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

Abstract

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. We previously reported that the CRM1-mediated nuclear protein export pathway is exacerbated in HGPS cells, provoking the mislocalization of numerous protein targets of CRM1. We showed that normalization of this mechanism by pharmacologically inhibiting CRM1 with LMB (specific CRM1 inhibitor), 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. We provide evidence that the beneficial effect of LMB is mechanistically based on a combinatory effect on mitochondrial biogenesis via upregulation of PGC-1α expression (master transcription cofactor of mitochondrial genes), 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.

A X‐linked nonsense APOO/MIC26 variant causes a lethal mitochondrial disease with progeria‐like phenotypes

“…and respiratory capacity, high ROS levels and low PGC1a levels also accumulated in Progeria. 44,45 Recently, null mutations in Metaxin-2…”

“…Typical “Progeria” disease known as Hutchinson‐Gilford syndrome (HGPA) occurs due to single gene mutation in nuclear gene Lamin A causing aberrant nuclear structure and cell division. Moreover, dysfunctional mitochondria with fragmented morphology, low membrane potential and respiratory capacity, high ROS levels and low PGC1a levels also accumulated in Progeria 44,45 . Recently, null mutations in Metaxin‐2 were found in progeroid disorder mandibuloacral dysplasia 46 .…”

Premature aging in genetic diseases: what conclusions can be drawn for physiological aging

“…Thus, this signalling cascade provides key mechanic insights that relate to NAD+ depletion known to play a fundamental role in the biology of aging ( Verdin, 2015 ). In HGPS, autophagy ( Marino et al, 2008 ), UPR ( Vidak et al, 2023 ) and mitophagy ( Monterrubio-Ledezma et al, 2023 ) are apparently not compromised but even increased likely in an attempt to compensate for massive progerin accumulation. Consistent with this notion Vidak and colleagues have shown that in HGPS UPR machinery of the endoplasmic reticulum senses nucleoplasmic progerin aggregates through clustered Sun proteins a mechanism that awaits to be tested in physiological age-related conditions ( Vidak et al, 2023 ).…”

Progerin, an Aberrant Spliced Form of Lamin A, Is a Potential Therapeutic Target for HGPS

“…HGPS cells exhibited enhanced nuclear protein export activity due to the progerin-driven overexpression of chromosomal region maintenance 1 (CRM1). Pharmacologically inhibiting CRM1 with Leptomycin B mitigates the senescent phenotype of HGPS cells [ 119 ]. High levels of interleukin-6 (IL-6), a pro-inflammatory cytokine associated with age-related processes, have been observed in HGPS cells and mouse models ( Lmna G609G/G609G ).…”