Pharmacological activation of AMPK rescues mitophagy defects in models of FBXL4-related mitochondrial DNA depletion syndrome

Distinct mitophagy pathways can eliminate not only damaged mitochondria but also healthy ones. In Mitochondrial DNA Depletion Syndrome 13 (MTDPS13), dysregulated BNIP3/NIX-driven mitophagy of functional mitochondria is thought to be the key pathological driver. Patient mutations in the E3 ubiquitin ligase FBXL4 impair the proteasomal degradation of the mitophagy receptors BNIP3 and NIX, causing their accumulation and excessive mitophagy. As a result, mitochondrial content and oxidative phosphorylation decline sharply across multiple tissues, leading to early mortality, with no effective treatments currently existing. In this study, we demonstrate that activating AMPK markedly suppresses BNIP3/NIX-dependent mitophagy and restores mitochondrial respiration in FBXL4-deficient cells. Using both fibroblasts derived from MTDPS13 patients and a chemically-induced in vivo model, we show that small molecule AMPK activation inhibits BNIP3/NIX-mediated mitophagy and recovers mitochondrial content. This work therefore highlights the therapeutic potential of targeting AMPK in MTDPS13.