(A) In the liver or hepatocytes, FoxO1 up-regulates fusion proteins (Mfn1 and Mfn2) but down-regulates fission proteins (Drp1 and Fis1), leading to enlarged mitochondria. (B) Estrogen receptor (ERα) signaling induces Drp1 via Polg1 in brown adipocytes. It is known that ERα signaling deactivates FoxO via PI3K/Akt in adipose tissue and the liver, raising the question whether FoxOs may account for ERα induced mitochondrial fission (indicated by question marks). (C) FoxO3 inhibits mitochondrial fission by repressing MIEF2 or inducing miR-484, which are cardioprotective in doxorubicin (DOX)-induced mouse cardiotoxicity. Notably, FoxO3 was shown to stimulate mitochondrial fission via Bnip3-calcineurin mediated dephosphorylation (activation) of Drp1 in phenylephrine (PE)-stressed adult cardiomyocytes or heart from rats. The discrepancy may arise from different models of cardio stress induced by DOX vs PE. (D) In intestinal crypt-based columnar cells, FoxO1 and FoxO3 dampens mitochondrial fission by transactivating miR-484 that in turn silences Fis1.