A diverse collection of mitochondrial diseases have been linked to mutations that affect either mitochondrial or nuclear genomes, and alter respiratory chain function, mitochondrial fission/fusion cycles, or mitochondrial quality control (Vafai and Mootha, 2012). A central feature of mitochondrial disease is the pleotropic nature of phenotypes, with some diseases eliciting highly tissue-specific effects and others affecting multiple organ systems. The basis of this pleiotropy is poorly understood, but could reflect differences in mitochondrial structure and concomitant links with respiratory chain activity within individual tissues (Vafai and Mootha, 2012).

Proper organization of the respiratory chain and other mitochondrial protein complexes within the mitochondrial inner membrane (MIM) relies on the formation of MIM invaginations referred to as cristae. These laminar structures with highly curved distal membrane arrangement are formed through the mitochondrial contact site (MICOS) complex, a cristae junction scaffold that is thought to both maintain close proximity of cristae membranes near the 'boundary' MIM as well as form connections between the cristae junction and the mitochondrial outer membrane (MOM) (Pfanner et al., 2014; van der Laan et al., 2016). MICOS is composed of several subunits located on the MIM and mitochondrial intermembrane space, including MIC25, MIC60, MIC10, MIC26, MIC27, MIC19, and this core complex has been shown to interact with SAM50, MTX1, and MTX2 on the MOM, presumably helping to position cristae structures in proximity to the MOM. Our recent proteomic analysis of the MICOS complex identified a previously unstudied single-pass transmembrane protein – C19ORF70/QIL1 – as a component of MICOS localized in the MIM (Guarani et al., 2015). Depletion of QIL1 by RNAi in tissue culture cell lines resulted in: (1) loss of cristae junction structures accompanied by the formation of MIMs with characteristic 'swirl' structures, (2) MICOS complex disassembly, (3) loss of MIC10, MIC26 and MIC27 protein levels, (4) failure to assemble into a MIC60-MIC19-MIC25 sub-complex, and (5) decreased mitochondrial respiration (Guarani et al., 2015). RNAi of the Drosophila QIL1 ortholog in muscle and nervous tissue lead to a similar mitochondrial phenotype in vivo (Guarani et al., 2015). Thus, QIL1 is required for assembly and maintenance of the MICOS complex and mitochondrial architecture. This mechanism of MICOS assembly and the role of QIL1 have recently been verified (Zerbes et al., 2016; Anand et al., 2016).

Building upon our recent discovery and mechanistic analysis of QIL1, we now report recessive non-functional alleles of QIL1 in two sibling patients with early onset fatal mitochondrial encephalopathy and recurrent liver disease. Molecular and cell biological studies revealed dramatic defects in mitochondrial organization in fibroblasts and muscle tissue derived from these patients that are associated with disassembly of the MICOS complex. MICOS assembly and mitochondrial architecture phenotypes in patient fibroblasts could be fully rescued by re-introduction of QIL1, but not other MICOS subunits, consistent with QIL1 mutation underlying the phenotypes observed. These data reveal a critical role for the MICOS core complex in mitochondrial health and disease.

We report herein QIL1 deficiency in 2 siblings who exhibited early onset severe mitochondrial disease. QIL1 deficiency was associated with transient neonatal deterioration with hypoglycemia, hyperlactacidemia and liver disease. In the first months of life, acute decompensations occurred with liver disease and hyperlactacidemia. This was associated with neurological disease, including developmental delay with cerebellar atrophy, eye disease with optic atrophy and sensorineural deafness. Liver disease also included liver nodules with high α-fetoprotein as observed in other mitochondrial disease such as TRMU gene mutations (Gaignard et al., 2013).

Liver associated with central nervous system dysfunction is often involved in mitochondrial disease especially those involving defects of mitochondrial DNA maintenance caused by nuclear gene mutations i.e. mitochondrial DNA depletion syndromes (resulting from POLG, DGUOK or MPV17 mutations for instance (Al-Hussaini et al., 2014; Naviaux and Nguyen, 2004). QIL1 deficiency in patient fibroblasts did not affect mitochondrial DNA abundance, but resulted in severely disorganized mitochondrial cristae. In principle, the deletion of exon 2, which encoded the single-pass transmembrane domain apparently involved in QIL1 tethering to the MIM (Figure 2), would be expected to greatly reduce the efficiency of MICOS assembly (Guarani et al., 2015; Zerbes et al., 2016). Given the presence of a premature stop codon in the mRNA for the QIL1 mutant, it is likely that the mRNA is degraded through non-sense mediated decay. We also detected generalized mitochondrial respiratory chain deficiencies in skeletal muscle from patient 1 consistent with a reduced mitochondrial respiration previously reported upon QIL1 RNAi mediated knockdown in human cell lines (Guarani et al., 2015). However, we detected only a mild complex IV (cytochrome c oxidase) deficiency in skin fibroblasts grown in culture. Interestingly, contrary to what was observed in RNAi-induced QIL1 depletion in HeLa cells (Guarani et al., 2015), there was no effect of QIL1 deficiency on fibroblasts’ basal respiration in agreement with the limited defect affecting complex IV and the normal respiratory chain enzyme activities in these cells. Differences in mitochondrial activities observed between muscle biopsies and skin fibroblasts from patients are commonly observed in mitochondrial disorders (Haas et al., 2008; Thorburn and Smeitink, 2001; van den Heuvel et al., 2004). It has been reported that nearly 50% of the children with a respiratory chain defect in muscle display normal enzyme activities in cultured skin fibroblasts (Thorburn, 2000) and respiratory chain defects are often not expressed in fibroblasts even in some well-recognized oxidative phosphorylation deficiencies (Robinson et al., 1990).

Nevertheless, patients’ fibroblasts exhibited high sensitivity to glucose deprivation, suggesting an inability to utilize the alternative mitochondrial energetic route to cope with glucose deprivation, in line with previous observations from other mitochondrial diseases (Robinson et al., 1992). Interestingly, an increase in cristae density has been reported upon general nutrient or glucose deprivation (Gomes et al., 2011; Rossignol et al., 2004), indicating an important link between mitochondrial architecture and nutrient utilization. It has been proposed that mitochondrial cristae architecture may control nutrient utilization via different mechanisms, including electron transport chain function, nutrient import and access (Stanley et al., 2014). Thus, differences between mitochondrial respiration defects observed in muscle and fibroblasts may not only reflect the pleiotropic nature of phenotypes of mitochondrial diseases, often eliciting highly tissue-specific effects (Vafai and Mootha, 2012), but also be related to cell-specific metabolic requirements and different mitochondrial pathways. Alternatively, skin fibroblasts may have possibly developed adaptive mechanisms over time to permit normal basal respiration under culture conditions. Nevertheless, QIL1 mutation in patient fibroblasts had a major impact on the abundance of other MICOS subunits, on MICOS assembly, and on the mitochondrial ultrastructure. A proposed model is shown in Figure 5J, wherein loss of QIL1 leads to loss of cristae structure and reduced levels of MIC60, MIC19, MIC25, MIC10, MIC26, and MIC27, with MIC10, MIC26 and MIC27 being affected to the largest extent (Figure 3A-B, Figure 5I and Figure 5—figure supplement 1N). Residual MIC60 and MIC19 could be found in an ~500 kDa complex in blue-native gels using quantitative proteomics (Figure 5F,J), suggesting that this sub-complex of MICOS does not require QIL1 for assembly (Guarani et al., 2015). Interestingly, overexpression of MIC10 and MIC27 in QIL1-defective fibroblasts resulted in a fraction of mitochondria containing cristae like structures, with very low levels of MICOS complex assembly observed by blue-native gels. The ability of MIC10 and MIC27 overexpression to promote cristae formation with low efficiency may relate to the ability of MIC10 to form large oligomers and promote membrane curvature independently of other MICOS subunits (Barbot et al., 2015; Bohnert et al., 2015) and MIC27 to bind cardiolipin which also promotes curvature (Weber et al., 2013). Interestingly, we observed that MIC27 expression increased MIC10 levels, and it is possible that the ability of MIC27 to support complex formation with low efficiency may reflect stabilization of MIC10 (Figure 5—figure supplement 1L,N). These findings are in line with previous observations by Koob et al who reported that MIC27 expression positively correlated with the levels of MIC10, and proposed that MIC26 and MIC27 modulate MIC10 levels (Koob et al., 2015). Zerbes at al also reported that MIC27 promotes the stability of the MIC10 oligomers (Zerbes et al., 2016). Further studies are needed to address the underlying mechanism. Additionally, we note that fibroblasts from patients have highly enlarged mitochondrial structures, suggesting loss of appropriate mitochondrial fission-fusion cycles, and the absence of mitophagic destruction of damaged mitochondria. Similar defects in fusion-fission cycles and development of swollen mitochondria has been observed in cells lacking the MICOS subunit MIC60, suggesting that the observed phenotype is a general property of disruption of cristae structures (Li et al., 2016).

An additional interesting feature of both patients examined here is persistent urinary excretion of 3-methylglutaconic acid that might also be ascribed to mitochondrial cristae disassembly (Supplementary file 1A). 3-methylglutaconic aciduria is observed in other mitochondrial diseases, but most specifically in a new category of nuclear-encoded mitochondrial-related diseases, namely genetic defects of phospholipid biosynthesis, remodeling and metabolism (Garcia-Cazorla et al., 2015; Lu and Claypool, 2015; Mayr, 2015; Wortmann et al., 2013, 2015).

In conclusion, this report demonstrates that primary defects in mitochondrial inner membrane cristae architecture as observed with QIL1 deficiency causes severe mitochondrial disease in human clinically indistinguishable from primary oxidative phosphorylation respiratory chain disease. This is also the first report of early onset fatal mitochondrial encephalopathy in patients with mutations in a core MICOS complex subunit. CHCHD10 haploinsufficiency, found in a family with neurodegenerative disorders and mitochondrial respiratory chain defects also demonstrates impaired MICOS complex stability, cristae formation and mitochondrial genome organization (Genin et al., 2015). Noticeably, alterations of different MICOS subunit protein levels and amino acid substitutions have been associated with several conditions, such as diabetic cardiomyopathy, neurodegeneration and cancer in cellular and animal model systems (Zerbes et al., 2012). Taken together, our results suggest that QIL1 and other MICOS subunits represent potential candidates for mutations in patients with unexplained early onset neurological deterioration with optic and cerebellar atrophy progressing over time combined with liver disease and 3-methylglutaconic aciduria.

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Author details

1. Virginia Guarani

   Department of Cell Biology, Harvard Medical School, Boston, United States

   Contribution

   VG, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Claude Jardel

   Competing interests

   No competing interests declared.

2. Claude Jardel

   1. Inserm U1016, Institut Cochin, CNRS UMR 8104, Paris, France
   2. Department of Biochemistry, APHP, GHU Pitié-Salpêtrière, Paris, France
   3. Université Paris-Descartes, Paris, France

   Contribution

   CJ, Conception and design, Acquisition of data, Analysis and interpretation of data

   Contributed equally with

   Virginia Guarani

   Competing interests

   No competing interests declared.

3. Dominique Chrétien

   UMR1141, PROTECT, INSERM, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France

   Contribution

   DC, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   No competing interests declared.

4. Anne Lombès

   1. Inserm U1016, Institut Cochin, CNRS UMR 8104, Paris, France
   2. Department of Biochemistry, APHP, GHU Pitié-Salpêtrière, Paris, France
   3. Université Paris-Descartes, Paris, France

   Contribution

   AL, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   No competing interests declared.

5. Paule Bénit

   UMR1141, PROTECT, INSERM, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France

   Contribution

   PB, Acquisition of data, Analysis and interpretation of data

   Competing interests

   No competing interests declared.

6. Clémence Labasse

   Neuromuscular morphology unit, Institut de Myologie, GHU Pitié-Salpêtrière, APHP, Paris, France

   Contribution

   CL, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   No competing interests declared.

7. Emmanuelle Lacène

   Neuromuscular morphology unit, Institut de Myologie, GHU Pitié-Salpêtrière, APHP, Paris, France

   Contribution

   EL, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   No competing interests declared.

8. Agnès Bourillon

   Department of Biochemistry, Hôpital Robert Debré, APHP, Paris, France

   Contribution

   AB, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   No competing interests declared.

9. Apolline Imbard

   Department of Biochemistry, Hôpital Robert Debré, APHP, Paris, France

   Contribution

   AI, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   No competing interests declared.

10. Jean-François Benoist

    Department of Biochemistry, Hôpital Robert Debré, APHP, Paris, France

    Contribution

    J-FB, Conception and design, Acquisition of data, Analysis and interpretation of data

    Competing interests

    No competing interests declared.

11. Imen Dorboz

    UMR1141, PROTECT, INSERM, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France

    Contribution

    ID, Conception and design, Acquisition of data, Analysis and interpretation of data

    Competing interests

    No competing interests declared.

12. Mylène Gilleron

    1. Inserm U1016, Institut Cochin, CNRS UMR 8104, Paris, France
    2. Department of Biochemistry, APHP, GHU Pitié-Salpêtrière, Paris, France
    3. Université Paris-Descartes, Paris, France

    Contribution

    MG, Conception and design, Acquisition of data, Analysis and interpretation of data

    Competing interests

    No competing interests declared.

13. Eric S Goetzman

    1. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, United States
    2. University of Pittsburgh, Pittsburgh, United States
    3. Children's Hospital of Pittsburgh of UPMC, Pittsburgh, United States

    Contribution

    ESG, Conception and design, Acquisition of data, Analysis and interpretation of data

    Competing interests

    No competing interests declared.

14. Pauline Gaignard

    Department of Biochemistry, Hôpital Bicêtre, APHP, Paris, France

    Contribution

    PG, Conception and design, Acquisition of data, Analysis and interpretation of data

    Competing interests

    No competing interests declared.

15. Abdelhamid Slama

    Department of Biochemistry, Hôpital Bicêtre, APHP, Paris, France

    Contribution

    AS, Conception and design, Acquisition of data, Analysis and interpretation of data

    Competing interests

    No competing interests declared.

16. Monique Elmaleh-Bergès

    Department of Radiology, Hôpital Robert Debré, APHP, Paris, France

    Contribution

    ME-B, Conception and design, Acquisition of data, Analysis and interpretation of data

    Competing interests

    No competing interests declared.

17. Norma B Romero

    Neuromuscular morphology unit, Institut de Myologie, GHU Pitié-Salpêtrière, APHP, Paris, France

    Contribution

    NBR, Conception and design, Acquisition of data, Analysis and interpretation of data

    Competing interests

    No competing interests declared.

18. Pierre Rustin

    UMR1141, PROTECT, INSERM, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France

    Contribution

    PR, Conception and design, Acquisition of data, Analysis and interpretation of data

    Competing interests

    No competing interests declared.

19. Hélène Ogier de Baulny

    Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, APHP, Paris, France

    Contribution

    HOdB, Conception and design, Acquisition of data, Analysis and interpretation of data

    Competing interests

    No competing interests declared.

20. Joao A Paulo

    Department of Cell Biology, Harvard Medical School, Boston, United States

    Contribution

    JAP, Conception and design, Acquisition of data, Analysis and interpretation of data

    Competing interests

    No competing interests declared.

21. J Wade Harper

    Department of Cell Biology, Harvard Medical School, Boston, United States

    Contribution

    JWH, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    wade_harper@hms.harvard.edu

    Competing interests

    JWH: Reviewing Editor, eLife

    "This ORCID iD identifies the author of this article:" 0000-0002-6944-7236

22. Manuel Schiff

    1. UMR1141, PROTECT, INSERM, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France
    2. Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, APHP, Paris, France

    Contribution

    MS, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    manuel.schiff@aphp.fr

    Competing interests

    No competing interests declared.

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