PET imaging of redox and energy states in stroke-like episodes of MELAS.
ABSTRACT In stroke-like episodes of patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), changes in oxidative stress and glucose metabolism and their sequence remain obscure. We developed a novel double imaging method using positron emission tomography (PET) with [(62)Cu]-diacetyl-bis(N4-methylthiosemicarbazone) ((62)Cu-ATSM) and [(18)F]-fluorodeoxyglucose ((18)FDG) to visualize the regional oxidative stress, glucose metabolism and blood flow in brain lesions of stroke-like episodes non-invasively and rapidly. These PET imagings were performed on a MELAS patient with stroke-like lesions, and clearly demonstrated that oxidative stress following hyperemia along with increased glucose metabolism plays crucial roles in the pathogenesis of MELAS stroke-like episodes.
Article: An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copperII.[show abstract] [hide abstract]
ABSTRACT: Radiolabeled diacetylbis(4-methylthiosemicarbazonato)copper(II) [Cu(II)(atsm)] is an effective positron-emission tomography imaging agent for myocardial ischemia, hypoxic tumors, and brain disorders with regionalized oxidative stress, such as mitochondrial myopathy, encephalopathy, and lactic acidosis with stroke-like episodes (MELAS) and Parkinson's disease. An excessively elevated reductive state is common to these conditions and has been proposed as an important mechanism affecting cellular retention of Cu from Cu(II)(atsm). However, data from whole-cell models to demonstrate this mechanism have not yet been provided. The present study used a unique cell culture model, mitochondrial xenocybrids, to provide whole-cell mechanistic data on cellular retention of Cu from Cu(II)(atsm). Genetic incompatibility between nuclear and mitochondrial encoded subunits of the mitochondrial electron transport chain (ETC) in xenocybrid cells compromises normal function of the ETC. As a consequence of this impairment to the ETC we show xenocybrid cells upregulate glycolytic ATP production and accumulate NADH. Compared to control cells the xenocybrid cells retained more Cu after being treated with Cu(II)(atsm). By transfecting the cells with a metal-responsive element reporter construct the increase in Cu retention was shown to involve a Cu(II)(atsm)-induced increase in intracellular bioavailable Cu specifically within the xenocybrid cells. Parallel experiments using cells grown under hypoxic conditions confirmed that a compromised ETC and elevated NADH levels contribute to increased cellular retention of Cu from Cu(II)(atsm). Using these cell culture models our data demonstrate that compromised ETC function, due to the absence of O(2) as the terminal electron acceptor or dysfunction of individual components of the ETC, is an important determinant in driving the intracellular dissociation of Cu(II)(atsm) that increases cellular retention of the Cu.Proceedings of the National Academy of Sciences 12/2011; 109(1):47-52. · 9.68 Impact Factor