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  • The non-glycosylated isoform of MIC26 is a constituent of the mammalian MICOS complex and promotes formation of crista junctions.

The non-glycosylated isoform of MIC26 is a constituent of the mammalian MICOS complex and promotes formation of crista junctions.

Biochimica et biophysica acta (2015-03-15)
Sebastian Koob, Miguel Barrera, Ruchika Anand, Andreas S Reichert
RESUMEN

Mitochondrial membrane architecture is important for organelle function. Alterations thereof are linked to a number of human disorders including diabetes and cardiomyopathy. The MICOS complex was recently reported to be a central player determining cristae structure and formation of crista junctions. Here we investigated the functional role of MIC26, a lipoprotein formerly termed APOO. Its levels are increased in diabetic heart tissue and in blood plasma of patients suffering from acute coronary syndrome. We demonstrate that human MIC26 exists in three distinct forms: (1) a glycosylated and secreted 55kDa protein, (2) an ER/Golgi-resident form thereof, and (3) a non-glycosylated 22kDa mitochondrial protein. The latter isoform spans the mitochondrial inner membrane and physically interacts with several MICOS complex subunits such as MIC60, MIC27, and MIC10. We further demonstrate that MIC26 and MIC27, a homologous protein formerly termed APOOL, regulate their levels in an antagonistic manner. Both proteins are positively correlated with the levels of MIC10 as well as tafazzin, an enzyme required for cardiolipin remodeling. Overexpression of MIC26 induced fragmentation of mitochondria, promoted ROS formation and resulted in impaired mitochondrial respiration. Downregulation of MIC26 induced a decrease in mitochondrial oxygen consumption, whereas mitochondrial network morphology and ROS levels remained unaffected. MIC26 depletion led to alterations in mitochondrial ultrastructure and caused a significant reduction in the number of crista junctions. In summary, we show that the human apolipoprotein MIC26 is a bona fide subunit of the MICOS complex and that MIC26 is linked to cardiolipin metabolism and promotes crista junction formation.

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