Mitofusin 2 keeps the respiratory chain on Q

Mourier et al. reveal that the mitochondrial fusion protein Mitofusin 2 (MFN2) is required to maintain production of the respiratory chain cofactor coenzyme Q.

The closely related GTPases MFN1 and MFN2 are both required for mitochondrial outer membrane fusion. Mfn1-deficient mice nevertheless seem perfectly healthy, but mice lacking Mfn2 die soon after birth. Moreover, only Mfn2 has been linked to human diseases, including the peripheral neuropathy Charcot-Marie-Tooth type 2A. Mourier et al. therefore investigated whether loss of Mfn2 affects mitochondrial function in other ways besides membrane fusion.

The researchers found that mitochondrial respiration and ATP production was impaired in Mfn2-deficient cardiomyocytes compared with wild-type and Mfn1-deficient cells. The levels and activities of individual respiratory chain protein complexes were unaltered in mitochondria lacking Mfn2, but the levels of coenzyme Q, an electron carrier that transfers electrons to respiratory chain complex III, were strongly reduced. Supplementing Mfn2-null cells with coenzyme Q partially restored respiratory chain function.

Coenzyme Q is synthesized from organic intermediates generated by the terpenoid biosynthetic pathway. Mourier et al. found that many of the enzymes and metabolites involved in this pathway were down-regulated in the absence of MFN2. Senior author Nils-Göran Larsson now wants to investigate how MFN2 regulates terpenoid synthesis. Because this pathway takes place across multiple subcellular compartments, one possibility is that MFN2 mediates mitochondrial contacts with other organelles. Larsson also hopes that coenzyme Q supplements could help treat patients with diseases caused by mutations in Mfn2.