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 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.

RESULTS

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.

CONCLUSIONS

Ethanol mildly exacerbates murine MFN2-related MSL, while rapamycin is tolerated. MFN2-related MSL may not be solely attributable to compromised oxidative phosphorylation.