On August 12, 2023, the research teams led by Professor Chenji Wang from the School of Life Sciences, Professor Lixiang Ma from the School of Basic Medical Sciences, and Professor Shimin Zhao from the Institute of Metabolism and Integrative Biology at Fudan University, together with the research group led by Professor Yucai Chen from Shanghai Children's Hospital, published a research paper entitled “FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome” in Cell Death & Differentiation.

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.

Fig. 1: A working model proposed in this study.

Link: https://doi.org/10.1038/s41418-023-01205-1