| The mitochondrial protein Apoptosis-inducing factor (AIF) is a redox active flavoprotein that has a dual role in the regulation of cell death and survival. We have previously identified a novel role for AIF in mitochondrial structure. Here, we examine the mechanism by which AIF controls mitochondrial structure and metabolism and found that AIF deficiency results in mitochondrial fragmentation, cristae malformation and a defect in oxidative phosphorylation. Mitochondrial AIF is essential for organelle fusion as the fission/fusion proteins Mnf1 and dnDrp1 fail to rescue the structural defect seen in AIF deficiency. In contrast, upregulation of Opa1 in AIF deficient neurons restores mitochondrial structure, metabolism and cellular survival. We show that AIF functions upstream of Opa1 because increased mitochondrial AIF cannot rescue neuronal cell death induced by Opa1 deficiency. AIF-deficient neurons display reduced Opa1 oligomerization resulting in impaired cristae formation. Furthermore, we show that AIF interacts with Opa1 to maintain Opa1 oligomerization. This interaction is critical during apoptosis signaling, as Opa1 oligomerization can be preserved by expression of mitochondrial AIF. Apart from AIF, we also identified novel factors that affect the degree of Opa1 oligomerization. Indeed, Opa1 oligomers seem to be modulated by cell metabolism according to levels of NADH and NAD+. These results identify a novel functional interaction between AIF, Opa1 and cell metabolism and links the control of mitochondrial structure with apoptosis signaling and the metabolic state of the cell. |
