Luijten Ineke, Weng Xiong, Kibildyte Ula, Buchan Jana, Onishi Ami, Mann Jake, McKay Eleanor, Savage David, Semple Robert K
Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Mol Med. 2025 Aug 4;31(1):273. doi: 10.1186/s10020-025-01314-2.
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.
Candidate exacerbating and mitigating approaches to MFN2-MSL were tested in human MFN2 fibroblasts, and in Mfn2 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.
Forcing galactose metabolism in human MFN2 dermal fibroblasts did not replicate the overt adipose mitochondrial phenotype. 50mmol ethanol had little effect on Mfn2 white preadipocytes, but increased mitochondrial content and blunted mitolysosome formation in Mfn2 brown preadipocytes. 20% EtOH consumption increased brown adipose tissue in female Mfn2 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 preadipocytes. In male Mfn2 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 preadipocytes.
Ethanol mildly exacerbates murine MFN2-related MSL, while rapamycin is tolerated. MFN2-related MSL may not be solely attributable to compromised oxidative phosphorylation.
线粒体融合蛋白2（MFN2）的R707W突变会导致使人衰弱的脂肪营养不良，其特征为下半身脂肪流失、上半身脂肪增生以及血脂异常性胰岛素抵抗。机械并发症包括因头颈部脂肪过度生长导致的气道受压。这种病症有时被称为多发性对称性脂肪瘤病（MSL），也可见于与过量饮酒密切相关的散发性病例。减轻细胞病理变化，或者相反，加剧这种变化，诱导受影响脂肪细胞的选择性死亡，都是潜在的治疗策略。
在人MFN2成纤维细胞、Mfn2小鼠及其衍生的前脂肪细胞中测试了针对MFN2-MSL的候选加剧和减轻方法。评估了细胞中的细胞存活、线粒体网络形态和综合应激反应标志物，以及小鼠的身体组成和代谢指标。
在人MFN2皮肤成纤维细胞中强制进行半乳糖代谢并未重现明显的脂肪线粒体表型。50mmol乙醇对Mfn2白色前脂肪细胞影响不大，但增加了Mfn2棕色前脂肪细胞的线粒体含量并减弱了线粒体溶酶体的形成。饮用20%乙醇会增加雌性Mfn2小鼠的棕色脂肪组织，并增加雄性小鼠的血清乳酸水平。雷帕霉素——一种候选的减轻治疗药物——增加了野生型前脂肪细胞的大小和线粒体溶酶体含量，并在较小程度上增加了Mfn2前脂肪细胞的上述指标。在雄性Mfn2小鼠中，雷帕霉素减少了体重增加、棕色脂肪量，并增加了血清成纤维细胞生长因子21（Fgf21）。最后一组线粒体应激源并未在Mfn2前脂肪细胞中引发选择性死亡或综合应激反应（ISR）。
乙醇会轻度加剧小鼠中与MFN2相关的MSL，而雷帕霉素具有耐受性。与MFN2相关的MSL可能并非完全归因于氧化磷酸化受损。
