Opa1 overexpression as potential therapy in mitochondrial diseases

Mitochondrial disorders are a group of highly invalidating human conditions due to defective oxidative phosphorylation, for which no effective treatment is nowadays available. In order to develop effective therapies for these disorders, I focused on an experimental approach based on the manipulation of mitochondrial morphology. Opa1 is a GTPase of the inner mitochondrial membrane involved in both mitochondrial fusion and cristae shaping. The role of OPA1 in mitodynamics has also a documented impact on controlling the assembly of the respiratory supercomplexes and respiratory proficiency. Based on these considerations, I tested whether Opa1 overexpression could mitigate the effects of a severe mitochondrial respiratory chain deficit in vivo. In this thesis, the effects of mild transgenic overexpression of Opa1 on two mouse models of defective mitochondrial bioenergetics, a constitutive knockout for Ndufs4 (Ndufs4-/-), encoding a structural component of complex I, and a muscle-specific conditional knockout for Cox15, (Cox15sm/sm), encoding a heme-a biosynthetic enzyme involved in complex IV hemylation and assembly are shown. Crossing of both models with an Opa1 transgenic mouse line (Opa1tg) was associated with clinical and biochemical improvement, but whilst the effect was limited in Ndufs4-/-::Opa1tg mice, the Cox15sm/sm::Opa1tg mice showed relevant amelioration of motor performance, remarkable prolongation of survival, and significant correction of mitochondrial respiration. This effect was associated with the increased amount of active cIV holocomplex and cIV-containing supercomplexes.