Journal Article

QIL1 mutation causes MICOS disassembly and early onset fatal mitochondrial encephalopathy with liver disease

Lacène, Emmanuelle, Gaignard, Pauline, Benoist, Jean-François, Bourillon, Agnès, Lombès, Anne, Bénit, Paule, Goetzman, Eric S, Harper, J Wade, Guarani, Virginia, Imbard, Apolline, Rustin, Pierre, Ogier de Baulny, Hélène, Dorboz, Imen, Elmaleh-Bergès, Monique, Romero, Norma B, Paulo, Joao A, Gilleron, Mylène, Jardel, Claude, Labasse, Clémence, Schiff, Manuel, Slama, Abdelhamid, Chrétien, Dominique

2016

Overview

Previously, we identified QIL1 as a subunit of mitochondrial contact site (MICOS) complex and demonstrated a role for QIL1 in MICOS assembly, mitochondrial respiration, and cristae formation critical for mitochondrial architecture ( Guarani et al., 2015 ). Here, we identify QIL1 null alleles in two siblings displaying multiple clinical symptoms of early-onset fatal mitochondrial encephalopathy with liver disease, including defects in respiratory chain function in patient muscle. QIL1 absence in patients’ fibroblasts was associated with MICOS disassembly, abnormal cristae, mild cytochrome c oxidase defect, and sensitivity to glucose withdrawal. QIL1 expression rescued cristae defects, and promoted re-accumulation of MICOS subunits to facilitate MICOS assembly. MICOS assembly and cristae morphology were not efficiently rescued by over-expression of other MICOS subunits in patient fibroblasts. Taken together, these data provide the first evidence of altered MICOS assembly linked with a human mitochondrial disease and confirm a central role for QIL1 in stable MICOS complex formation.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publication,eLife Sciences Publications, Ltd
• Subject: 3-methylglutaconic aciduria / Age / Amino acids / Biochemistry / Biochemistry, Molecular Biology / Cell Biology / Cristae / Cytochrome-c oxidase / Deoxyribonucleic acid / DNA / early-onset fatal mitochondrial encephalopathy / Electron transport / Female / Fibroblasts / Gene mutations / Genetic aspects / Health aspects / Hepatic encephalopathy / Human Biology and Medicine / Humans / Infant, Newborn / Life Sciences / liver disease / Liver diseases / Liver Diseases - genetics / Liver Diseases - pathology / Male / Membrane Proteins - deficiency / MICOS / Microbial Sensitivity Tests / Mitochondria / mitochondrial disease / Mitochondrial diseases / Mitochondrial Encephalomyopathies - genetics / Mitochondrial Encephalomyopathies - pathology / Mitochondrial Proteins - deficiency / Musculoskeletal system / Mutation / Overexpression / Patients / Physiological aspects / Proteins / QIL1 / Research Advance / Respiration / Siblings / Ultrasonic imaging / Urine