(A) In the liver, FoxO1 may induce Hmox1, Fxn, and Urod, which disrupt mitochondrial ETC and NAD/NADH ratio, thereby suppressing NAD-dependent Sirt1-Pgc1α-NRF1-Tfam pathway in mitochondrial biogenesis. Glucagon activated FoxO1 represses NRF1 and accounts for reduced mitochondrial biogenesis in the liver. (B) In contrast with the liver, FoxO1 induces Cyb5r3 and maintains ETC activity and NAD/NADH ratio in the pancreas. It is unclear but of interest whether the FoxO1–Cyb5r3 axis regulates mitochondrial biogenesis via the known NAD-dependent Sirt1-Pgc1α-NRF1-Tfam pathway (indicated by question marks). (C) In the heart, FoxO1 activation due to diabetes causes mitochondrial abnormality by dysregulating PDK4 and CPT1 via a to-be-defined mechanism (indicated by question marks). (D) In cancer cells, FoxO3 suppresses mitochondrial biogenesis and function by inhibiting c-Myc/Tfam signaling cascade.