RESUMEN
Nuclear genetic disorders causing mitochondrial DNA (mtDNA) depletion are clinically and genetically heterogeneous, and the molecular etiology remains undiagnosed in the majority of cases. Through whole-exome sequencing, we identified recessive nonsense and splicing mutations in FBXL4 segregating in three unrelated consanguineous kindreds in which affected children present with a fatal encephalopathy, lactic acidosis, and severe mtDNA depletion in muscle. We show that FBXL4 is an F-box protein that colocalizes with mitochondria and that loss-of-function and splice mutations in this protein result in a severe respiratory chain deficiency, loss of mitochondrial membrane potential, and a disturbance of the dynamic mitochondrial network and nucleoid distribution in fibroblasts from affected individuals. Expression of the wild-type FBXL4 transcript in cell lines from two subjects fully rescued the levels of mtDNA copy number, leading to a correction of the mitochondrial biochemical deficit. Together our data demonstrate that mutations in FBXL4 are disease causing and establish FBXL4 as a mitochondrial protein with a possible role in maintaining mtDNA integrity and stability.
Asunto(s)
ADN Mitocondrial/genética , Proteínas F-Box/genética , Predisposición Genética a la Enfermedad , Encefalomiopatías Mitocondriales/genética , Mutación/genética , Ubiquitina-Proteína Ligasas/genética , Acidosis Láctica/complicaciones , Acidosis Láctica/genética , Acidosis Láctica/patología , Secuencia de Bases , Niño , Preescolar , Segregación Cromosómica/genética , Transporte de Electrón/genética , Proteínas F-Box/química , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Dosificación de Gen/genética , Genes Recesivos/genética , Humanos , Lactante , Recién Nacido , Masculino , Encefalomiopatías Mitocondriales/complicaciones , Encefalomiopatías Mitocondriales/patología , Datos de Secuencia Molecular , Músculo Esquelético/patología , Fosforilación Oxidativa , Linaje , Transporte de Proteínas , Ubiquitina-Proteína Ligasas/químicaRESUMEN
Mitochondrial dynamics are essential for maintaining organelle stability and function. Through fission, fusion and mitophagic events, optimal populations of mitochondria are retained. Subsequently, alterations in such processes can have profound effects on the individual mitochondrion and the cell within which they reside. Neurons are post-mitotic energy-dependent cells and, as such, are particularly vulnerable to alterations in cellular bioenergetics and increased stress that may occur as a direct or indirect result of mitochondrial dysfunction. The trafficking of mitochondria to areas of higher energy requirements, such as synapses, where mitochondrial densities fluctuate, further highlights the importance of efficient mitochondrial dynamics in neurons. PD (Parkinson's disease) is a common progressive neurodegenerative disorder which is characterized by the loss of dopaminergic neurons within the substantia nigra. Complex I, the largest of all of the components of the electron transport chain is heavily implicated in PD pathogenesis. The exact series of events that lead to cell loss, however, are not fully elucidated, but are likely to involve dysfunction of mitochondria, their trafficking and dynamics.