Replacement of the C6ORF66 Assembly Factor (NDUFAF4) Restores Complex I Activity in Patient Cells

Marcus, Dana; Lichtenstein, Michal; Saada, Ann; Lorberboum-Galski, Haya

doi:10.2119/molmed.2012.00343

Cited by 22 publications

(17 citation statements)

References 39 publications

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“…The consequences of NDUFAF4 variants for CI assembly in patient fibroblasts have previously not been studied. 2,6,11 Our recently published detailed human CI assembly model has shown that the CI assembly process mirrors its modular architecture: 1 subunits of the different functional modules are assembled separately and most intermodular association does not take place until the final steps of CI biogenesis. NDUFAF4 is associated with assembly intermediates of the Q-module.…”

Section: Discussionmentioning

confidence: 99%

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

Baertling

Sánchez‐Caballero²,

Brand³

et al. 2017

Eur J Hum Genet

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Mitochondrial respiratory chain complex I consists of 44 different subunits and can be subgrouped into three functional modules: the Q-, the P- and the N-module. NDUFAF4 (C6ORF66) is an assembly factor of complex I that associates with assembly intermediates of the Q-module. Via exome sequencing, we identified a homozygous missense variant in a complex I-deficient patient with Leigh syndrome. Supercomplex analysis in patient fibroblasts revealed specifically altered stoichiometry. Detailed assembly analysis of complex I, indicative of all of its assembly routes, showed an accumulation of parts of the P- and the N-module but not the Q-module. Lentiviral complementation of patient fibroblasts with wild-type NDUFAF4 rescued complex I deficiency and the assembly defect, confirming the causal role of the variant. Our report on the second family affected by an NDUFAF4 variant further characterizes the phenotypic spectrum and sheds light into the role of NDUFAF4 in mitochondrial complex I biogenesis.

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Section: Discussionmentioning

confidence: 99%

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

Baertling

Sánchez‐Caballero²,

Brand³

et al. 2017

Eur J Hum Genet

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“…In the past decade, several groups have been successful in this endeavor. A group out of Hebrew University–Hadassah Medical School, led by Hala Lorberboum-Galski, has developed and successfully delivered functional proteins to the mitochondria in vitro to restore defects in the electron transport chain (51) and acetyl Co-A production (52) associated with life-threatening mitochondrial disease. Other groups have also demonstrated the ability to deliver functional copies of proteins into cells to alleviate dysfunctional proteins associated with mitochondrial and lysosomal diseases.…”

Section: Busting Out: Escape From the Endosomementioning

confidence: 99%

Breaking in and busting out: cell-penetrating peptides and the endosomal escape problem

LeCher

Nowak

McMurry

2017

Biomolecular Concepts

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Cell-penetrating peptides (CPPs) have long held great promise for the manipulation of living cells for therapeutic and research purposes. They allow a wide array of biomolecules from large, oligomeric proteins to nucleic acids and small molecules to rapidly and efficiently traverse cytoplasmic membranes. With few exceptions, if a molecule can be associated with a CPP, it can be delivered into a cell. However, a growing realization in the field is that CPP-cargo fusions largely remain trapped in endosomes and are eventually targeted for degradation or recycling rather than released into the cytoplasm or trafficked to a desired subcellular destination. This ‘endosomal escape problem’ has confounded efforts to develop CPP-based delivery methods for drugs, enzymes, plasmids, etc. This conceptual overview provides a brief history of CPP research and discusses current issues in the field with a primary focus on the endosomal escape problem, of which several promising potential solutions have been developed. Are we on the verge of developing technologies to deliver therapeutics such as siRNA, CRISPR/Cas complexes and others that are currently failing because of an inability to get into cells, or are we just chasing after another promising but unworkable technology? We make the case for optimism.

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“…While TAT–Ndi1 was introduced into Langendorff‐perfused rat hearts, this fusion protein was not only localized to mitochondria but also significantly ameliorated reperfusion injury. In 2013, Marcus et al . applied the TAT system to deliever the protein NADH dehydrogenase (ubiquinone) complex I, assembly factor 4 (NDUFAF4; or C6orf66) into patient cells and their mitochondria, leading to the proper assembly and function of complex I.…”

Section: Tat‐mediated Protein Transduction For Complex I Deficiencymentioning

confidence: 99%

Therapeutic applications of the TAT‐mediated protein transduction system for complex I deficiency and other mitochondrial diseases

Lin

Kao

2015

Annals of the New York Academy of Sciences

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Among the five enzyme complexes in the oxidative phosphorylation system, NADH-coenzyme Q oxidoreductase (also called complex I) is the largest, most intricate, and least understood. This enzyme complex spans the inner mitochondrial membrane and catalyzes the first step of electron transfer by the oxidation of NADH, and thereby provides two electrons for the reduction of quinone to quinol. Complex I deficiency is associated with many severe mitochondrial diseases, including Leber hereditary optic neuropathy and Leigh syndrome. However, to date, conventional treatments for the majority of genetic mitochondrial diseases are only palliative. Developing a reliable and convenient therapeutic approach is therefore considered to be an urgent need. Targeted proteins fused with the protein transduction domain of human immunodeficiency virus 1 transactivator of transcription (TAT) have been shown to enter cells by crossing plasma membranes while retaining their biological activities. Recent developments show that, in fusion with mitochondrial targeting sequences (MTSs), TAT-MTS-bound cargo can be correctly transported into mitochondria and restore the missing function of the cargo protein in patients' cells. The available evidence suggests that the TAT-mediated protein transduction system holds great promise as a potential therapeutic approach to treat complex I deficiency, as well as other mitochondrial diseases.

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Replacement of the C6ORF66 Assembly Factor (NDUFAF4) Restores Complex I Activity in Patient Cells

Cited by 22 publications

References 39 publications

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

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

Breaking in and busting out: cell-penetrating peptides and the endosomal escape problem

Therapeutic applications of the TAT‐mediated protein transduction system for complex I deficiency and other mitochondrial diseases

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