Mitofusins as mitochondrial anchors and tethers

Mitochondria have their own genomes and their own agendas. Like their primitive bacterial ancestors, mitochondria interact with their environment and organelle colleagues at their physical interfaces, the outer mitochondrial membrane. Among outer membrane proteins, mitofusins (MFN) are increasingly recognized for their roles as arbiters of mitochondria-mitochondria and mitochondria-reticular interactions. This review examines the roles of MFN1 and MFN2 in the heart and other organs as proteins that tether mitochondria to each other or to other organelles, and as mitochondrial anchoring proteins for various macromolecular complexes. The consequences of MFN-mediated tethering and anchoring on mitochondrial fusion, motility, mitophagy, and mitochondria-ER calcium cross-talk are reviewed. Pathophysiological implications are explored from the perspective of mitofusin common functioning as tethering and anchoring proteins, rather than as mediators of individual processes. Finally, some informed speculation is provided for why mouse MFN knockout studies show severe multi-system phenotypes whereas rare human diseases linked to MFN mutations are limited in scope.