Journal Article

Preclinical evaluation of candidate “kill or cure” strategies to treat MFN2-related lipodystrophy

Buchan, Jana, McKay, Eleanor, Luijten, Ineke, Weng, Xiong, Onishi, Ami, Mann, Jake, Savage, David, Kibildyte, Ula, Semple, Robert K.

2025

Overview

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 MFN2 R707W/R707W fibroblasts, and in Mfn2 R707W/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 MFN2 R707W/R707W dermal fibroblasts did not replicate the overt adipose mitochondrial phenotype. 50mmol ethanol had little effect on Mfn2 R707W/R707W white preadipocytes, but increased mitochondrial content and blunted mitolysosome formation in Mfn2 R707W/R707W brown preadipocytes. 20% EtOH consumption increased brown adipose tissue in female Mfn2 R707W/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 Mfn2 R707W/R707W preadipocytes. In male Mfn2 R707W/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 Mfn2 R707W/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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adipocytes - drug effects / Adipocytes - metabolism / Alcohol / Animals / Apoptosis / Biomedical and Life Sciences / Biomedicine / Body fat / Disease Models, Animal / Endoplasmic reticulum / Ethanol - pharmacology / Female / Fibroblasts / Fibroblasts - drug effects / Fibroblasts - metabolism / Gene expression / GTP Phosphohydrolases - genetics / GTP Phosphohydrolases - metabolism / Humans / Hyperplasia / Insulin resistance / Lipodystrophy / Lipomatosis, Multiple Symmetrical - drug therapy / Lipomatosis, Multiple Symmetrical - genetics / Lipomatosis, Multiple Symmetrical - metabolism / Lipomatosis, Multiple Symmetrical - pathology / Male / Metabolism / MFN2 / Mice / Mitochondria - drug effects / Mitochondria - metabolism / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Mitofusin / Molecular Medicine / Multiple symmetrical lipomatosis / Mutation / Pathology / Penicillin / Rapamycin