Changes in mitochondrial morphology and bioenergetics in human lymphoblastoid cells with four novel OPA1 mutations.

 http://www.iovs.org/content/early/2015/03/04/iovs.14-16288.long

 Shu-Huei Kao, May-Yung Yen, An-Guor Wang et al

OPA1 is a GTPase protein required for mitochondrial inner membrane fusion. Long and short isoforms of OPA1 exist, a mixture of both of them seems to be necessary for normal mitochondrial fusion. Dissipation of membrane potential induces OPA1 cleavage into its short isoforms and this causes mitochondrial fragmentation.

In this paper they investigate four different human OPA1 mutations in lymphoblastoid cells, to find out whether they affect mitochondrial morphology and bioenergetics in different ways. Two of their mutants only have OPA1 short isoforms, the other two also have some long isoforms.

Normal control cells showed a balanced mitochondrial network between filamentous and fragmented states. In all of the OPA1 mutated cells, mitochondria became more fragmented. The proportions of filamentous, intermediate and fragmented networks were 37%, 44% and 19% in control cells, and 1%, 22%, 77% in the OPA1 mutant cells. Membrane potential and ATP concentrations were reduced in mutant cells (ATP concentration ranged from 56% to 63% of that of control cells).

Additionally, all the OPA1 mutants showed decreases in oxygen consumption rate, maximal respiratory rate and increases (3-5 fold) in proton leak. Higher levels of ROS and oxidative damaged were also found in the mutant cells (a 2-fold increase in hydrogen peroxide and a 3-4 fold increase in superoxide). Also, a 4-8 fold increase in lipid-peroxidation was observed. OPA1 deficient cells preferred glycolysis rather than OXPHOS.

No significant differrences between the different OPA1 mutations were observed.