Mitochondrial dysfunction is a key determinant of the rare disease lymphangioleiomyomatosis and provides a novel therapeutic target

Abstract

Lymphangioleiomyomatosis (LAM) is a rare and progressive systemic disease affecting mainly young women of childbearing age. A deterioration in lung function is driven by neoplastic growth of atypical smooth muscle-like LAM cells in the pulmonary interstitial space that leads to cystic lung destruction and spontaneous pneumothoraces. Therapeutic options for preventing disease progression are limited and often end with lung transplantation temporarily delaying an inevitable decline. To identify new therapeutic strategies for this crippling orphan disease, we have performed array based and metabolic molecular analysis on patient-derived cell lines. Our results point to the conclusion that mitochondrial biogenesis and mitochondrial dysfunction in LAM cells provide a novel target for treatment.

Normalization of enzyme expression and activity regulating vitamin A metabolism increases RAR-beta expression and reduces cellular migration in diseases caused by tuberous sclerosis gene mutations

“…Additionally, miR-378a-5p overexpression in a rat cardiomyocyte study was associated with ALDH2 downregulation therefore downregulation of miR-378a-5p (Figure 2A) in the present work supported upregulation of ALDH2 in our initial array ( Figure 1A) [31]. Upregulation of miR-29b have been recently shown to promote cell migration in TSC2-de cient cells through RARβ activation [19] which we repeatedly detected in our previous [6] and present experiments (S Figure 3). The schematic depiction of individual targets of miRNA-s in vitamin A metabolism and deregulation in the presence of TSC mutation is shown in Figure 2B.…”

“…Just as in the angiomyolipoma cell line S102, in the LAM cell lines ADH1, ADH4 and ALDH1A1-2-3 showed the exact same pattern of expression ( Figure 1C). The mTOR activation induced downregulation of RARβ expression [6] was con rmed at protein level by western blotting and immuno uorescent staining in patient derived LAM cell lines and the angiomyolipoma cell line S102 ( Figure 1D, E). To con rm the cell line data in primary LAM lung tissues (S Figure 2), six individual lung tissue samples were stained for RARβ protein ( Figure 1F).…”

“…Activation of the mTOR pathway can change anabolic cell growth processes such as protein and lipid synthesis in correlation with external growth factor or nutrient intake [5]. In our initial study of LAM, apart from detecting morphological abnormalities in mitochondria and suppression of ROS production, we identi ed downregulation of the proliferation suppressor nuclear receptors of the retinoic acid gene family RAR and RXR as well as several miRNA-s that regulate RAR expression including miR29b [6]. Receptors of retinoic acid (RA), a metabolite of vitamin A, are grouped into two distinct classes: retinoic acid receptors (RAR) and retinoid x receptors (RXR) [7].…”

“…Receptors of retinoic acid (RA), a metabolite of vitamin A, are grouped into two distinct classes: retinoic acid receptors (RAR) and retinoid x receptors (RXR) [7]. Both classes of nuclear receptors have three subtypes (α, β, and γ) and in-patient derived LAM cell lines RARβ mRNA expression was found signi cantly reduced [6]. Interestingly, RARβ is the receptor that was associated with the anti-tumour effects of RA [8] [9] [10].…”

Human pluripotent stem cell modeling of tuberous sclerosis complex reveals lineage-specific therapeutic vulnerabilities

“…Our data reconcile these previous observations by revealing that TSC2 -/neural lineage cells, but not NCCs or hPSCs, uniquely develop elevated endosomal signaling mechanisms, and that these are established during early stages of lineage specification. Mitochondrial and metabolic defects, as well as proteasome dysfunction, have also been identified as potential therapeutic targets for both neurological and mesenchymal TSC (Abdelwahab et al, 2019;Ebrahimi-Fakhari et al, 2016;McKenna III et al, 2018;Parkhitko et al, 2014;Siroky et al, 2012;Van Scheppingen et al, 2016). These previous studies did not, however, permit analysis of the development of these phenotypes during lineage specification;…”