Fbxl4, or F-box and leucine-rich repeat protein 4, is a mitochondrial protein. It forms an SCF-FBXL4 ubiquitin E3 ligase complex that localizes to the mitochondrial outer membrane. This complex is involved in the regulation of mitophagy, a key mitochondrial quality control mechanism, by ubiquitinating and degrading mitophagy receptors BNIP3 and NIX [1,2,3,4,5]. It also plays roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics [6].

Fbxl4 -/- mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Knockout of either Bnip3 or Nix can rescue the metabolic derangements and viability of these Fbxl4 -/- mice, indicating that hyperactivated mitophagy due to Fbxl4 deficiency is a cause of mitochondrial disease [1]. In addition, FBXL4-knockout mice show a global reduction in mitochondrial proteins and mtDNA depletion, while lysosomal proteins are upregulated, suggesting increased mitochondrial turnover via autophagy [7].

In conclusion, Fbxl4 is crucial for restraining basal mitophagy through the degradation of BNIP3 and NIX, safeguarding against mitochondrial depletion. Studies using Fbxl4-knockout mouse models have revealed its role in mitochondrial diseases such as mitochondrial DNA depletion syndrome, highlighting its significance in understanding the pathophysiology of these disorders and potentially guiding therapeutic strategies [1,4,6,7].