Mitophagy removes excessive and damaged mitochondria by autophagy. Its regulatory mechanisms and physiological functions remain poorly understood. We recently revealed that mitophagy mediated by two mitophagy receptors BNIP3 and NIX is actively surveilled and repressed at low level in somatic cells. We identified a PPTC7-SCFFBXL4 pathway in which PPTC7 detects BNIP3 and NIX and targets them for degradation by SCF FBXL4. This mitophagy repression pathway is critical to maintaining mitochondrial quantity and animal viability under normal and stress conditions. Notably, loss-of-function mutations of FBXL4 cause a devastating degenerative disease MTDPS13 (mtDNA depletion syndrome 13). We show that the lethality of Fbxl4-/- mice is rescued by knocking out Bnip3 or Nix, indicating excessive mitophagy as a cause of human disease. In this talk, I will discuss our unpublished results characterizing the impacts of BNIP3 and NIX on cellular mitophagy level, mitochondrial quantity, as well as cellular physiology in mice. Our published and unpublished results together suggest an essential role of mitophagy mediated by BNIP3 and NIX in determining mitochondrial quantity and cellular physiology.