The new findings revealing coupling of mitochondrial structure and function
Most of the cells produce cellular energy from mitochondria while consuming oxygen.
Besides that mitochondria regulate redox homeostasis in the cell by production of oxygen radicals. These can participate in cellular signalization. Both features are not often valid for some cancer cells, which survive under conditions of limited oxygen supply (i.e. hypoxia). Their mitochondrial energy production is minimal and mitochondria are significantly prooxidant. Mitochondrial production of cell energy (ATP molecules) is sophisticated machinery where electron transport chain must be well tuned with ATP synthase enzyme. Both can be found in inner mitochondrial membrane which folds into sacks called cristae. Formation and shape of cristae is regulated by protein complexes (e.g. MICOS) and various oligomerized proteins or protein isoforms (e.g. ATP synthase, OPA1). We found that various cristae conformations in relation to participating regulatory proteins and suitable substrate have impact on mitochondrial production of cellular energy (ATP). Specifically, mitochondria of HepG2 cells (cells of hepatocellular carcinoma) in hypoxic conditions show, compared to atmospheric conditions, inflated/wide cristae. This is accompanied by downregulation of protein Mitofilin, which is part of MICOS complex and suppressed oligomerization of ATP synthase. It results in low ATP production by mitochondria. Such basic knowledge linking production of mitochondrial ATP to cristae morphology might be used in future for development of new drugs, which aim specifically the cells with different mitochondrial metabolism as for example some cancer cells.
Plecitá-Hlavatá, Lydie - Engstová, Hana - Alán, Lukáš - Špaček, Tomáš - Dlasková, Andrea - Smolková, Katarína - Špačková, Jitka - Tauber, Jan - Strádalová, Vendula - Malínský, Jan - Lessard, M. - Bewersdorf, J. - Ježek, Petr . Hypoxic HepG2 cell adaptation decreases ATP synthase dimers and ATP production in inflated cristae by mitofilin down-regulation concomitant to MICOS clustering . FASEB Journal. 2016, roč. 30, 5, p. 1941-1957 . IF = 5.299