FBXL 4 deficiency increases mitochondrial removal by autophagy

Abstract

Pathogenic variants in FBXL 4 cause a severe encephalopathic syndrome associated with mt DNA depletion and deficient oxidative phosphorylation. To gain further insight into the enigmatic pathophysiology caused by FBXL 4 deficiency, we generated homozygous Fbxl4 knockout mice and found that they display a predominant perinatal lethality. Surprisingly, the few surviving animals are apparently normal until the age of 8–12 months when they gradually develop signs of mitochondrial dysfunction and weight loss. One‐year‐old Fbxl4 knockouts show a global reduction in a variety of mitochondrial proteins and mt DNA depletion, whereas lysosomal proteins are upregulated. Fibroblasts from patients with FBXL 4 deficiency and human FBXL 4 knockout cells also have reduced steady‐state levels of mitochondrial proteins that can be attributed to increased mitochondrial turnover. Inhibition of lysosomal function in these cells reverses the mitochondrial phenotype, whereas proteasomal inhibition has no effect. Taken together, the results we present here show that FBXL 4 prevents mitochondrial removal via autophagy and that loss of FBXL 4 leads to decreased mitochondrial content and mitochondrial disease.

Therapy Prospects for Mitochondrial DNA Maintenance Disorders

“…Although proteins of this family participate in Skp1-cullin1-F-box (SCF)-dependent proteasomal ubiquitin-dependent protein catabolic process, FBXL4 has also been associated with mitochondrial dynamics [ 106 ]. However, studies conducted in Fbxl4 knockout mice have revealed that the molecular phenotype caused by FBXL4 mutations (mtDNA depletion observed in patients [ 45 ]) may be mediated by a global decrease in mitochondrial content due to the dysregulation of autophagy rather than a primary dysfunctional mtDNA maintenance [ 114 ]. C1QBP (complement component 1 Q subcomponent-binding protein) is a mitochondrial matrix protein of unknown function which is thought to be involved in inflammation and mitochondrial ribosome synthesis.…”

Neddylation regulation of mitochondrial structure and functions

“…Furthermore, a recent study showed that SKP2, another well-characterized F-box protein, regulated the stability of IDH1/2, the key TCA cycle enzymes, and SKP2 knockdown promoted the TCA cycle by reducing glycolysis [ 51 ]. Other studies revealed that FBXL7 and FBXL4 modulated mitochondrial morphology and function through survivin and other uncharacterized substrates [ 52 – 56 ]. FBXO7 and FBXO11 (also characterized as a NEDD8 E3) were shown to regulate mitochondrial morphology and function, as well as mitochondrial elimination by modulating PARP activation, apoptosis, and mitophagy, respectively [ 57 – 59 ].…”

Visualizing, quantifying, and manipulating mitochondrial DNA in vivo

“…Modulation of mitophagy may comprise a therapeutic strategy in mitochondrial diseases ( 131 , 132 ). Mitophagy can be stimulated by drugs such as the antibiotic actinonin ( 133 ) or the anti-diabetic metformin ( 134 ).…”

“…Caloric restriction may extend lifespan in part by effects on mitophagy ( 136 ). Conversely, increased mitophagy may also be involved in mitochondrial diseases ( 132 ). Reactive oxygen species may also affect mitophagy and impact many diseases and the aging process ( 136 ).…”