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

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

Abstract

International audiencePreviously, 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

Topics: [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology
Publisher: eLife Sciences Publication
Year: 2016
DOI identifier: 10.7554/eLife.17163
OAI identifier: oai:HAL:inserm-01376755v1
Provided by: Hal-Diderot

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