FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome

Mitochondria are essential organelles found in eukaryotic cells that play a crucial role in ATP production through oxidative phosphorylation (OXPHOS). Mitochondrial DNA depletion syndrome (MTDPS) is a group of genetic disorders characterized by the reduction of mtDNA copy number, leading to deficiencies in OXPHOS and mitochondrial functions. Mutations in FBXL4, a substrate-binding adaptor of Cullin 1-RING ubiquitin ligase complex (CRL1), are associated with MTDPS, type 13 (MTDPS13). Here, we demonstrate that, FBXL4 directly interacts with the mitophagy cargo receptors BNIP3 and BNIP3L, promoting their degradation through the ubiquitin-proteasome pathway via the assembly of an active CRL1(FBXL4) complex. However, MTDPS13-associated FBXL4 mutations impair the assembly of an active CRL1(FBXL4) complex. This results in a notable accumulation of BNIP3/3L proteins and robust mitophagy even at basal levels. Excessive mitophagy was observed in Knockin (KI) mice carrying a patient-derived FBXL4 mutation and cortical neurons (CNs)-induced from MTDPS13 patient human induced pluripotent stem cells (hiPSCs). In summary, our findings suggest that abnormal activation of BNIP3/BNIP3L-dependent mitophagy impairs mitochondrial homeostasis and underlies FBXL4-mutated MTDPS13.

Automated summary

Mitochondria are essential organelles in eukaryotic cells that produce ATP through OXPHOS. MTDPS is a genetic disorder characterized by reduced mtDNA copy number, resulting in OXPHOS and mitochondrial function deficiencies. Mutations in FBXL4 are associated with MTDPS13. It was found that FBXL4 interacts with BNIP3 and BNIP3L and promotes their degradation through the ubiquitin-proteasome pathway. However, MTDPS13-associated FBXL4 mutations impair this process, leading to excessive mitophagy and mitochondrial dysfunction.