MITOCHONDRIAL DISEASES I (Oral): I.5Perturbed mitochondrial homeostasis in the pathogenesis of mitochondrial disorders

Abstract

Mitochondrial disorders come with an impressive variability of symptoms, organ involvement, and clinical course, which considerably impact the quality of life and quite often shorten the lifespan expectancy. The last 20 years have witnessed an exponential increase in understanding the genetic and biochemical mechanisms leading to disease. More recently, several homeostatic pathways, including the quality control and adaptive mechanisms controlling the bioenergetics proficiency and biogenesis of the mitochondrial network, have become a central issue to elucidate pathogenic mechanisms and develop rational therapies in mitochondrial disease. Indeed, new experimental approaches have recently been emerging, some of which have shown potential efficacy at the preclinical level: for instance, activators of mitochondrial biogenesis, modulators of autophagy and mTORC1 pathway, and regulators of mitochondrial dynamics and mitochondrial architecture. We and others have shown that activation of the PGC1a-dependent mitochondriogenic axis partially rescues the phenotype of COX-deficiency mouse models. Conversely, suppression of ROS production by expressing the alternative oxidase (AOX) worsens the phenotype and anticipates the fatal outcome of a mouse model of COX deficiency restricted to skeletal muscle (Cox15sm/sm). Autophagy is an intracellular recycling process that delivers misfolded proteins and dysfunctional organelles to lysosomes. This bulk degradation process may be impaired in several pathological conditions including mitochondrial disorders, where its activation can be exploited for the clearance of dysfunctional mitochondria and the restoration of the normal energy homeostasis and metabolism. Rapamycin is an inhibitor of mTOR complex 1 (mTORC1) that can both induce autophagy, through new autophagosome formation, and increase the autophagic flux by enhancing lysosomal biogenesis. Rapamycin improves the clinical conditions of the Cox15sm/sm mouse model, rescuing the myopathy caused by COX deficiency. This is the result of a coordinated activation of autophagy together with increased lysosomes, possibly through the action of TFEB, a master regulator of lysosomal biogenesis.