Distribution and Apoptotic Function of Outer Membrane Proteins Depend on Mitochondrial Fusion

• Published in: Molecular cell 2014-06, Vol.54 (5), p.870-878
• Main Authors: Weaver, David, Eisner, Verónica, Liu, Xingguo, Várnai, Péter, Hunyady, László, Gross, Atan, Hajnóczky, György
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; bcl-2 Homologous Antagonist-Killer Protein - metabolism; BH3 Interacting Domain Death Agonist Protein - metabolism; Cell Line; cytochrome c; fibroblasts; Gene Knockout Techniques; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; guanosinetriphosphatase; Humans; loci; Mice; mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes - metabolism; Mitochondrial Proteins - metabolism; Muscle Fibers, Skeletal - metabolism; outer membrane proteins; Protein Transport; Rats; Voltage-Dependent Anion Channel 2 - genetics
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2014.03.048

Cells deficient in mitochondrial fusion have been shown to have defects linked to the exchange of inner membrane and matrix components. Because outer-mitochondrial membrane (OMM) constituents insert directly from the cytoplasm, a role for fusion in their intermitochondrial transfer was unanticipated. Here, we show that fibroblasts lacking the GTPases responsible for OMM fusion, mitofusins 1 and 2 (MFN1 and MFN2), display more heterogeneous distribution of OMM proteins. Proteins with different modes of OMM association display varying degrees of heterogeneity in Mfn1/2−/− cells and different kinetics of transfer during fusion in fusion-competent cells. Proapoptotic Bak exhibits marked heterogeneity, which is normalized upon expression of MFN2. Bak is critical for Bid-induced OMM permeabilization and cytochrome c release, and Mfn1/2−/− cells show dysregulation of Bid-dependent apoptotic signaling. Bid sensitivity of Bak-deficient mitochondria is regained upon fusion with Bak-containing mitochondria. Thus, OMM protein distribution depends on mitochondrial fusion and is a locus of apoptotic dysfunction in conditions of fusion deficiency. [Display omitted] •OMM proteins are more heterogeneously distributed in cells lacking OMM fusion•OMM fusion supports the transfer of signaling molecules, including Bak, BAD, and AKAPs•Bak transfer by fusion is needed for tBid-induced OMM permeabilization•OMM protein distribution is a locus of apoptotic dysfunction in fusion deficiency Defective mitochondrial fusion is known to undermine cell health, but the mechanisms are only beginning to be elucidated. Here, Weaver et al. show that even distribution of outer-mitochondrial membrane proteins among the organelles depends on functioning fusion. Uneven distribution of Bak in fusion-lacking cells results in dysfunctional apoptosis.