F-box and leucine-rich repeat protein 4 (FBXL4)

F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein encoded by the FBXL4 gene and a member of the F-box protein family, characterized by an F-box motif and multiple leucine-rich repeats[1][4][7][9]. FBXL4 acts as a substrate recognition component of mitochondria-localized SCF (Skp1-Cullin-F-box) E3 ubiquitin ligase complexes, crucial for phosphorylation-dependent ubiquitination and mitophagy restriction[4][5]. The protein is localized in the mitochondrial intermembrane space and plays a key role in regulating mitochondrial DNA (mtDNA) maintenance, mitochondrial homeostasis, and overall bioenergetic function[2][5][7][9]. Loss-of-function mutations in FBXL4 cause FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome (OMIM #615471), which presents as early-onset multisystemic mitochondrial disease most prominently affecting the brain and muscles, often leading to severe developmental delay, hypotonia, lactic acidosis, and high childhood mortality[2][6][7][9]. FBXL4 deficiency disrupts the stability of mitochondrial DNA and reduces oxidative phosphorylation, underpinning the disease pathology[5][6][7]. FBXL4 is not currently considered a direct therapeutic target for small molecule or biologic drugs, and no drug interventions are known to act on it directly[4][7][9].

Other names

F-box and leucine rich repeat protein 4FBXL4FBL4FBL5MTDPS13F-box protein FBL4F-box protein FBL5

Not established for therapeutic targeting in humans; disruptions affect mitochondrial DNA content and function