Publication year
2013Author(s)
Source
Human Molecular Genetics, 22, 15, (2013), pp. 3138-3151ISSN
Publication type
Article / Letter to editor
Display more detailsDisplay less details
Organization
Human Genetics
Dermatology
Laboratory of Genetic, Endocrine and Metabolic Diseases
Paediatrics - OUD tm 2017
Pathology
CMBI
Journal title
Human Molecular Genetics
Volume
vol. 22
Issue
iss. 15
Page start
p. 3138
Page end
p. 3151
Subject
IGMD 3: Genomic disorders and inherited multi-system disorders; IGMD 3: Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory; IGMD 8: Mitochondrial medicine; IGMD 8: Mitochondrial medicine NCMLS 4: Energy and redox metabolism; N4i 1: Pathogenesis and modulation of inflammation NCMLS 1: Infection and autoimmunity; NCMLS 4: Energy and redox metabolism IGMD 8: Mitochondrial medicine; NCMLS 6: Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory; NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disorders; Laboratory Medicine Radboud University Medical CenterAbstract
It is estimated that the human mitochondrial proteome consists of 1000-1500 distinct proteins. The majority of these support the various biochemical pathways that are active in these organelles. Individuals with an oxidative phosphorylation disorder of unknown cause provide a unique opportunity to identify novel genes implicated in mitochondrial biology. We identified a homozygous deletion of CEP89 in a patient with isolated complex IV deficiency, intellectual disability and multisystemic problems. CEP89 is a ubiquitously expressed and highly conserved gene of unknown function. Immunocytochemistry and cellular fractionation experiments showed that CEP89 is present both in the cytosol and in the mitochondrial intermembrane space. Furthermore, we ascertained in vitro that downregulation of CEP89 resulted in a severe decrease in complex IV in-gel activity and altered mobility, suggesting that the complex is aberrantly formed. Two-dimensional BN-SDS gel analysis revealed that CEP89 associates with a high-molecular weight complex. Together, these data confirm a role for CEP89 in mitochondrial metabolism. In addition, we modeled CEP89 loss of function in Drosophila. Ubiquitous knockdown of fly Cep89 decreased complex IV activity and resulted in complete lethality. Furthermore, Cep89 is required for mitochondrial integrity, membrane depolarization and synaptic transmission of photoreceptor neurons, and for (sub)synaptic organization of the larval neuromuscular junction. Finally, we tested neuronal Cep89 knockdown flies in the light-off jump reflex habituation assay, which revealed its role in learning. We conclude that CEP89 proteins play an important role in mitochondrial metabolism, especially complex IV activity, and are required for neuronal and cognitive function across evolution.
This item appears in the following Collection(s)
- Academic publications [245348]
- Faculty of Medical Sciences [93207]
Upload full text
Use your RU credentials (u/z-number and password) to log in with SURFconext to upload a file for processing by the repository team.