Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1

Monterrubio-Ledezma F, Navarro-García F, Massieu L, Mondragón-Flores R, Soto-Ponce LA, Magaña JJ, Cisneros B.

Cells. 2023 Jan 10;12(2):275. doi: 10.3390/cells12020275.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by the expression of progerin, a mutant variant of Lamin A. Recently, HGPS studies have gained relevance because unraveling its underlying mechanism would help to understand physiological aging. The CRM1 (Chromosomal Maintenance 1, also known as Exportin 1)-mediated nuclear protein export pathway is exacerbated in HGPS cells, provoking the mislocalization of numerous protein targets of CRM1. The normalization of this mechanism by pharmacologically inhibiting CRM1 with LMB (Leptomycin B), mitigates the senescent phenotype of HGPS cells. Since mitochondrial dysfunction is a hallmark of HGPS, in this study we analyze the effect of LMB on mitochondrial function. Remarkably, LMB treatment induced the recovery of mitochondrial function in HGPS cells, as shown by the improvement in mitochondrial morphology, mitochondrial membrane potential, and ATP levels, which consequently impeded the accumulation of ROS but not mitochondrial superoxide. The beneficial effect of LMB is mechanistically based on a combinatory effect on mitochondrial biogenesis and mitophagy through the recovery of lysosomal content. The use of exportin CRM1 inhibitors constitutes a promising strategy to treat HGPS and other diseases characterized by mitochondrial impairment.