期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1865, 期 11, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbadis.2019.165536
关键词
Mitochondria; Mitochondrial DNA depletion; Mitochondrial fusion; FBXL4; Dichloroacetate
资金
- Genome Canada
- Canadian Institutes of Health Research
- Ontario Genomics Institute
- Genome Alberta
- Genome British Columbia
- Genome Quebec
- Children's Hospital of Eastern Ontario Foundation
- Alberta Children's Hospital Research Institute (ACHRI)
- Alberta Children's Hospital Foundation
- Natural Sciences and Engineering Research Council of Canada [NSERC - RGPIN-2016-04083]
- Queen Elizabeth II Graduate Scholarship
- ACHRI Graduate Studentship
- Mito Canada
- Ontario Research Fund
Mutations in FBXL4 (F-Box and Leucine rich repeat protein 4), a nuclear-encoded mitochondrial protein with an unknown function, cause mitochondrial DNA depletion syndrome. We report two siblings, from consanguineous parents, harbouring a previously uncharacterized homozygous variant in FBXL4 (c.1750 T > C; p.Cys584Arg). Both patients presented with encephalomyopathy, lactic acidosis and cardiac hypertrophy, which are reported features of FBXL4 impairment. Remarkably, dichloroacetate (DCA) administration to the younger sibling improved metabolic acidosis and reversed cardiac hypertrophy. Characterization of FBXL4 patient fibroblasts revealed severe bioenergetic defects, mtDNA depletion, fragmentation of mitochondrial networks, and abnormalities in mtDNA nucleoids. These phenotypes, observed with other pathogenic FBXL4 variants, confirm the pathogenicity of the p.Cys584Arg variant. Although treating FBXL4 fibroblasts with DCA improved extracellular acidification, in line with reduced lactate levels in patients, DCA treatment did not improve any of the other mitochondria' functions. Nonetheless, we highlight DCA as a potentially effective drug for the management of elevated lactate and cardiomyopathy in patients with pathogenic FBXL4 variants. Finally, as the exact mechanism through which FBXL4 mutations lead to mtDNA depletion was unknown, we tested the hypothesis that FBXL4 promotes mitochondrial fusion. Using a photo-activatable GFP fusion assay, we found reduced mitochondrial fusion rates in cells harbouring a pathogenic FBXL4 variant. Meanwhile, overexpression of wildtype FBXL4, but not the p.Cys584Arg variant, promoted mitochondria' hyperfusion. Thus, we have uncovered a novel function for FBXL4 in promoting mitochondrial fusion, providing important mechanistic insights into the pathogenic mechanism underlying FBXL4 dysfunction.
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