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Elife. 2016 Sep 13;5. pii: e17163. doi: 10.7554/eLife.17163.

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

Author information

1
Department of Cell Biology, Harvard Medical School, Boston, United States.
2
Inserm U1016, Institut Cochin, CNRS UMR 8104, Paris, France.
3
Department of Biochemistry, APHP, GHU Pitié-Salpêtrière, Paris, France.
4
Université Paris-Descartes, Paris, France.
5
UMR1141, PROTECT, INSERM, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
6
Neuromuscular morphology unit, Institut de Myologie, GHU Pitié-Salpêtrière, APHP, Paris, France.
7
Department of Biochemistry, Hôpital Robert Debré, APHP, Paris, France.
8
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, United States.
9
University of Pittsburgh, Pittsburgh, United States.
10
Children's Hospital of Pittsburgh of UPMC, Pittsburgh, United States.
11
Department of Biochemistry, Hôpital Bicêtre, APHP, Paris, France.
12
Department of Radiology, Hôpital Robert Debré, APHP, Paris, France.
13
Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, APHP, Paris, France.

Abstract

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.

KEYWORDS:

3-methylglutaconic aciduria; MICOS; QIL1; cell biology; early-onset fatal mitochondrial encephalopathy; human; human biology; liver disease; medicine; mitochondrial disease

PMID:
27623147
PMCID:
PMC5021520
DOI:
10.7554/eLife.17163
[Indexed for MEDLINE]
Free PMC Article

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