1. Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis
- Author
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François-Xavier Mauvais, Olivier Pelle, Yamina Hamel, Corinne Lebreton, Pascale de Lonlay, Marine Madrange, Peter van Endert, David N. Brindley, Patrick Nusbaum, Xiaoyun Tang, Mathieu P Rodero, Perrine Renard, Ivan Nemazanyy, Caroline Tuchmann-Durand, Nicolas Goudin, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de référence pour les maladies métaboliques héréditaires [CHU Necker Enfants Malades - AP-HP], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Alberta, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Rodero, Mathieu, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
- Subjects
Autophagosome ,Male ,late endosome ,[SDV]Life Sciences [q-bio] ,autophagosome ,Myoblasts ,0302 clinical medicine ,Phosphatidylinositol Phosphates ,Medicine ,Receptor ,Child ,Late endosome ,0303 health sciences ,mitochondrial quality control ,GTPase-Activating Proteins ,Chloroquine ,3. Good health ,Cell biology ,Mitochondria ,[SDV] Life Sciences [q-bio] ,Child, Preschool ,Female ,medicine.symptom ,Rhabdomyolysis ,Signal Transduction ,Mitochondrial DNA ,hydroxychloroquine ,Endosome ,Phosphatidate Phosphatase ,Inflammation ,Endosomes ,DNA, Mitochondrial ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Humans ,lipin1 ,030304 developmental biology ,business.industry ,Autophagosomes ,TLR9 ,rab7 GTP-Binding Proteins ,Toll-like receptor 9 ,medicine.disease ,inflammation ,rhabdomyolysis ,business ,Lysosomes ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Summary LPIN1 mutations are responsible for inherited recurrent rhabdomyolysis, a life-threatening condition with no efficient therapeutic intervention. Here, we conduct a bedside-to-bench-and-back investigation to study the pathophysiology of lipin1 deficiency. We find that lipin1-deficient myoblasts exhibit a reduction in phosphatidylinositol-3-phosphate close to autophagosomes and late endosomes that prevents the recruitment of the GTPase Armus, locks Rab7 in the active state, inhibits vesicle clearance by fusion with lysosomes, and alters their positioning and function. Oxidized mitochondrial DNA accumulates in late endosomes, where it activates Toll-like receptor 9 (TLR9) and triggers inflammatory signaling and caspase-dependent myolysis. Hydroxychloroquine blocks TLR9 activation by mitochondrial DNA in vitro and may attenuate flares of rhabdomyolysis in 6 patients treated. We suggest a critical role for defective clearance of oxidized mitochondrial DNA that activates TLR9-restricted inflammation in lipin1-related rhabdomyolysis. Interventions blocking TLR9 activation or inflammation can improve patient care in vivo., Graphical abstract, Highlights Lipin1 deficiency causes mitophagosome and late endosome dysfunction in human myoblasts Damaged mitochondria trigger TLR9-mediated inflammation and myoblast death Mitochondrial DNA elimination or blockade of TLR9 activation prevent myoblast death Hydroxychloroquine sulfate treatment may prevent rhabdomyolysis episodes in patients, Hamel et al. investigate the mechanism underlying life-threatening rhabdomyolysis in human lipin1 deficiency. They find that endosomal accumulation of mitochondrial DNA in myoblasts induces inflammation and cell death mediated by TLR9 activation in vitro. Treatment of 6 patients with hydroxychloroquine sulfate suggests benefits in preventing rhabdomyolysis episodes.
- Published
- 2021