Mitochondrial DNA haplogroup
background and environmental toxics in Leber's hereditary optic
neuropathy. The project aims at determining
the influence of mtDNA haplogroup background in cell death
following exposure to different environmental toxics in order to
explain some aspects of the penetrance of the disease in the
population.
OPA1 isoforms and functions
. OPA1 is a nuclear gene encoding
for the mitochondrial dynamin-related GTPase OPA1, whose mutations
cause autosomal dominant optic atrophy, the most common hereditary
optic neuropathy. OPA1 has been shown to be required for
mitochondrial fusion and cristae structural maintenance, thus
influencing also the apoptotic pathway. The occurrence of eight
isoforms in mammalians is likely to explain multiple OPA1
functions. The project aims at evaluating the role of OPA1 on
mitochondrial DNA integrity and stability, possibly identifying the
protein domains involved in this function. Interaction between OPA1
and other proteins will be analyzed by means of biochemical and
genetic analysis to gain information on its cellular
functions.
Oxidative phosphorylation
dysfunction and permeability transition pore. Opening of the inner
membrane permeability transition pore (PTP), a high-conductance
channel, has been implicated in cell death. In this study we
investigate whether the voltage threshold for PTP opening is
influenced by mtDNA mutations affecting subunits of the oxidative
phosphorylation complexes. Our aim is to assess whether PTP opening
may represent the final common pathway through which respiratory
chain defects cause cell death.
Mitochondrial DNA mutations and
cancer predisposition. In addition to various
neurodegenerative disorders, mitochondrial DNA mutations are
associated also to some types of tumour. The aim of the project is
the identification of the molecular signals, generated by
mitochondria bearing mtDNA mutations, and directed to the nucleus
to promote cell survival and tumour progression. We will take
advantage of oncocytoma cell models recently developed in our
laboratory and of a wide collection of tumor biopsies.
