Mitochondria are central players in the life and death of cells. The energy−dependence of retinal ganglion cells (RGCs) and their axons, which form the optic nerve, is singularly skewed. Mitochondria are very abundant in the unmyelinated part of the axons anterior to the lamina cribrosa, their number suddenly decreases as the myelin sheath begins more posteriorly. Mitochondrial biogenesis occurs within the cellular somata, needing the coordinated interaction of nuclear and mitochondrial genomes. Mitochondria are then transported down the axons and located at critical sites where they are functionally needed. Leber’s hereditary optic neuropathy (LHON) is the paradigm of mitochondrial optic neuropathies where mitochondrial pathogenesis is certified by the association with specific mutations in the mitochondrial DNA. The recent identification of mutations in the nuclear gene OPA1 as the causative factor in dominant optic atrophy (DOA) brought the unexpected finding that this gene encodes for a mitochondrial protein. The strong similarities between LHON and DOA suggest a common core of molecular events in their pathophysiology. In this project, which follows a long−lasting effort on this topic supported by previous Telethon projects, we focus on the identification of such a common core of molecular events, to resolve the open questions of incomplete penetrance, male prevalence in LHON, and tissue−specificity targeting the RGCs/optic nerve system. Based on previous studies and our preliminary results we explore the interconnected relationship among bioenergetic defect, mitochondrial biogenesis, mitochondrial network organization, and cell priming to apoptosis. We use a multilevel approach, ranging from purely genetic studies, to cell modeling of the disease, to in vivo investigations on the patients. The final understanding should allow for therapy in this group of blinding, inherited neurodegenerative disorders.
V Carelli, R Lodi (2008). Pathogenic mechanisms for degeneration of retinal ganglion cells in mitochondrial optic neuropathies (Prog. Telethon n. GGP06233).
Pathogenic mechanisms for degeneration of retinal ganglion cells in mitochondrial optic neuropathies (Prog. Telethon n. GGP06233)
CARELLI, VALERIO;LODI, RAFFAELE
2008
Abstract
Mitochondria are central players in the life and death of cells. The energy−dependence of retinal ganglion cells (RGCs) and their axons, which form the optic nerve, is singularly skewed. Mitochondria are very abundant in the unmyelinated part of the axons anterior to the lamina cribrosa, their number suddenly decreases as the myelin sheath begins more posteriorly. Mitochondrial biogenesis occurs within the cellular somata, needing the coordinated interaction of nuclear and mitochondrial genomes. Mitochondria are then transported down the axons and located at critical sites where they are functionally needed. Leber’s hereditary optic neuropathy (LHON) is the paradigm of mitochondrial optic neuropathies where mitochondrial pathogenesis is certified by the association with specific mutations in the mitochondrial DNA. The recent identification of mutations in the nuclear gene OPA1 as the causative factor in dominant optic atrophy (DOA) brought the unexpected finding that this gene encodes for a mitochondrial protein. The strong similarities between LHON and DOA suggest a common core of molecular events in their pathophysiology. In this project, which follows a long−lasting effort on this topic supported by previous Telethon projects, we focus on the identification of such a common core of molecular events, to resolve the open questions of incomplete penetrance, male prevalence in LHON, and tissue−specificity targeting the RGCs/optic nerve system. Based on previous studies and our preliminary results we explore the interconnected relationship among bioenergetic defect, mitochondrial biogenesis, mitochondrial network organization, and cell priming to apoptosis. We use a multilevel approach, ranging from purely genetic studies, to cell modeling of the disease, to in vivo investigations on the patients. The final understanding should allow for therapy in this group of blinding, inherited neurodegenerative disorders.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
