QIL1 mutation causes MICOS disassembly and early onset fatal mitochondrial encephalopathy with liver disease.
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.
Department of Cell Biology, Harvard Medical School, Boston, United States.
Virginia
V
Guarani
Inserm U1016, Institut Cochin, CNRS UMR 8104, Paris, France.|Department of Biochemistry, APHP, GHU Pitié-Salpêtrière, Paris, France.|Université Paris-Descartes, Paris, France.
Claude
C
Jardel
UMR1141, PROTECT, INSERM, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
Dominique
D
Chrétien
Inserm U1016, Institut Cochin, CNRS UMR 8104, Paris, France.|Department of Biochemistry, APHP, GHU Pitié-Salpêtrière, Paris, France.|Université Paris-Descartes, Paris, France.
Anne
A
Lombès
UMR1141, PROTECT, INSERM, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
Paule
P
Bénit
Neuromuscular morphology unit, Institut de Myologie, GHU Pitié-Salpêtrière, APHP, Paris, France.
Clémence
C
Labasse
Neuromuscular morphology unit, Institut de Myologie, GHU Pitié-Salpêtrière, APHP, Paris, France.
Emmanuelle
E
Lacène
Department of Biochemistry, Hôpital Robert Debré, APHP, Paris, France.
Agnès
A
Bourillon
Department of Biochemistry, Hôpital Robert Debré, APHP, Paris, France.
Apolline
A
Imbard
Department of Biochemistry, Hôpital Robert Debré, APHP, Paris, France.
Jean-François
JF
Benoist
UMR1141, PROTECT, INSERM, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
Imen
I
Dorboz
Inserm U1016, Institut Cochin, CNRS UMR 8104, Paris, France.|Department of Biochemistry, APHP, GHU Pitié-Salpêtrière, Paris, France.|Université Paris-Descartes, Paris, France.
Mylène
M
Gilleron
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, United States.|University of Pittsburgh, Pittsburgh, United States.|Children's Hospital of Pittsburgh of UPMC, Pittsburgh, United States.
Eric S
ES
Goetzman
Department of Biochemistry, Hôpital Bicêtre, APHP, Paris, France.
Pauline
P
Gaignard
Department of Biochemistry, Hôpital Bicêtre, APHP, Paris, France.
Abdelhamid
A
Slama
Department of Radiology, Hôpital Robert Debré, APHP, Paris, France.
Monique
M
Elmaleh-Bergès
Neuromuscular morphology unit, Institut de Myologie, GHU Pitié-Salpêtrière, APHP, Paris, France.
Norma B
NB
Romero
UMR1141, PROTECT, INSERM, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
Pierre
P
Rustin
Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, APHP, Paris, France.
Hélène
H
Ogier de Baulny
Department of Cell Biology, Harvard Medical School, Boston, United States.
Joao A
JA
Paulo
Department of Cell Biology, Harvard Medical School, Boston, United States.
J Wade
0000-0002-6944-7236
JW
Harper
UMR1141, PROTECT, INSERM, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.|Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, APHP, Paris, France.
Manuel
M
Schiff
D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency*; D008826:Microbial Sensitivity Tests; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000172:deficiency*; D009154:Mutation; D035781:Siblings
C000621991:MICOS13 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins
3-methylglutaconic aciduria; MICOS; QIL1; cell biology; early-onset fatal mitochondrial encephalopathy; human; human biology; liver disease; medicine; mitochondrial disease