FBXL4 is a mitochondrial F-box protein that functions as a substrate-recognition component of the SCF-FBXL4 ubiquitin E3 ligase complex, playing a critical role in restricting mitophagy and maintaining mitochondrial homeostasis 1. FBXL4 mediates the ubiquitination and proteasomal degradation of the mitophagy receptors NIX and BNIP3, thereby suppressing basal mitophagy under steady-state conditions 21. Additionally, FBXL4 regulates mitochondrial dynamics by promoting Drp1 ubiquitination and degradation, preventing hyperactivation of Drp1-mediated mitochondrial fission 3. Loss of FBXL4 function leads to excessive accumulation of NIX and BNIP3, resulting in uncontrolled mitophagy and mitochondrial depletion 2. Biallelic FBXL4 mutations cause mitochondrial DNA depletion syndrome 13 (MTDPS13), a severe multisystem genetic disorder characterized by lactic acidemia, developmental delay, hypotonia, seizures, and combined electron transport chain deficiencies due to impaired mtDNA maintenance 4. Recent evidence demonstrates FBXL4's protective role in heart failure with preserved ejection fraction, where it rescues diastolic dysfunction and mitochondrial injury through Drp1 regulation 3. The stability of the SCF-FBXL4 complex and its substrate recognition require functional F-box and leucine-rich repeat domains, which are disrupted in disease-causing mutations 1.