Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models

Area of Science:

• Genetics and Molecular Biology
• Mitochondrial Biology
• Translational Medicine

Background:

• Pathogenic FBXL4 gene variants cause a multisystemic mitochondrial disorder with lactic acidemia.
• Current therapeutic options for FBXL4-related disease are limited, necessitating the development of new treatments.
• Understanding disease mechanisms requires robust preclinical models.

Purpose of the Study:

• To characterize translational C. elegans and zebrafish models of FBXL4 deficiency.
• To investigate disease mechanisms underlying FBXL4-related mitochondrial disorder.
• To identify and validate preclinical therapeutic leads for FBXL4 deficiency.

Main Methods:

• Established and analyzed fbxl-1 C. elegans and fbxl4sa12470 zebrafish mutant models.
• Utilized FBXL4-/- human fibroblasts for validation studies.
• Assessed mitochondrial function, lactate metabolism, and neurological/muscular activity.
• Investigated the therapeutic potential of dichloroacetate (DCA).

Main Results:

• FBXL4-deficient models exhibited developmental delay, impaired motor function, and mitochondrial dysfunction.
• Dichloroacetate (DCA) treatment improved fecundity, neuromotor activity, and mitochondrial function in C. elegans.
• DCA demonstrated efficacy in zebrafish and human fibroblasts, mitigating brain death, neurological deficits, and mitochondrial defects.

Conclusions:

• C. elegans and zebrafish serve as valuable translational models for FBXL4 deficiency research.
• Dichloroacetate (DCA) is a promising therapeutic candidate for FBXL4-related mitochondrial disease.
• Further clinical investigation of DCA in human patients is warranted.