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Mfn1 is an outer-mitochondrial-membrane mitofusin that promotes mitochondrial fusion through a GTP-dependent mechanism. It forms complexes with itself and with Mfn2. Fusion lets separate mitochondria exchange components, contributing to maintenance of a functional mitochondrial network. ^[ref]

Mouse fibroblasts deficient in Mfn1 showed a severe reduction in fusion and fragmented organelles. Rescue experiments supported a causal role for Mfn1, while comparison with Mfn2-deficient cells revealed overlapping and distinct functions. The combination of genetic loss, direct fusion assessment and rescue is more informative than inferring a fusion mechanism from a still image of mitochondrial shape.

Mfn2 is an outer-mitochondrial-membrane mitofusin involved in GTP-dependent mitochondrial fusion. Its activity helps join the outer boundaries of neighbouring mitochondria, enabling later mixing of their contents through the coordinated fusion machinery. Mfn2 can associate with itself or with Mfn1. ^[ref]

In the mouse study, loss of Mfn2 produced fragmented mitochondria in embryonic fibroblasts and a placental defect distinct from the phenotype of Mfn1 deficiency. These comparisons show why two related proteins need not be interchangeable in every cell type. Network fragmentation alone does not identify whether reduced fusion or increased fission caused the change.

Mitochondrial fusion is the joining of previously separate mitochondria, allowing their internal contents to mix. Because each mitochondrion has two boundary cell membranes, complete mitochondrial fusion requires joining both the outer and the inner mitochondrial membrane. Together with mitochondrial fission-fusion cycle, it makes mitochondria a changing network rather than a fixed collection of bean-shaped objects.

A useful experiment distinguishes joining from mere contact. Hsiuchen Chen and colleagues mixed mouse cells carrying differently coloured fluorescent proteins targeted to the mitochondrial interior, then fused the cells so both labelled populations shared one cytoplasm. Appearance of both colours within the same mitochondria reported content mixing. Loss of either mitofusin Mfn1 or Mfn2 reduced this mixing and produced fragmented mitochondria; restoring the missing protein rescued the defect. Mitochondrial fusion therefore has a measurable molecular requirement and permits exchange within the mitochondrial population.^[ref]

The mitochondrial fission-fusion cycle is continuous remodeling of a mitochondrial population by division and merger. In mammalian biological cells, mitofusins promote fusion of outer mitochondrial membranes, while OPA1 supports fusion of inner mitochondrial membranes. Fusion mixes matrix contents and permits functional complementation between mitochondria. Genetic disruption and rescue of mitofusins demonstrated their requirement for normal mitochondrial fusion.^[ref]

For fission, recruited Drp1 assembles at constrictions and uses GTP-dependent remodeling to help divide the organelle.^[ref] The balance controls network shape, distribution and quality control. Division can help distribute mitochondria to daughter biological cells and segregate damaged portions for mitophagy; fusion can restore mixed contents. These are regulated competing events in a network, not an obligatory synchronized sequence that every mitochondrion completes on a fixed timetable.