Optic atrophy 1 mediates mitochondria remodeling and dopaminergic neurodegeneration linked to complex I deficiency.

Mitochondrial complex I dysfunction has long been associated with Parkinson's disease (PD). Recent evidence suggests that mitochondrial involvement in PD may extend beyond a sole respiratory deficit and also include perturbations in mitochondrial fusion/fission or ultrastructure. Whether and how alterations in mitochondrial dynamics may relate to the known complex I defects in PD is unclear. Optic atrophy 1 (OPA1), a dynamin-related GTPase of the inner mitochondrial membrane, participates in mitochondrial fusion and apoptotic mitochondrial cristae remodeling. Here we show that complex I inhibition by parkinsonian neurotoxins leads to an oxidative-dependent disruption of OPA1 oligomeric complexes that normally keep mitochondrial cristae junctions tight. As a consequence, affected mitochondria exhibit major structural abnormalities, including cristae disintegration, loss of matrix density and swelling. These changes are not accompanied by mitochondrial fission but a mobilization of cytochrome c from cristae to intermembrane space, thereby lowering the threshold for activation of mitochondria-dependent apoptosis by cell death agonists in compromised neurons. All these pathogenic changes, including mitochondrial structural remodeling and dopaminergic neurodegeneration, are abrogated by OPA1 overexpression, both in vitro and in vivo. Our results identify OPA1 as molecular link between complex I deficiency and alterations in mitochondrial dynamics machinery and point to OPA1 as a novel therapeutic target for complex I cytopathies, such as PD.

Putative glucosensing property in rat and human activated microglia.

Microglial cells involved in the pathogenesis of many neurodegenerative diseases acquire the features of cytotoxic and phagocytic cells in response to certain pathogens and inflammatory signals. K(ATP) channels are energy sensors of ATP availability that link the cell's metabolic state to its membrane excitability. In pancreatic beta cells, they promote glucose-dependent insulin secretion, and in neurones, hyperpolarization that protects against hypoxic damage. This study analyses activated microglia in an in vivo rat neurodegenerative model based on acute hippocampal glutamate receptor overactivation and in postmortem samples from patients with Alzheimer's disease. We demonstrate that in activated microglia the K(ATP) channel components SUR-1 or SUR-2 are present together with glucokinase. Our results indicate that, according to glucose availability, these channels may modify microglia membrane potential. The functional relevance of these channels is seen as a new mechanism modulating the effects of external signals on microglia.

In vivo neuroprotective adaptation of the glutamate/glutamine cycle to neuronal death.

Synaptic increase of glutamate level, when not coupled to a heightened energy production, renders neurons susceptible to death. Astrocyte uptake and recycling of synaptic glutamate as glutamine is a major metabolic pathway dependent on energy metabolism, which inter-relationships are not fully understood and remain controversial. We examine how the glutamate-glutamine cycle and glucose metabolism are modified in two in vivo models of severe and mild brain injury. Graded reductions of glutaminase, the glutamate synthetic enzyme, were evidenced combined with increases in glutamine synthetase, the inactivating glutamate enzyme. Increased lactate dhydrogenase (LDH) activity was only present after a more severe injury. These results indicate an in vivo adaptation of the glutamate-glutamine cycle in order to increase the net glutamine output, reduce glutamate excitotoxicity, and avoid neuronal death. We conclude that the graded modification of the glutamate-glutamine correlation and neuronal lactate availability may be key factors in the apoptotic and necrotic neuronal demise, whose control may prove highly useful to potentiate neuronal survival.

Localization of monoamine oxidase A and B and semicarbazide-sensitive amine oxidase in human peripheral tissues.

Monoamine oxidase (MAO) A and B and semicarbazide-sensitive amine oxidase (SSAO) localizations in peripheral human tissues were compared by immunohistochemistry. The primary antibodies used were mouse monoclonal anti-human MAO-A (6G11/E1) and anti-human MAO-B (3F12/G10/2E3) and a rabbit polyclonal anti-bovine SSAO antibody. Immunoreactivities of the samples, obtained from 6 routine autopsy cases, showed different distributions in the tissues studied (heart, lung, duodenum, liver, pancreas, spleen, thyroid gland, adrenal gland and kidney). The relative MAO-A, MAO-B and SSAO distributions indicated a widespread distribution of these enzymes in the human body that is characterized by a matching cellular pattern in only few tissues. These differences suggest that each amine oxidase may play a specific function in, at least some, peripheral tissues.