FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

Abstract

To maintain both mitochondrial quality and quantity, cells selectively remove damaged or excessive mitochondria through mitophagy, which is a specialised form of autophagy. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation and mitochondrial damage. However, the mechanisms that govern the removal of specific dysfunctional mitochondria under steady‐state conditions to fine‐tune mitochondrial content are not well understood. Here, we report that SCF FBXL4 , an SKP1/CUL1/F‐box protein ubiquitin ligase complex, localises to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that the pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13) do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism whereby FBXL4 actively suppresses mitophagy by preventing NIX and BNIP3 accumulation. We propose that the dysregulation of NIX and BNIP3 turnover causes excessive basal mitophagy in FBXL4‐associated mtDNA depletion syndrome. image How are specific dysfunctional mitochondria removed under steady‐state conditions? This study shows that FBXL4, encoded by the gene mutated in encephalopathic mtDNA depletion syndrome (MTDPS13), suppresses steady‐state mitophagy through ubiquitylation and turnover of NIX and BNIP3 mitophagy receptors. SCF ubiquitin ligase receptor FBXL4 localises to the mitochondrial outer membrane to mediate the ubiquitylation and degradation of BNIP3 and NIX mitophagy receptors. FBXL4 deficiency results in elevated mitophagy due to the stabilisation of NIX/BNIP3 mitophagy receptors. MTDPS13‐associated variants in FBXL4 are less efficient at mediating the turnover of BNIP3 and NIX and mitophagy restriction.