Selective degradation of mitochondria via mitophagy is crucial for cellular homeostasis. Accumulation of damaged mitochondria due to impairment in mitophagy is a hallmark of neurodegenerative diseases such as Parkinson’s Disease (1). However, unregulated mitophagic degradation of functional mitochondria can also lead to severe consequences, as observed in Mitochondrial DNA Depletion Syndrome 13 (MTDPS13) (2-4). We recently demonstrated that distinct mitophagy pathways differentially target damaged versus functional mitochondria. Interestingly, AMPK activation specifically blocked NIX-mediated mitophagy of functional mitochondria while enhancing Pink1/Parkin-dependent degradation of damaged mitochondria (5). Thus, we aimed to determine the therapeutic potential of AMPK activators for MTDPS13. Loss of function mutation in FBXL4, a Cullin-1-based E3 ubiquitin ligase that targets mitophagy receptor NIX for proteasomal degradation, leads to MTDPS13. These individuals show elevated NIX levels and excessive mitophagy. These results in substantial loss of mitochondrial content and severe impairments in oxidative phosphorylation (OXPHOS) in multiple organs, eventually leading to early mortality. Herein, we demonstrate that AMPK activation reduces excessive NIX-mediated mitophagy observed in FBXL4 knockout cells (FBXL4 KO). Thus, restoring mitochondrial content to levels comparable to wild-type cells. We have demonstrated similar inhibition of mitophagy in FBXL4 KO cells with several AMPK activators that are in clinical trials. MK-8722, one of the most potent AMPK activators, also rescues OXPHOS deficiencies observed in FBXL4 knockout cells. In vivo, MK-8722 decreases basal and FBXL4-mediated mitophagy in the liver and hippocampus, underscoring its physiological relevance. In fibroblasts derived from patients harbouring FBXL4 mutations, AMPK activation inhibits mitophagy and restores mitochondrial content. Furthermore, our data suggest that metformin, a widely prescribed antidiabetic agent that activates AMPK, can reduce the basal level of mitophagy in vivo. Thus, highlighting its potential for repurposing in FBXL4-related mitochondrial disorders. Our findings identify AMPK activators as a promising therapeutic strategy for mitochondrial depletion syndromes.