Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome

Mitochondrial complex I (CI) is an essential component in energy production through oxidative phosphorylation. Most CI subunits are encoded by nuclear genes, translated in the cytoplasm, and imported into mitochondria. Upon entry, they are embedded into the mitochondrial inner membrane. How these membrane-associated proteins cope with the hydrophilic cytoplasmic environment before import is unknown. In a forward genetic screen to identify genes that cause neurodegeneration, we identified sicily, the Drosophila melanogaster homologue of human C8ORF38, the loss of which causes Leigh syndrome. We show that in the cytoplasm, Sicily preprotein interacts with cytosolic Hsp90 to chaperone the CI subunit, ND42, before mitochondrial import. Loss of Sicily leads to loss of CI proteins and preproteins in both mitochondria and cytoplasm, respectively, and causes a CI deficiency and neurodegeneration. Our data indicate that cytosolic chaperones are required for the subcellular transport of ND42.

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Leigh Syndrome Associated With Mitochondrial Complex I Deficiency Due to a Novel Mutation in the NDUFS1 Gene

Archives of Neurology ◽

10.1001/archneur.62.4.659 ◽

2005 ◽

Vol 62 (4) ◽

pp. 659 ◽

Cited By ~ 52

Author(s):

Miguel A. Martín ◽

Alberto Blázquez ◽

Luis G. Gutierrez-Solana ◽

Daniel Fernández-Moreira ◽

Paz Briones ◽

...

Keyword(s):

Complex I ◽

Novel Mutation ◽

Leigh Syndrome ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Complex I Deficiency

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NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect

European Journal of Human Genetics ◽

10.1038/ejhg.2017.133 ◽

2017 ◽

Vol 25 (11) ◽

pp. 1273-1277 ◽

Cited By ~ 12

Author(s):

Fabian Baertling ◽

Laura Sánchez-Caballero ◽

Mariël A M van den Brand ◽

Liesbeth T Wintjes ◽

Maaike Brink ◽

...

Keyword(s):

Complex I ◽

Leigh Syndrome ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Complex I Assembly ◽

Assembly Defect

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A high mutation load of m.14597A>G in MT-ND6 causes Leigh syndrome

Scientific Reports ◽

10.1038/s41598-021-90196-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yoshihito Kishita ◽

Kaori Ishikawa ◽

Kazuto Nakada ◽

Jun-Ichi Hayashi ◽

Takuya Fushimi ◽

...

Keyword(s):

Cell Lines ◽

Complex I ◽

Neurodegenerative Disorder ◽

Rflp Analysis ◽

Leigh Syndrome ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Mutation Load ◽

Atp Production ◽

Cybrid Cell

AbstractLeigh syndrome (LS) is an early-onset progressive neurodegenerative disorder associated with mitochondrial deficiency. m.14597A>G (p.Ile26Thr) in the MT-ND6 gene was reported to cause Leberʼs hereditary optic neuropathy (LHON) or dementia/dysarthria. In previous reports, less than 90% heteroplasmy was shown to result in adult-onset disease. Here, by whole mitochondrial sequencing, we identified m.14597A>G mutation of a patient with LS. PCR–RFLP analysis on fibroblasts from the patient revealed a high mutation load (> 90% heteroplasmy). We performed functional assays using cybrid cell models generated by fusing mtDNA-less rho0 HeLa cells with enucleated cells from patient fibroblasts carrying the m.14597A>G variant. Cybrid cell lines bearing the m.14597A>G variant exhibited severe effects on mitochondrial complex I activity. Additionally, impairment of cell proliferation, decreased ATP production and reduced oxygen consumption rate were observed in the cybrid cell lines bearing the m.14597A>G variant when the cells were metabolically stressed in medium containing galactose, indicating mitochondrial respiratory chain defects. These results suggest that a high mutation load of m.14597A>G leads to LS via a mitochondrial complex I defect, rather than LHON or dementia/dysarthria.

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Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout mice

PeerJ ◽

10.7717/peerj.3339 ◽

2017 ◽

Vol 5 ◽

pp. e3339 ◽

Cited By ~ 6

Author(s):

Mei Wang ◽

Ya-Ping Huang ◽

Han Wu ◽

Ke Song ◽

Cong Wan ◽

...

Keyword(s):

Embryonic Development ◽

Complex I ◽

Molecular Mechanisms ◽

Leigh Syndrome ◽

Developmental Rate ◽

Early Embryonic Development ◽

Preimplantation Embryos ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Exon 2

Background The NDUFS4 gene encodes an 18-kD subunit of mitochondria complex I, and mutations in this gene lead to the development of a severe neurodegenerative disease called Leigh syndrome (LS) in humans. To investigate the disease phenotypes and molecular mechanisms of Leigh syndrome, the Ndufs4 knockout (KO) mouse has been widely used as a novel animal model. Because the homozygotes cannot survive beyond child-bearing age, whether Ndufs4 and mitochondrial complex I influence early embryonic development remains unknown. In our study, we attempted to investigate embryonic development in Ndufs4 KO mice, which can be regarded as a Leigh disease model and were created through the CRISPR (clustered regularly interspaced short palindromic repeat) and Cas9 (CRISPR associated)-mediated genome editing system. Methods We first designed a single guide RNA (sgRNA) targeting exon 2 of Ndufs4 to delete the NDUFS4 protein in mouse embryos to mimic Leigh syndrome. Then, we described the phenotypes of our mouse model by forced swimming and the open-field test as well as by assessing other behavioral characteristics. Intracytoplasmic sperm injection (ICSI) was performed to obtain KO embryos to test the influence of NDUFS4 deletion on early embryonic development. Results In this study, we first generated Ndufs4 KO mice with physical and behavioral phenotypes similar to Leigh syndrome using the CRISPR/Cas9 system. The low developmental rate of KO embryos that were derived from knockout gametes indicated that the absence of NDUFS4 impaired the development of preimplantation embryos. Discussion In this paper, we first obtained Ndufs4 KO mice that could mimic Leigh syndrome using the CRISPR/Cas9 system. Then, we identified the role of NDUFS4 in early embryonic development, shedding light on its roles in the respiratory chain and fertility. Our model provides a useful tool with which to investigate the function of Ndufs4. Although the pathological mechanisms of the disease need to be discovered, it helps to understand the pathogenesis of NDUFS4 deficiency in mice and its effects on human diseases.

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Structural Effects of Leigh Syndrome Mutations on the Function of Human Mitochondrial Complex-I Q module

Biochemistry & Physiology Open Access ◽

10.4172/2168-9652.s2-004 ◽

2013 ◽

Vol s2 ◽

Author(s):

Tulika M Jaokar ◽

Ranu Sharma ◽

Suresh CG

Keyword(s):

Complex I ◽

Leigh Syndrome ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Structural Effects

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Mutated ND2 impairs mitochondrial complex I assembly and leads to Leigh Syndrome

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2006.08.003 ◽

2007 ◽

Vol 90 (1) ◽

pp. 10-14 ◽

Cited By ~ 42

Author(s):

Cristina Ugalde ◽

Reetta Hinttala ◽

Sharita Timal ◽

Roel Smeets ◽

Richard J.T. Rodenburg ◽

...

Keyword(s):

Complex I ◽

Leigh Syndrome ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Complex I Assembly

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Roles for Mitochondrial Complex I subunits in regulating synaptic transmission and growth

10.1101/2021.12.30.474605 ◽

2022 ◽

Author(s):

Bhagaban Mallik ◽

C. Andrew Frank

Keyword(s):

Complex I ◽

Genetic Factors ◽

Protein Complexes ◽

Leigh Syndrome ◽

Genetic Screen ◽

Mitochondrial Complex I ◽

Subunit Gene ◽

Mitochondrial Complex ◽

Parkinsons Disease ◽

Cellular Bioenergetics

To identify conserved components of synapse function that are also associated with human diseases, we conducted a genetic screen. We used the Drosophila melanogaster neuromuscular junction (NMJ) as a model. We employed RNA interference (RNAi) on selected targets and assayed synapse function by electrophysiology. We focused our screen on genetic factors known to be conserved from human neurological or muscle functions (321 total RNAi lines screened). Knockdown of a particular Mitochondrial Complex I (MCI) subunit gene (ND-20L) lowered levels of NMJ neurotransmission. Due to the severity of the phenotype, we studied MCI function further. Knockdown of core MCI subunits concurrently in neurons and muscle led to impaired neurotransmission. Further, pharmacology targeting MCI phenocopied the impaired neurotransmission phenotype. Finally, MCI subunit knockdowns led to profound cytological defects, including reduced NMJ growth and altered NMJ morphology. Mitochondria are essential for cellular bioenergetics and produce ATP through oxidative phosphorylation. Five multi-protein complexes achieve this task, and MCI is the largest. Impaired Mitochondrial Complex I subunits in humans are associated with disorders such as Parkinsons disease, Leigh syndrome, and cardiomyopathy. Together, our data present an analysis of Complex I in the context of synapse function and plasticity. We speculate that in the context of human MCI dysfunction, similar neuronal and synaptic defects could contribute to pathogenesis.

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