consumption. Mitigating the cellular pathology, or, conversely, exacerbating it, inducing selective death of affected adipocytes, are potential therapeutic strategies.
Methods: Candidate exacerbating and mitigating approaches to MFN2-MSL were tested in human MFN2R707W/R707W fibroblasts, and in Mfn2R707W/R707W mice and derived preadipocytes. Cell survival, mitochondrial network morphology and integrated stress response markers were assessed in cells, and body composition and metabolic indices in mice.
Results: Forcing galactose metabolism in human MFN2R707W/R707W dermal fibroblasts did not replicate the overt adipose mitochondrial phenotype. 50mmol ethanol had little effect on Mfn2R707W/R707W white preadipocytes, but increased mitochondrial content and blunted mitolysosome formation in Mfn2R707W/R707W brown preadipocytes. 20% EtOH consumption increased brown adipose tissue in female Mfn2R707W/R707W mice, and serum lactate in males. Rapamycin - a candidate mitigating treatment - increased size and mitolysosome content of WT preadipocytes, and to a lesser degree of Mfn2R707W/R707W preadipocytes. In male Mfn2R707W/R707W mice, rapamycin reduced weight gain, brown adipose mass, and increased serum Fgf21. Finally, a panel of mitochondrial stressors solicited no selective death or ISR in Mfn2R707W/R707W preadipocytes.
Conclusions: Ethanol mildly exacerbates murine MFN2-related MSL, while rapamycin is tolerated. MFN2-related MSL may not be solely attributable to compromised oxidative phosphorylation.
期刊介绍：
Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.
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