Evidence that FBXL4 mutations cause Mitochondrial Disease

"Mutations in FBXL4, Encoding a Mitochondrial Protein, Cause Early-Onset Mitochondrial Encephalomyopathy" [2013]

• Original Publication identifying the FBXL4  gene in connection with Mitochondrial Disease

• Coauthored by labs from the United States, Germany, Italy, Saudi Arabia, and Austria.

• https://pmc.ncbi.nlm.nih.gov/articles/PMC3769923/

Evidence that FBXL4 regulates Mitophagy (retirement of mitochondria)

NEW findings in 2023 - Multiple labs across the world individually concluded the mitophagy pathway (BNIP3/NIX) which FBXL4 regulates. Understanding what this gene does is the first step to developing treatment. 

• Summary article

  • https://www.embopress.org/doi/full/10.15252/embj.2023114542 

• [2023] A mitochondrial SCF‐FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease

  • Beijing, China

  • https://www.embopress.org/doi/full/10.15252/embj.2022113033

• [2023] FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels

  • Liverpool, UK and Frankfurt, Germany

  • https://pubmed.ncbi.nlm.nih.gov/37102372/

• [2023] FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

  • Australia and United States

  • https://pubmed.ncbi.nlm.nih.gov/37161784/ 

• [2023] FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome

  • Shanghai, China

  • https://www.nature.com/articles/s41418-023-01205-1 

Evidence that PPTC7 is an essential cofactor for FBXL4

NEW findings in 2024 - Multiple labs across the world individually concluded the involvement of PPTC7 with FBXL4 processing. PPTC7 opens a new door for potential future treatment of FBXL4.

• [2024] A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass

  • Beijing, China

  • https://www.sciencedirect.com/science/article/abs/pii/S1097276523010146 

• [2024] Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX

  • Washington University (St. Louis) and University of Texas-Dallas

  • https://pmc.ncbi.nlm.nih.gov/articles/PMC11239977/ 

• [2024] PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/BNIP3L-dependent mitophagy

  • Shanghai, China

  • https://www.biorxiv.org/content/10.1101/2024.06.20.599818v1.full 

• [2024] PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4

  • Australia

  • https://pmc.ncbi.nlm.nih.gov/articles/PMC11316107/