Fbxl4, or F-box and leucine-rich repeat protein 4, is a mitochondrial protein. It functions as an integral outer-membrane protein forming an SCF-FBXL4 ubiquitin E3 ligase complex, which is involved in the regulation of mitophagy, a fundamental mitochondrial quality-control mechanism. It also plays roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics, making it biologically important [1,3,5].

Fbxl4 knockout (KO) mouse models have been crucial in understanding its functions. Fbxl4-/-mice exhibit elevated levels of mitophagy receptors BNIP3 and NIX, hyperactive mitophagy, and perinatal lethality. Knockout of either Bnip3 or Nix can rescue the metabolic derangements and viability of Fbxl4-/-mice, indicating that Fbxl4 restrains basal mitophagy by degrading BNIP3 and NIX [1]. In another context, in a "two-hit" mouse model mimicking obesity and hypertension, transfection of FBXL4 rescued against heart failure with preserved ejection fraction (HFpEF)-compromised diastolic function, cardiac geometry, and mitochondrial integrity by regulating mitochondrial dynamics through Drp1 [2].

In conclusion, Fbxl4 is essential for maintaining mitochondrial homeostasis. Its function in restraining mitophagy through the degradation of BNIP3 and NIX is critical. Model-based research, especially the Fbxl4 KO mouse models, has revealed its significance in mitochondrial-related diseases such as mitochondrial DNA depletion syndrome and HFpEF, providing insights into potential therapeutic strategies for these conditions [1,2,4].