Although mutations in CYTB (cytochrome b) or BCS1L have been reported in isolated defects of mitochondrial respiratory chain complex III (cIII), most cIII-defective individuals remain genetically undefined. We identified a homozygous nonsense mutation in the gene encoding tetratricopeptide 19 (TTC19) in individuals from two families affected by progressive encephalopathy associated with profound cIII deficiency and accumulation of cIII-specific assembly intermediates. We later found a second homozygous nonsense mutation in a fourth affected individual. We demonstrated that TTC19 is embedded in the inner mitochondrial membrane as part of two high–molecular‐weight complexes, one of which coincides with cIII. We then showed a physical interaction between TTC19 and cIII by coimmunoprecipitation. We also investigated a Drosophila melanogaster knockout model for TTC19 that showed low fertility, adult-onset locomotor impairment and bang sensitivity, associated with cIII deficiency. TTC19 is a putative cIII assembly factor whose disruption is associated with severe neurological abnormalities in humans and flies.
At a glance
- Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex. Science 281, 64–71 (1998). et al.
- Isolation of the eleven protein subunits of the bc1 complex from beef heart. Methods Enzymol. 126, 224–237 (1986). , , &
- Blue native PAGE. Nat. Protoc. 1, 418–428 (2006). , &
- Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. Hum. Mol. Genet. 16, 1241–1252 (2007). et al.
- Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome. Am. J. Hum. Genet. 79, 878–889 (2006). et al.
- A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123 (2008). et al.
- PtdIns(3)P controls cytokinesis through KIF13A mediated recruitment of FYVE-CENT to the midbody. Nat. Cell Biol. 12, 362–371 (2010). et al.
- The mitochondrial targeting presequence of the Rieske iron-sulfur protein is processed in a single step after insertion into the cytochrome bc1 complex in mammals and retained as a subunit in the complex. J. Biol. Chem. 268, 8387–8390 (1993). , , &
- Bcs1p, an AAA-family member, is a chaperone for the assembly of the cytochrome bc(1) complex. EMBO J. 18, 5226–5233 (1999). , , , &
- Further insights into the assembly of the yeast cytochrome bc1 complex based on analysis of single and double deletion mutants lacking supernumerary subunits and cytochrome b . Eur. J. Biochem. 271, 1209–1218 (2004). , , &
- PPR (pentatricopeptide repeat) proteins in mammals: important aids to mitochondrial gene expression. Biochem. J. 416, e5–e6 (2008). &
- The PPR motif—a TPR-related motif prevalent in plant organellar proteins. Trends Biochem. Sci. 25, 46–47 (2000). &
- Genetic dissection of meiotic cytokinesis in Drosophila males. Mol. Biol. Cell 15, 2509–2522 (2004). et al.
- Drosophila couch potato mutants exhibit complex neurological abnormalities including epilepsy phenotypes. Genetics 169, 2137–2149 (2005). &
- Post-transcriptional silencing and functional characterization of the Drosophila melanogaster homolog of human Surf1. Genetics 172, 229–241 (2006). et al.
- Fly motion vision. Annu. Rev. Neurosci. 33, 49–70 (2010). , &
- Mitochondrial respiratory chain complex assembly and function during human fetal development. Mol. Genet. Metab. 94, 120–126 (2008). et al.
- The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. Bioessays 21, 932–939 (1999). &
- Maturation of steroid receptors: an example of functional cooperation among molecular chaperones and their associated proteins. Cell Stress Chaperones 5, 76–86 (2000). &
- BCS1L is expressed in critical regions for neural development during ontogenesis in mice. Gene Expr. Patterns 7, 266–273 (2007). et al.
- Mitochondrial oxidative phosphorylation changes in the life span. Molecular aspects and physiopathological implications. Biochim. Biophys. Acta 1276, 87–105 (1996).
- Clinical and molecular findings in children with complex I deficiency. Biochim. Biophys. Acta 1659, 136–147 (2004). et al.
- Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. Am. J. Physiol. Cell Physiol. 292, C125–C136 (2007). et al.
- Characterization of SURF-1 expression and Surf-1p function in normal and disease conditions. Hum. Mol. Genet. 8, 2533–2540 (1999). et al.
- Down-regulation of CXCR4 expression by SDF-KDEL in CD34(+) hematopoietic stem cells: an antihuman immunodeficiency virus strategy. J. Virol. Methods 16, 30–37 (2009). et al.
- Paroxysmal non-kinesigenic dyskinesia is caused by mutations of the MR-1 mitochondrial targeting sequence. Hum. Mol. Genet. 18, 1058–1064 (2009). et al.
- Needle biopsy of skeletal muscle. Muscle Nerve 7, 594 (1984). &
- Cytochemistry and immunocytochemistry of mitochondria in tissue sections. Methods Enzymol. 264, 509–521 (1996). &
- Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am. J. Hum. Genet. 63, 1609–1621 (1998). et al.
- Blue native electrophoresis to study mitochondrial and other protein complexes. Methods 26, 327–334 (2002). , &
- Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal. Biochem. 166, 368–379 (1987). &
- In vivo and in organello analyses of mitochondrial translation. Methods Cell Biol. 80, 571–588 (2007). , , , &
- In vivo labeling and analysis of human mitochondrial translation products. Methods Enzymol. 264, 197–211 (1996).
- Systematic generation of high-resolution deletion coverage of the Drosophila melanogaster genome. Nat. Genet. 36, 288–292 (2004). et al.
- A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila . Nature 448, 151–156 (2007). et al.
- Supplementary Text and Figures (7M)
Supplementary Note, Supplementary Figures 1–12 and Supplementary Tables 1–5