Abstract
Mitochondrial morphogenesis is a key process of cell physiology. It is essential for the proper function of this double membrane-delimited organelle, as it ensures the packing of the inner membrane in a very ordered pattern called cristae. In yeast, the mitochondrial ATP synthase is able to form dimers that can assemble into oligomers. Two subunits (e and g) are involved in this supramolecular organization. Deletion of the genes encoding these subunits has no effect on the ATP synthase monomer assembly or activity and only affects its dimerization and oligomerization. Concomitantly, the absence of subunits e and g and thus, of ATP synthase supercomplexes, promotes the modification of mitochondrial ultrastructure suggesting that ATP synthase oligomerization is involved in cristae morphogenesis. We report here that in mammalian cells in culture, the shRNA-mediated down-regulation of subunits e and g affects the stability of ATP synthase and results in a 50% decrease of the available functional enzyme. Comparable to what was shown in yeast, when subunits e and g expression are repressed, ATP synthase dimers and oligomers are less abundant when assayed by native electrophoresis. Unexpectedly, mammalian ATP synthase dimerization/oligomerization impairment has functional consequences on the respiratory chain leading to a decrease in OXPHOS activity. Finally these structural and functional alterations of the ATP synthase have a strong impact on the organelle itself leading to the fission of the mitochondrial network and the disorganization of mitochondrial ultrastructure. Unlike what was shown in yeast, the impairment of the ATP synthase oligomerization process drastically affects mitochondrial ATP production. Thus we propose that mutations or deletions of genes encoding subunits e and g may have physiopathological implications.
Highlights
Mitochondria host various functions and are at the center of eukaryotic cells metabolism
They achieve the ultimate steps of the oxidative catabolism responsible for the conversion of nutrients into the molecular energy currency ATP. This central role explains the growing interest in mitochondria as these organelles appear to be involved in a broad range of human pathologies. Mitochondria harbor in their inner membrane the protein complexes involved in the oxidative phosphorylation process (OXPHOS) which is constituted by the four complexes of the respiratory chain, the F1F0 ATP synthase and both the ATP/ADP carrier and Pi/H+ carrier
Previous work performed in yeast had demonstrated that the down-regulation of subunit e induces a decrease in the amount of subunit g, while the down-regulation of subunit g had no effect on subunit e accumulation, suggesting that only the assembly of subunit g in the yeast ATP synthase was dependent on the presence of the subunit e [15]
Summary
Mitochondria host various functions and are at the center of eukaryotic cells metabolism They achieve the ultimate steps of the oxidative catabolism responsible for the conversion of nutrients into the molecular energy currency ATP. This central role explains the growing interest in mitochondria as these organelles appear to be involved in a broad range of human pathologies (see [1,2] for review). The ATP synthase complex is responsible for the production of the majority of cellular ATP under aerobic conditions
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