Fundc1

eart failure is a complex disease in which the heart is unable to provide sufficient oxygenated blood for the surrounding tissues.Heart failure has emerged as an epidemic in the Western world over the past 2 decades and most often affects patients with coronary artery disease.The pathophysiology of heart failure remains unclear; however, its progression is linked to mitochondrial dysfunction. 1 In support of this view, mitochondrial disorders caused by ablation of TFAM (mitochondrial transcription factor A) or ANT1 (adenine nucleotide translocator) proteins are detrimental to heart function and lead to heart failure.2,3 In this issue of Circulation, Wu et al 4 show that FUNDC1 (FUN14 domain containing 1), a protein localized in the outer mitochondrial membrane, contributes to optimal cardiac function through a previously unrecognized role in the communication between mitochondria and the endoplasmic reticulum (ER).Moreover, they demonstrate that disruption of this protein function causes heart failure.Between ≈5% and 20% of mitochondrial outer membranes are in close contact (20 nm distance) with the ER. 5 Biochemically isolated in 1990 by Vance 6 using a Percoll gradient centrifugation method, these ER-mitochondria contacts were described as a fraction X, which contains mitochondrial-associated ER membranes (MAMs).Recent studies document that mitochondria are in contact with the ER and that this contact plays a key role in the maintenance of organelle architecture and in overall cellular homeostasis.Thus, ER stress increases ER-mitochondria contacts, thereby promoting mitochondrial respiration and ATP synthesis.7 Moreover, ER-mitochondria contacts participate in the activation of apoptosis and in autophagosome formation.8 A relative dearth of ER-mitochondria contacts has been reported in cancer cells and in insulin-resistant cells.In contrast, an increase in ER-mitochondrial contacts has been reported in neurodegeneration.Overall, current data support the notion that these contacts play a key role in cellular function.The biochemical characterization of MAMs has revealed that they contain enzymes required for the synthesis of phosphatidylethanolamine from phosphatidylserine and that they have the capacity for phospholipid transfer between ER and mitochondria.ER-mitochondria contacts also participate in the transfer of calcium between these 2 organelles.In support of this idea, the mitochondrial calcium uniporter, located at the inner mitochondrial membrane, manifests K d values of 20 to 30 µmol/L, ie, much greater than cytosol concentrations of free calcium.This observation suggests that close ER-mitochondria contacts induce calcium accumulation (Figure).Furthermore, several reports have demonstrated the existence of a complex involving VDAC (voltage-dependent anion channel), GRP75 (75 kDa glucose-regulated protein), and IP3R (inositol 1,4,5-trisphosphate receptor) proteins that is localized in ER-mitochondria contacts (Figure ).This complex channels the transfer of Ca 2+ between the ER and mitochondria.