Characterization of a Mouse Model of Mitophagy-Driven Mitochondrial DNA Depletion Syndrome

Document Type

Article

Publication Date

2025

Keywords

JMG

Abstract

Mitochondrial DNA Depletion Syndromes (MDDS) are rare genetic disorders that reduce mitochondrial DNA (mtDNA) abundance in cells, impairing mitochondrial function. Some forms of MDDS result from excessive mitophagy, a process which destroys healthy mitochondria and results in profound metabolic dysfunction. F-Box and Leucine Rich Repeat Protein 4 (FBXL4) negatively regulates mitophagy by promoting degradation of mitophagy receptors BNIP3 and BNIP3L/NIX. While Fbxl4 knockout mice have revealed embryonic lethality, patient-derived variants that are associated with severe multi-systemic symptoms and result in early childhood mortality remain unstudied in-vivo. To address this, our lab has generated a mouse model carrying the clinically identified C584R missense mutation to investigate the mechanism by which this variant causes mitochondrial and subsequent organ dysfunction. Evidence from this characterization verifies decreased mtDNA copy number, upregulation of BNIP3 and BNIP3L/NIX, and decreased oxidative phosphorylation in Fbxl4C584R mice. Further investigation of the Fbxl4C584R mouse will provide novel insight into the pathology of FBXL4-mediated MDDS and may reveal therapeutic targets for patients with Fbxl4 mutations.

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