RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia
Nathalie Launay, Montserrat Ruiz, Laura Planas-Serra, Edgard Verdura, Agustí Rodríguez-Palmero, Agatha Schlüter, Leire Goicoechea, Cristina Guilera, Josefina Casas, Felix Campelo, Emmanuelle Jouanguy, Jean-Laurent Casanova, Odile Boespflug-Tanguy, Maria Vazquez Cancela, Luis González Gutiérrez-Solana, Carlos Casasnovas, Estela Area-Gomez, Aurora Pujol
Nathalie Launay, Montserrat Ruiz, Laura Planas-Serra, Edgard Verdura, Agustí Rodríguez-Palmero, Agatha Schlüter, Leire Goicoechea, Cristina Guilera, Josefina Casas, Felix Campelo, Emmanuelle Jouanguy, Jean-Laurent Casanova, Odile Boespflug-Tanguy, Maria Vazquez Cancela, Luis González Gutiérrez-Solana, Carlos Casasnovas, Estela Area-Gomez, Aurora Pujol
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Research Article Metabolism Neuroscience

RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia

Abstract

The Rad50 interacting protein 1 (Rint1) is a key player in vesicular trafficking between the ER and Golgi apparatus. Biallelic variants in RINT1 cause infantile-onset episodic acute liver failure (ALF). Here, we describe 3 individuals from 2 unrelated families with novel biallelic RINT1 loss-of-function variants who presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, and dysmorphic features, broadening the previously described phenotype. Our functional and lipidomic analyses provided evidence that pathogenic RINT1 variants induce defective lipid–droplet biogenesis and profound lipid abnormalities in fibroblasts and plasma that impact both neutral lipid and phospholipid metabolism, including decreased triglycerides and diglycerides, phosphatidylcholine/phosphatidylserine ratios, and inhibited Lands cycle. Further, RINT1 mutations induced intracellular ROS production and reduced ATP synthesis, affecting mitochondria with membrane depolarization, aberrant cristae ultrastructure, and increased fission. Altogether, our results highlighted the pivotal role of RINT1 in lipid metabolism and mitochondria function, with a profound effect in central nervous system development.

Authors

Nathalie Launay, Montserrat Ruiz, Laura Planas-Serra, Edgard Verdura, Agustí Rodríguez-Palmero, Agatha Schlüter, Leire Goicoechea, Cristina Guilera, Josefina Casas, Felix Campelo, Emmanuelle Jouanguy, Jean-Laurent Casanova, Odile Boespflug-Tanguy, Maria Vazquez Cancela, Luis González Gutiérrez-Solana, Carlos Casasnovas, Estela Area-Gomez, Aurora Pujol

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Figure 8

Glucose deprivation promotes LD accumulation and increases mitochondrial fragmentation.

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Glucose deprivation promotes LD accumulation and increases mitochondrial...
(A) 3D rendering of a confocal image stack of control (CTL) and patient (P1 and P3) fibroblasts incubated with glucose (untreated) or without glucose (−Gluc) for 16 hours. Cells were labelled with an anti-TOMM20 antibody (mitochondria) and oil red O (LDs), and Imaris analysis was applied to detect LD-mitochondria surface contacts. Scale bar: 5 μm. A zoomed-in view is shown for each image; scale bar: 0.7 μm. (B) Quantification of the number of LDs per cell in the presence and absence of glucose. n > 50 cells for each genotype and condition. Patient (P1 and P3) and control (CTL, n = 3) fibroblasts. (C) Quantification of the percentage of LDs in contact with mitochondria per cell in control (CTL) and patient (P1 and P3) fibroblasts in the presence or absence of glucose. n > 50 cells for each genotype and condition. CTL=3. (D) Representative immunoblots of P-DRP1s616, P-DRP1s637, and DRP1 protein levels in control (CTL) and patient (P1 and P3) fibroblasts incubated with or without glucose (–Gluc). The total amount of α-tubulin (α-tub) was used as a loading control. (CTL n=6). Blots run in parallel using identical samples are shown. (E) Quantification of the P-DRP1S616/ P-DRP1S637 ratio relative to the control cells. All data are shown as the mean ± SD. Results were obtained from 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001. The data were analyzed by 2-way ANOVA followed by Tukey’s test for multiple comparisons.